text:
FLT1, Fms-like tyrosine kinase 1, VEGFR1; RGD, Arg-Gly-Asp; RRM2, ribonucleotide reductase subunit M2.
Gene Knockout
Antisense
Activation of proto-oncogenes such as Ras, B-Raf, Myc, or EGFR through various mechanisms is a key factor in carcinogenesis. For example, mutations of the Ras oncogene occur in many types, including pancreatic cancer, where about 90% of cases carry a mutation of the K-ras gene. 13,14 Knockout of oncogenes driving tumor development in transgenic mouse models of cancer can lead to complete regression, confirming their potential value as drug targets. 15 Antisense technology has been studied as a strategy to knock down expression of oncogenes. This approach is based on the possibility of inhibiting transcription of a particular mRNA by transfecting short double-stranded DNA oligonucleotides into target cells that bind and inactivate the target mRNA in a sequence-specific manner. 16 The development of oligonucleotides with modified DNA backbone that increases the stability of the molecule in vivo allowed for the development of clinical protocols involving intravenous application of antisense molecules targeting, for example, mutant Kras or the anti-apoptotic genes BCL-2 and Survivin. 17 Clinical trials with oblimersen sodium (G3139), an antisense oligonucleotide directed against BCL-2, have demonstrated increased survival of patients with advanced melanoma in combination with chemotherapy compared to chemotherapy alone. 18 An interesting variant of the antisense approach that is currently being tested clinically is GRN163L, a lipid-modified 13-mer DNA-oligonucleotide that acts as a telomerase RNA template antagonist. 19
Cancer-Selective Viruses in Clinical Trials
Phase I/II, Phase II, or Phase III clinical trials. June 2012. Clinicaltrials.gov.
EGFR, epidermal growth factor receptor; GFP, green fluorescent protein; GusA, β-glucuronidase; ICAM1, intercellular adhesion molecule 1; IFN, interferon; IV, intravenous; DAF, decay accelerating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; LacZ, β-galactosidase; NSCLC, non–small-cell lung cancer; PKR, protein kinase R.
The discovery of the possibility of silencing gene expression in mammalian cells with high efficiency using RNA interference (RNAi) has spurred renewed interest in the gene knock-down as a therapeutic strategy. This approach, first described in the worm Caenorhabditis elegans, takes advantage of a cellular gene silencing machinery that involves the RNA-induced silencing complex (RISC) and degrades double-stranded RNAs with high efficacy. 20 The introduction of short RNAs with complementary sequence to any cellular transcript activates this mechanism. RNAi can silence target genes with high efficacy. However, off-target effects that result in sequence-specific though unpredictable knock-down of additional genes represent a potential problem that has not been fully resolved at this point. 21 Nevertheless, novel targeting and delivery mechanisms have been developed that hold the promise of therapeutic application of RNAi-based agents in cancer. 20 For instance, a recently reported nanoparticle-based delivery system shows great promise for systemic delivery of siRNA. These synthetic nanoparticles consist of a cyclodextrin-based polymer, a human transferrin protein (TF) targeting ligand displayed on the exterior of the nanoparticle to engage TF receptors (TFR) on the surface of the cancer cells, a hydrophilic polymer (polyethylene glycol [PEG] used to promote nanoparticle stability in biological fluids), and siRNA designed to reduce the expression of the Ribonucleotide Reductase subunit M2 (RRM2). Tumor-specific targeting is achieved via the interaction of the TF targeting ligand with TFR, which is known to be upregulated in malignant cells. 22 Moreover, the size of these nanoparticles, about 70 nm in diameter, favors their exit from the bloodstream in leaky tumor vasculature and accumulation in the tumor bed via the enhanced permeability and retention (EPR) effect. RRM2, an enzyme catalyzing a rate-limiting step in DNA synthesis, is an established anticancer target. 23 These particles (CALAA-01), currently in Phase I clinical studies, have been administered systemically to humans and have shown specific gene inhibition—a reduction in both mRNA and protein. 24
Another well-established anticancer target is the KRAS oncogene. Most pancreatic adenocarcinomas are caused by a somatic mutation in KRAS, most commonly KRAS G12D. In vitro and animal studies suggest that selective inhibition of the mutant, but not the WT KRAS expression, leads to apoptosis of targeted cancer cells. An siRNA specifically targeting mRNA encoding KRAS G12D, coated by a biodegradable polymeric matrix, siG12D LODER (Local Drug EluteR), is currently in Phase 0/I to evaluate its safety and tolerability. Apart from these two particular RNAi therapeutics, at least another six are currently undergoing clinical testing, thanks to recent advancements in the understanding of RNAi biology and in the areas of RNAi specificity, stability, and delivery. Most are delivered employing synthetic carriers, such as cationic liposomes, anionic liposomes, and polymeric particles. As more attention is focused on safe and effective methods for delivering siRNA to tumors, the clinical value of this approach will likely increase dramatically. siRNA-based therapy has the potential of addressing undruggable oncogene targets, combinatorial approaches to cancer cell killing, and drug resistance, but this potential will not be realized until the challenges of delivery and uptake have been fully addressed.
Killing Cancer Cells by Delivering Prodrug Converting Enzymes and Other Enzymes
For more than 60 years chemotherapeutic agents have been used for the treatment of cancer. However, their use is often limited by damage to normal cells, drug resistance, and low chemical stability. One strategy to overcome limitations of classical chemotherapeutic agents is the use of prodrugs. A prodrug is a fairly nontoxic compound that needs to be transformed before acting as a pharmacon. Such a transformation can be catalyzed by endogenous enzymes, in which case tissue distribution of such endogenous enzymes dictates where the active pharmacon is produced. Alternatively, gene-directed enzyme prodrug therapy (GDEPT) can specifically deliver such enzymes to diseased cells where they can activate nontoxic prodrugs into toxic agents. Progress in this field has been reviewed recently by Duarte and colleagues. 25
Thymidine Kinase
The first GDEPT system described was the thymidine kinase gene of the herpes simplex virus (HSV-TK) in combination with the prodrug nucleoside analog ganciclovir. The enzyme thymidine kinase (TK) is naturally present in bacteria, viruses, and mammals, where it is involved in the salvage pathway of nucleotide biosynthesis. Thus, high TK activity is found in proliferating cells such as cancer cells. TK also converts ganciclovir to ganciclovir monophosphate, which is subsequently converted by cellular kinases into the toxic ganciclovir triphosphate nucleotide. The HSV-TK is three orders of magnitude more efficient than any human kinase catalyzing this first activation step. Hence, several gene therapy approaches combining HSV-TK and ganciclovir have been developed.
For instance, retroviral vectors were used to deliver HSV-TK in a brain tumor model. Because retroviruses integrate only in proliferating cells, gene delivery and expression would be tumor selective in the context of normal, nonproliferating brain cells. 26 A further advantage of this approach was thought to result from the "bystander effect," the killing of uninfected neighboring cells that occurs when HSV-TK–expressing cells are exposed to ganciclovir, which can be observed in vitro and in vivo. 27 To increase transduction of target cells with retroviruses, virus-producing cells (VPCs) were used to inoculate target tumors instead of virus suspension. Preclinical studies in a rat glioma model demonstrated that this delivery of a retrovirus expressing HSV-TK resulted in high transduction levels and frequent tumor regressions following ganciclovir administration. 28 Initial clinical studies were promising and demonstrated in responses of small glioblastomas following VPC injection. 29 However, when standard therapy (surgical resection and radiotherapy) was compared to standard therapy plus injection of retrovirus-producing cells in a Phase III trial, no differences in progression-free and overall survival were observed between the two groups. 30 Smaller, preoperative studies suggested that lack of transduction of tumor cells is the dominant reason for the failure of this approach. 31 Despite the disappointing results of this trial, it represents an early and innovative effort to use gene therapy to kill cancer cells selectively.
Cytosine Deaminase
In contrast to thymidine kinase, the enzyme cytosine deaminase (CD) is not present in mammalian cells, but in several bacteria and fungi. It catalyzes the amidine hydrolysis of cytosine to uracil and ammonia, and several cytosine analogs such as halogenated cytosines are substrates as well. One such substrate is the prodrug 5′-fluorocytosine (5′-FC) which is activated by CD to 5′-fluorouracil (5′-FU). 5′-FU kills cells mainly by inhibition of thymidilate synthetase and by incorporation into DNA. The safety and efficacy of a CD and 5′-FC prodrug therapy are currently being assessed in Phase I/II trials in which 5′-FC and a recombinant Bifidobacterium longum (a live bacterium normally found in the digestive tract) that has been modified to produce CD are given orally to patients with various solid tumors.
Carboxylesterase
Another well-studied prodrug-converting enzyme is carboxylesterase (CE). CE expression is widely distributed in human tissues; nonetheless, targeted gene delivery to enhance CE expression specifically in tumor cells is a promising approach to increase the local availability of cytostatic drugs. CE is involved in the activating metabolism of various commonly used chemotherapeutics: It activates paclitaxel-2-ethylcarbonate to the microtubule-stabilizing agent paclitaxel/taxol and is involved in the multistep conversion of capecitabine to the pyrimidine analog 5′-fluorocytidine (5′-FC). Moreover, CE converts the relatively nontoxic camptothecin analog CPT-11/irinotecan to SN38, a potent topoisomerase I inhibitor. Because the human CE is comparatively inefficient in catalyzing this conversion, several gene therapeutic strategies using the more effective rabbit CE were developed and shown to be successful in tissue culture and animal models. Also, secreted mutants of this enzyme are being studied to enhance the spread of the toxic metabolite and thereby the bystander effect. For instance, Oosterhoff and colleagues show increased killing of colon carcinoma cells on infection with adenovirus expressing secreted CE (Ad5-Δ24-sCE) combined with CPT-11 treatment. 32 Even though CPT-11 also reduced viral replication, the overall cytotoxicity of virus combined with CPT-11 was still higher than cell killing achieved by the virus alone. Nonetheless, this exemplifies the complications of using chemotherapeutic agents in combination with oncolytic viruses; it is crucial to know the kinetics of both viral replication and drug metabolism to design a suitably timed treatment regimen. This is not only essential for oncolytic viruses as vectors for GDEPT, but for the combination of any oncolytic virus with chemotherapeutic agents. 33
Sodium-Iodide Symporter
Not only prodrug-converting enzymes are being pursued as gene therapeutics. Several vectors have been developed to deliver genes for various other enzymes, including the one for the sodium iodide symporter (NIS). The endogenously expressed NIS is an integral plasma membrane glycoprotein that mediates active I − transport into thyroid follicular cells. The rationale for its use in gene therapy approaches is twofold: targeted expression of NIS in cancer cells renders these cells susceptible to uptake of radioactive iodine, which, depending on the isotope used, can be harnessed to kill and/or to image targeted cells. For instance, measles virus (MV) strains that have been engineered to express the human NIS (MV-NIS) have shown significant antitumor activity against various cancer lines and orthotopic xenografts. Expression of NIS in infected glioma cells resulted in effective concentration of radioactive iodine, which allowed for in vivo monitoring of localization of MV-NIS infection by measuring uptake of 123I and led to a significant increase of MV-NIS antitumor activity. 34 A Phase I study is ongoing to establish the safety of intrapleural administration of this MV-NIS in patients with malignant pleural mesothelioma.
Another interesting approach is the retroviral delivery of a multidrug resistance pump (MDR1) gene into peripheral blood progenitor cells (PBPCs). The rationale behind this is not to kill cancer cells, but to prevent some of the toxicities of an intensive chemotherapy regimen in patients. PBPCs are isolated from the patient, genetically modified ex vivo, and transferred back into the patient. The hope is that introduction of the MDR1 gene into the patients' PBPCs renders these cells and their offspring resistant to the toxic effects of certain chemotherapeutic agents, by pumping out chemotherapeutic agents before they can exert a cytotoxic effect. 35–39
Many other strategies have been devised to express prodrug-converting enzymes, or other potentially toxic genes, in cancer cells selectively. Most of these depend on tumor-selective gene expression to drive the gene of interest, such as the promoters for the androgen receptor or prostate-specific antigen (PSA), 40–42 for tyrosinase (selective for melanoma), 43 or for alpha-lactalbumin (selective for breast cancer). 44 More generic tumor-selective–specific promoters include E2F-1, which is upregulated through loss of the RB checkpoint, and telomerase reverse transcriptase (TERT), which is also upregulated in most cancers. 45,46
Genes That Boost the Immune System
Although oncolytic viruses can kill cancer cells directly via viral replication and by delivery of cytotoxic genes or prodrug-converting enzymes, it is becoming more and more evident that the great potential of viruses as gene therapeutic vectors lies in their immune-modulatory capability. This feature can be further enhanced by the addition of immune-modulatory genes into the viral genome. For virus-based therapies to be successful, both host immune system avoidance and potent immune stimulation need to be combined. One approach to boosting antitumor immune responses involves the administration of cytokines to increase the activity of immune effector cells systemically or to enhance the presentation of antigens in tumor cells themselves. A wide range of cytokine genes have been engineered into an equally wide range of vectors and viruses. IL-2, IL-4, and IL-12 have been studied extensively, as well as interferons, members of the tumor necrosis factor (TNF) family, and granulocyte-macrophage colony-stimulating factor (GM-CSF).
TNFerade is an exciting example of this approach. This replication-incompetent adenovirus expresses TNF under the control of the Early Growth Response Factor 1 (EGRr-1) promoter, which is strongly activated in response to cellular stress such as iodizing radiation or chemotherapy. 47 TNFerade was injected in Phase I studies to up to 4 × 1011 pu (particle units) without dose-limiting toxicities occurring. In agreement with this favorable safety profile, serum TNF levels remained consistently low. However, in esophageal cancer, relatively high rates of thromboembolic complications occurred that were potentially induced by the study medication. This problem was not observed in trials of this agent in pancreatic cancer. In this disease the maximum tolerated dose (MTD) of TNFerade in combination with chemoradiation treatment was determined to be 4 × 1011 pu. At that dose level, clinical responses and evidence for prolonged median survival were seen in an interim analysis of a Phase III study in locally advanced pancreatic cancer in combination with chemoradiotherapy. 48
GM-CSF
Of cytokines tested in oncolytic virus and vaccine models so far, GM-CSF seems to be the most potent at generating antitumor immune responses. HSV-, adenovirus-, and vaccinia virus–based vectors encoding GM-CSF have shown great promise in early clinical trials, and studies are still ongoing (see Table 54-2). Arming viruses with GM-CSF aims to activate the immune system primarily by attracting and activating dendritic cells (DCs). GM-CSF has been clinically tested in peptide and whole-cell vaccine strategies as well as oncolytic virus approaches. Notably, only virus-based GM-CSF expression seems to generate a potent and sustained antitumor immune response, suggesting that the context in which GM-CSF is expressed is crucial. Virus-based GM-CSF expression and DC recruitment are tightly coupled to tumor cell death and subsequent release of a vast array of tumor antigens. Remarkably, for both HSV and vaccinia expressing GM-CSF, not only injected but also noninjected tumors responded. The studies mentioned earlier are among the first to combine oncolysis with immune system activation using armed, replication-competent viruses. Further exploitation of the immune system is a focus of current gene therapy and vaccine studies. 49
Naturally Occurring Viruses That Replicate Selectively in Cancer Cells
Cancer cells provide an environment that is permissive for replication of a number of naturally occurring viruses. This is because checkpoints and defense mechanisms are disabled in cancer cells, allowing them to grow and survive and to evade detection by the immune system. In some cases these mechanisms are also used to defend normal cells against virus replication. Cancer cells may therefore be vulnerable to virus infection while normal cells are protected. Because infection usually leads to cell death, this vulnerability could potentially be exploited for cancer therapy. Indeed, several naturally occurring viruses are under clinical evaluation in a variety of cancer indications (see Table 54-2).
Reovirus
Reoviruses replicate selectively in many cancer cells. During infection of normal cells, their double-stranded RNA genomes activate a cellular protein kinase (PKR) that restricts viral replication by blocking translation of viral mRNA. For reasons that are unclear, this kinase activity is suppressed in cancer cells in which the Ras pathway is hyperactivated, allowing productive viral replication. 50 Based on this selectivity, and the capacity of reoviruses to replicate quickly and kill infected cells, reoviruses are undergoing clinical evaluation. One of these, Reolysin, is being tested in Canada, the United Kingdom, and the United States using clinical protocols that include local or systemic delivery of Reolysin as a monotherapy, and local delivery in combination with radiation therapy for patients with advanced cancers. Intravenous administration of this virus was well tolerated in a Phase I study. Although no objective tumor responses were observed, disease stabilization of up to 6 months was observed in a subset of patients. 51
The rhabdovirus vesicular stomatitis virus (VSV) has a single-stranded RNA genome. Selectivity for cancer cells is thought to be the result of their failure to elicit a protective interferon response, thus allowing lytic replication. VSV variants with mutations in the matrix (M) protein enhance VSV's effectiveness, at least in animal models. 52 Systemic delivery of VSV has been shown to be effective and safe against laboratory models of multifocal and invasive malignant gliomas. 53 M protein mutant viruses have also shown efficacy against prostate cancer cell lines and others. 52
Measles viruses, like VSV, contain negative-stranded RNA genomes but are members of the paramyxovirus family. Replication-competent attenuated Edmonston B measles vaccine strain (MV-Edm) is nonpathogenic and has potent antitumor activity against several human tumors. The virus is selectively oncolytic, eliciting extensive cell-to-cell fusion and ultimately leading to cell death. An attenuated strain of MV has been genetically engineered to produce carcinoembryonic antigen, which can be used as a serum marker of virus replication. 12 This virus had potent antitumor activity against gliomas in vitro, as well as in animal models. 54 This virus is undergoing clinical evaluation in patients with glioblastoma multiforme and multiple myeloma.
Lytic strains of the avian paramyxovirus Newcastle disease virus (NDV) selectively kill cancer cells in culture and in mouse models. 55 The molecular basis of selectivity is not fully understood, but appears to be facilitated by high levels of N-myc, at least in neuroblastoma cells. Cytotoxicity is due to multiple caspase-dependent pathways of apoptosis independent of interferon signaling competence. 55,56 Several Phase I studies of intravenously infused NDV have been performed using various doses and administration schedules. 57,58 Main toxicities included moderate flu-like symptoms and mild gastrointestinal symptoms. Interestingly, a two-step intrapatient dose-escalation of the NDV strain PV701 aiming at desensitizing resulted in significant reduction of the intensity of adverse events. Patients developed only moderate levels of neutralizing antibodies, and the serum clearing of virus was not significantly different during the course of treatment. 59 Disease stabilization as well as objective tumor responses were observed in Phase I studies, in particular in patients who had received higher doses. A complete remission was observed in a patient with glioblastoma multiforme treated with the NDV strain NDV-HUJ. 57
Viruses Engineered to Replicate Selectively
In addition to naturally occurring viruses, many efforts have been made to engineer viruses to replicate in tumor cells selectively. Such agents kill cells through lytic mechanisms and potentially spread from one infected cell to another, amplifying the dose of the selective killing agent. Selectivity for cancer cells can be achieved by several strategies. The first uses DNA synthetic enzymes produced by proliferating tumor cells to support replication of DNA viruses that are otherwise defective. The second takes advantage of genetic defects in cancer cells that supply functions that have been specifically deleted from the oncolytic agent, and the third uses tumor-selective promoters to drive replication of conditionally replicating viruses.
Herpes Simplex Viruses
One of the first viruses designed to replicate in cancer selectively were HSVs that had been engineered so that they were unable to express viral genes necessary for DNA replication, such as thymidine kinase or ribonucleotide reductase. Proliferating cells would provide these essential functions, whereas resting normal cells would not. HSV G207 is an example of such an oncolytic virus. In addition to inactivation of a subunit of the viral ribonucleotide reductase gene, both copies of the neurovirulence gene, the gamma(1)34.5 gene, are deleted to further reduce replication in normal tissues. 60 Although direct tumor cell killing represents a major mechanism of action of these viruses, evidence from experiments in immunocompetent mouse models suggests that also a vaccination effect mediated by activated T lymphocytes contributes to the effect. 61 Phase I clinical trials of G207 and a related virus, HSV1716, have been completed and demonstrated the safety of these viruses. 62 Another related HSV mutant, NV1020, has been tested in a Phase I study in patients with hepatic metastases from colorectal cancer. The virus was administered into the hepatic artery in a Phase I study. Only mild toxicity was observed, and a decline in CEA levels was suggestive of some antitumor activity. 63 Many innovative approaches have been employed to improve the clinical value of HSV viruses, including expression of prodrug-converting enzymes to elicit bystander cells and the addition of genes encoding cytokines to boost immune recognition of tumor cells. The latter approach has been taken into the clinic in the form of the HSV mutant OncoVex(GM-CSF), a conditionally replicating HSV-1 mutant that expresses the cytokine GM-CSF. A Phase I/II trial with intratumorally injected Oncovex GM-CSF demonstrated that this agent is well tolerated. 64 Side effects included mainly fever, flu-like symptoms, and inflammation at the injection site. Clinical evidence for tumor necrosis was found; however, no detailed objective response assessments have been published at this point.
Vaccinia
Using a similar strategy, attenuated strains of another large DNA virus, vaccinia, have been created and shown to replicate selectively in cancer cells. 65 Vaccinia virus (VV) strains have several attributes that render them ideally suited for their use as oncolytic agents. First, VV vectors are derived from vaccine strains that have been used safely in millions of children worldwide for immunization against smallpox. Thus, their safety profile, genetic stability, and other pharmacological parameters are extremely well documented. Second, these viruses have several suitable biological properties: vaccinia has evolved mechanisms for stability in the bloodstream and spread to distant sites, including resistance to antibody and complement-mediated neutralization. Moreover, because of their relatively large size (about 200 nm), vaccinia virions preferentially accumulate in tumor tissues, where neovasculature has increased permeability ("leaky tumor vasculature"). The relatively large size also results in a large transgene capacity (25 to 50 kb), which allows for the expression of several therapeutic and monitoring genes. Last but not least, VV replication is promoted by EGFR/Ras pathway signaling, 66,67 which is frequently hyperactivated in cancer cells. A genetically engineered vaccinia that has shown great promise in recent clinical trials is JX-594. 68 This virus is a derivative of a smallpox-vaccine strain carrying an inactivated TK gene to increase tumor specificity, and two transgenes: one encoding GM-CSF to stimulate antitumor immune responses and the other β-galactosidase, as a surrogate marker for viral gene expression. JX-594 has demonstrated great success on local-regional and intravenous delivery to patients in terms of safety, cancer selectivity, oncolysis, chemosensitization, and induction of immune and antitumor responses (Figure 54-1 , Table 54-3 ). Notably, in a Phase I clinical trial, intravenously delivered JX-594 was capable of replicating selectively in metastases from a variety of tumor types, representing a milestone in the development of oncolytic agents for systemic administration. Moreover, intravenous JX-594 therapy led to a reduction in the outgrowth of new metastases in patients over time. Seven Phase I and II clinical trials are currently ongoing to test this agent's safety and efficacy further in various solid tumors. 69,70
Figure 54-1 Representative tumor response to JX-594 treatment (A) Patient 201 with a primary hepatocellular carcinoma received direct intratumoral injections into the liver tumor, which led to a RECIST PR. Direct injection of a previously noninjected tumor in the neck, after four previous cycles of JX-594 treatment in the liver, led to RECIST and Choi response at this site as well, despite the presence of high concentrations of neutralizing antibodies to JX-594. Physical examination and CT and PET-CT scans of the metastatic tumor in the neck region, before and after induction of high-titer antibodies, illustrate this response. (B, C) Patient 103 with metastatic squamous cell carcinoma of the lung received six rounds of JX-594 intratumoral injections. (B) CT scan and (C) tumor cross-section areas before and after treatment. Arrow indicates initiation of JX-594 treatment. CT, Computed tomography; PET, positron emission tomography; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors. (Adapted from Park BH, Hwang T, Liu TC, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008;9:533-542.)
Representative Patient Response to JX-594
∗ RECIST: Response Evaluation Criteria in Solid Tumors: Partial response (PR) is a maximum diameter decrease of ≥30%, progressive disease (PD) is an increase of ≥20%, and stable disease (SD) is a change in diameter between these two cutoffs.
∗∗ Choi criteria: response (+) is maximum diameter decrease of ≥10% or density decrease of ≥15%.
† HU: Hounsfield units, also CT units: related to the composition and nature of the tissue imaged, represents the density of tissue.
Adapted from Park BH, Hwang T, Liu TC, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008;9:533-542.
Whereas G207 and related viruses were engineered to take advantage of permissive conditions in cancer cells relative to quiescent cells, ONYX-015 was designed to exploit lack of functional p53 in tumor cells. ONYX-015 is an adenovirus that lacks the E1B 55K gene. This gene encodes a protein that binds p53 and targets it for degradation. In the absence of E1B 55K, ONYX-015 was expected to replicate poorly in normal cells, in which functional p53 could abort lytic, productive replication. In contrast, cancer cells should be permissive for ONYX-015 because E1B 55k should be unnecessary in cells that lack p53. 71
Extensive analysis of the molecular mechanisms underlying ONYX-015 replication revealed that the virus does indeed replicate selectively in tumor cells. Whereas replication of this virus is mediated through the p53 pathway, tumor selectivity is mostly based on the ability of tumor cells to complement other functions of E1B 55K unrelated to p53. 72–74 These functions relate to the ability of E1B 55K to facilitate the export of viral mRNAs and shut down host protein synthesis. Nonetheless, ONYX-015 advanced to Phase III trials in the United States, after encouraging signs of safety and efficacy. The analysis of clinical tumor specimens obtained following injection of ONYX-015 provided unambiguous evidence for its tumor selectivity. Replicating virus was found (1) in head and neck cancer following intratumoral injection, (2) in liver metastases from gastrointestinal cancer after intra-arterial injection, and (3) in lung tumors following intravenous injection. 75–77 Furthermore, objective tumor responses were observed in several clinical Phase II studies. Single-agent treatment with ONYX-015 induced objective responses in 14% of patients with recurrent head and neck cancer. 77 In a subsequent study, the virus was combined with standard chemotherapy. Only a single tumor was injected with ONYX-015, leaving a subgroup of patients with additional uninjected control lesions. Interestingly, the response rate of tumors injected with the virus was significantly greater than those of noninjected lesions, and the time to progression was significantly longer for injected tumors. 75 Further evidence of antitumor activity of ONYX-015 was found in three patients with 5-FU/leucovorin-refractory liver metastases from colorectal cancer that experienced minor responses (30% to 48% shrinkage) following intra-arterial infusion of ONYX-015 into the hepatic artery. 78
Meanwhile, a closely related adenovirus, H101, has recently been developed by Shanghai Sunway Biotech and approved for treatment of head and neck cancer in China 3 after a clinical Phase III study demonstrated a dramatically higher tumor response rate in patients who had received H101 in combination with cisplatin and 5-fluorouracil (78.8% versus 39.6%, respectively). 79
Delta-24 (also known as dl922-947 or ONYX-838) is another adenovirus mutant that targets cancer cells selectively. 80 The E1a region contains a small deletion that prevents binding to RB. As a result, this virus cannot replicate efficiently in normal cells, because RB represses E2F activity that is essential for replication (in addition to transcribing genes involved in DNA synthesis, E2F activates transcription of the viral E2 region; this is how E2F was first named and identified). In cancer cells, E2F activity is not repressed by RB, because RB itself is mutated or inactivated indirectly through loss of p16INK4a, amplification of cyclin D1, or by other means. Tumor cells therefore provide a permissive environment for replication of Delta-24. A modified version of Delta-24 has entered clinical trials for the treatment of glioblastoma. 81,82 This virus, Delta-24 RGD, has been engineered to increase infectivity by the addition of an RGD sequence in its fiber gene. 83 Likewise, adenoviruses designated KD1 and KD3 contain two small deletions in E1A that abolish its binding to pRB but leave the ability of E1A to transactivate viral genes intact. These have been shown to replicate with great efficiency in tumor cells, but fail to replicate efficiently in normal cells. 84
A second-generation version of Delta-24 was engineered to express human p53. 85,86 Ad24-p53 more effectively killed most human cancer cell lines tested in vitro than did its parent Ad24 and had significant activity against xenografts in vivo. 85 To further improve potency of this virus, the p53 transgene was engineered so that it is resistant to degradation by Mdm2. 85 Adenoviruses have also been engineered to take advantage of unregulated TCF transcriptional activity, a characteristic of colorectal cancer cells that lack the APC tumor suppressor or contain activating mutations in beta-catenin. 87,88
An array of creative approaches has been employed to make viruses replicate selectively based on abnormal transcription activity in cancer cells. These include viruses that use unregulated E2F activity resulting from loss of the RB tumor suppressor pathway to drive the E2F-1 promoter, the telomerase promoter, prostate-specific promoters and regulatory elements to drive proliferation in prostate cancer cells, and many others. These approaches have been reviewed recently by Fukazawa and colleagues. 89
Challenges and Future Perspective
Gene therapeutic agents and oncolytic viruses have highly diverse physical and biological properties and act through complex molecular mechanisms, making predictions about their pharmacological and pharmacodynamic behavior in humans difficult. Preclinical model systems are therefore particularly important elements in the selection process for further clinical development.
Mouse xenograft tumor models of human cancer cell lines in nude mice allow for efficient assessment of antitumor activities of novel gene delivery and oncolytic agents in a broad variety of human tumor types. However, these models have significant limitations due to the lack of a functional immune system and differences in structure and composition of the tumor stroma. To address these limitations, immunocompetent tumor models have been developed. Such models have been instrumental for assessing the impact of immune-modulatory genes in the genome of oncolytic adenoviruses on virus replication and antitumor effect. 90 In addition, orthotopic implantation of allografts in immunocompetent models allows for testing novel vectors in tumors growing an organotypic microenvironment that more closely resembles the situation in humans. 91–93 Despite these improved murine models, limitations remain. For example, normal and malignant mouse tissues only poorly support replication of human adenoviruses. Another example is the difference between the sequences of human and mouse cytokines, which makes the generation of mouse-specific variants of immune-modulatory agents necessary. Other species offer potentially advantageous features. For example, normal and malignant Syrian hamster cells support adenovirus replication. Using this model, intratumoral injection of an oncolytic adenovirus resulted in suppression not only of the primary tumor but also of distant metastases following virus entry into the bloodstream. 94 Similar results were obtained in cotton rats. 95 In addition, replication-competent viruses for use in canine models have been developed. 96
Biodistribution and systemic effects of novel gene therapy and oncolytic viral agents are fundamentally different from small-molecule or antibody-based anticancer therapies and therefore difficult to predict. To address this, novel in vivo imaging strategies allowing for real-time monitoring of the effects of such agents in animals as well as in humans have been developed and will play a major role in the further development of this therapeutic approach. Distribution of nonviral and viral particles can be directly assessed by radioactive or fluorescent labeling. The biodistribution of liposomes, for example, can be followed after labeling with radioactive isotopes (e.g., 99mTc) or gadolinium by scintigraphy or magnetic resonance imaging, respectively. 97,98 A variety of strategies have been pursued to monitor viral agents. Green-fluorescent protein and firefly luciferase are transgenes that allow for the detection of cells infected with viruses carrying an expression cassette for either of these genes through the detection of fluorescent light or bioluminescence, respectively—in animal models, at least. 99,100 The use of prodrug-converting enzymes opens the possibility of using the enzyme activity for imaging purposes. The most developed approach is expression of the prodrug converting enzyme HSV-TK, which not only converts ganciclovir into cytotoxic phosphorylated derivatives but also phosphorylates uracil derivatives labeled with radioactive iodine and acylguanosines labeled with radioactive fluorine, which are then also retained within the cell and detectable by positron emission tomography (PET). This approach has been successfully used in a variety of vectors in small animals. Recently, it has also been demonstrated to be an effective imaging strategy in a pilot study in patients with liver cancer. 101 A similar approach involves the vector-mediated delivery of receptors with only limited physiologic expression, such as the dopamine D2 receptor or the somatostatin receptor subtype 2. PET imaging probes for both receptors are already clinically available for imaging of neuroendocrine tumors. A third technology has been developed using the sodium-iodide symporter, which is a transmembrane transporter protein that is physiologically predominantly expressed in the thyroid gland. 102 Ectopic expression of this protein leads to accumulation of radioactive iodine, which can be detected by radionuclide imaging using a gamma camera or PET. The potential advantage of this approach is that cytotoxic radionuclides such as 131 I can be used therapeutically. 103
The complexity of the host-vector interaction and the resulting dynamics of virus and tumor cell replication are theoretically amenable to in silico modeling of virus and tumor cell population dynamics. Such mathematical models created important insights into the kinetics of human immunodeficiency virus (HIV) infection and treatment 104,105 and have been, at a theoretical level, developed for oncolytic viruses and their interaction with tumor cells and the host immune system. 106,107 Experimental validation of these models is currently being actively pursued by several laboratories.
Safety and Toxicity
The use of viruses either as vectors for the delivery of therapeutic genes or, in mutant form, as therapeutics themselves raised significant concerns not only in regard to the safety of individuals treated with such agents but also because of the potential risks for others. In particular, the occurrence of recombinant viruses that regain wild-type properties or demonstrate even greater toxicity was feared. For this reason, extensive safety studies were performed. For example, the biohazard potential of AdCMV-p53 was investigated in France in the context of clinical trials of this virus in head and neck cancer. No evidence for any environmental risk from intratumoral injection of the virus was found. 108
Immune and Cytokine Response
A major concern with respect to the use of viral particles as therapeutic agents is the induction of neutralizing antibodies that could limit the efficacy of such agents. In the case of adenovirus this is of particular relevance, as at least 50% of patients present with preexisting antibodies against adenovirus type 5, resulting from earlier infections. 75–78,109,110 It is therefore not surprising that almost all of the patients treated with viral agents developed high titers of neutralizing antibodies following the first administration of the virus. Preclinical studies suggest that the presence of such antibodies might reduce the efficacy of adenoviral treatments. 111 At this point, this has not been clearly demonstrated clinically. In contrast, following intra-arterial infusion of ONYX-015 into the hepatic artery or intravenous administration, the virus was cleared rapidly from the bloodstream.
Improving Tumor Killing by Improving Tumor Cell Access
Viral vectors and oncolytic agents have been engineered to improve their ability to infect cancer cells, either to increase selectivity or to increase potency. Adenoviruses have been the focus of many of these efforts. This is because it is believed that the utility of adenovirus vectors is limited because of the low expression of CAR, the high-affinity receptor that is necessary for efficient attachment to the cell membrane. 112 This is of particular concern in many advanced cancers, in which CAR levels are often low relative to normal cells or well-differentiated cancers. 113,114 Many attempts have been made to address this problem. Wickham and co-workers 115 modified the C terminus of the adenoviral fiber protein by the addition of either an RGD-containing peptide or seven lysine residues. Dmitriev and colleagues 116,117 have also shown that the incorporation of an RGD-containing peptide in the H1 loop of the fiber knob domain results in the ability of the virus to utilize an alternative receptor during the cell entry process. The modified virus was able to infect primary tumor cells and tumor cell lines more efficiently than unmodified virus. 116,118 The RGD/fiber modification was subsequently introduced into the Delta-24 virus, described above. Gu and associates have successfully redirected cell binding and uptake of an adenovirus through fibroblast growth factor receptors (FGFRs), suggesting that redirecting the native tropism of adenovirus may offer therapeutic benefit. 119
Virotherapy and other gene-therapeutic approaches represent a novel class of targeted anticancer agents that is distinct from traditional treatment modalities.
The initial focus of this field was to invent and test new agents that kill cancer cells selectively, based on the genetic lesions that cause this disease. This goal has been achieved using a rich variety of viruses, vectors, genes, and approaches, in laboratory and animal model settings. Some of these approaches have been translated into clinical research projects; however, until very recently, clinical results have been disappointing in terms of increased survival or meaningful patient benefit. 120 Although most treatment regimens have shown great safety, some early gene therapeutic trials raised serious concerns in this regard—the death of a patient with ornithine transcarbamylase deficiency, and the leukemia caused by gene therapy in four severe combined immunodeficiency (SCID) patients. 121 These rare adverse effects and the initial lack of compelling clinical activity, together with the potential risk and cost of manufacturing these agents, has dampened the initial enthusiasm in this field, as well as interfered with significant investments. However, substantial advances in our understanding of cancer biology and validation of targets, as well as the promise shown by some of the very recent gene therapeutic clinical trials, have led to a paradigm shift: anticancer gene therapy is now on an upswing again.
Nonetheless, significant hurdles still exist and need to be addressed. One of the biggest remaining challenges is delivery, including delivery to the tumor site, spread within the tumor, undesired clearance by the liver, neutralizing antibodies, and complement. Another significant difficulty for many of the approaches currently in development is the lack of appropriate preclinical models.
For gene therapy strategies to be clinically successful, they likely have to be included in multimodality treatment approaches and go far beyond killing cancer cells: they need to be anti-angiogenic and immune-modulatory, and they must prevent or overcome resistance to therapy. Intelligent vector design and clever combination regimens will, it is hoped, bring us closer to achieving this goal. Recent studies have demonstrated synergistic effects of combination therapies consisting of conventional chemo- or radio- and virotherapy. Moreover, combinatorial therapies with more "modern" approaches, such as the use of nanotechnology and cellular carriers, hold great promise. For instance, polymer-coated adenoviruses have shown a significantly enhanced half-life when compared to naked viruses, and the use of appropriate cellular carriers has been demonstrated to improve delivery and induction of desirable immune responses against the tumor.
Furthermore, clinical studies will likely yield better patient benefits and increase the chance for approval if factors can be pinpointed that predict efficacy—such as tumor type, histology, and molecular signatures.
Taken together, the recent advances in cancer biology, virology, biotechnology, and nanotechnology, as well as interdisciplinary collaborations, will expedite the development of this therapeutic platform and, we can hope, improve patients' lives in the very near future.
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2. Kaye F.J. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer . Oncogene . 2002 ; 21 : 6908 – 6914 .
3. Garber K. China approves world's first oncolytic virus therapy for cancer treatment . J Natl Cancer Inst . 2006 ; 98 : 298 – 300 .
4. Zhang W.W. , Alemany R. , Wang J. , Koch P.E. , Ordonez N.G. , Roth J.A. Safety evaluation of Ad5CMV-p53 in vitro and in vivo . Hum Gene Ther . 1995 ; 6 : 155 – 164 .
5. Barak Y. , Juven T. , Haffner R. , Oren M. mdm2 expression is induced by wild type p53 activity . EMBO J . 1993 ; 12 : 461 – 468 .
6. Xu M. , Kumar D. , Srinivas S. et al. Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity . Hum Gene Ther . 1997 ; 8 : 177 – 185 .
7. Reed J.C. , Miyashita T. , Krajewski S. et al. Bcl-2 family proteins and the regulation of programmed cell death in leukemia and lymphoma . Cancer Treat Res . 1996 ; 84 : 31 – 72 .
8. Molinier-Frenkel V. , Le Boulaire C. , Le Gal F.A. et al. Longitudinal follow-up of cellular and humoral immunity induced by recombinant adenovirus-mediated gene therapy in cancer patients . Hum Gene Ther . 2000 ; 11 : 1911 – 1920 .
The Molecular Biology of Breast Cancer
From Bench to Bedside with Targeted Therapies
Molecular Pathogenesis of Pancreatic Adenocarcinoma
Cancer Therapeutics
Genetic Mouse Models of Cancer


Chile's state-owned mining giant, Codelco, is benefiting from a surge in global prices but struggling for political freedom to manage its business for long-term gain.
REAPING THE FRUITS OF THREE DECADES OF ECONOMIC REFORM AND A global commodities boom, Chile is enjoying unprecedented prosperity. The economy has expanded at an annual average rate of 5.5 percent for the past 20 years. Average incomes have soared to $11,270 on a purchasing-power parity basis, according to the World Bank, which ranks the country just behind Russia, Mexico and Malaysia but comfortably ahead of Bulgaria, Romania and Turkey. The transformation can be seen along the 2,700-mile length of this nation, from the humming factories and rising glass-walled skyscrapers of the capital, Santiago, to the mechanized, export-oriented farms in the fertile south.
The aspirations of Chileans, however, are rising even faster than the country's fortunes, posing a challenge for the government of President Michelle Bachelet. The Socialist leader won election in January 2006 as the country's first female president by promising a bigger piece of the economic pie to poor and working-class citizens. But Bachelet's economic policies have been more pragmatic than populist, fueling discontent among many of her supporters. The government increased spending by 9 percent this year, compared with 6 percent in 2006; more-generous education and health budgets boosted social outlays by 11.2 percent. Yet the largesse hasn't been nearly enough to satisfy critics.
Nowhere is the change of sentiment more evident than at Corporación Nacional del Cobre, or Codelco, the state-owned mining company that is the world's biggest copper producer. In June and July workers protesting for pay increases stoned management vehicles, derailed a train laden with copper ore and staged wildcat strikes that paralyzed El Teniente, the world's largest underground mine, costing the company some $250 million in lost revenues. Codelco subsequently reached agreements with its workers, but those deals merely raised its costs without quelling the growing labor militancy and political polarization in the country.
The increased social tensions have effectively stalled a package of reforms aimed at making Codelco more competitive by running it on commercial grounds rather than as an arm of the state. The most important elements of the package — pushed by the company and, ostensibly, by the government — would remove political appointees from Codelco's board of directors and make the copper giant as transparent as its private sector competitors by requiring it to file regular financial statements. But the government is too distracted coping with flare-ups of popular discontent to put its full weight behind the reform package.
"It is getting harder and slower to push through the reforms," concedes Karen Poniachik, the minister of Mining. In addition to dwindling support on the left, the conservative opposition in Congress senses the government's vulnerability and plunging popularity and is now unwilling to back reforms at Codelco that it had advocated for years.
The political stalemate hasn't yet exacted a toll on Chile's economy because of the unprecedented size of the country's copper windfall. Soaring demand from China's burgeoning factories has sent the price of the metal skyrocketing in recent years. Notwithstanding a roughly 16 percent drop in prices since early October because of fears of a global economic slowdown, copper was trading at $3.1570 a pound on the New York Mercantile Exchange late last month, up 353 percent since the end of 2002. Chile's copper export earnings quadrupled over three years, to $30 billion in 2006. To preserve that bounty, the government — taking a page from the playbooks of other resource-rich developing nations — has established two funds to invest its copper earnings in overseas markets. Those funds held a total of $12.57 billion at the end of September (see box).
Yet failure to reform Codelco threatens to erode the country's single-biggest moneymaker. The company's costs are significantly higher than those of its private sector rivals, and its massive profit transfers to the government could frustrate its attempt to ramp up production in the current bull market. Pretax profits surged 88 percent in 2006 from a year earlier, to $9.2 billion, on a 63 percent rise in revenues, to $17.1 billion. The company turned over $8.3 billion of its profits to the government, an amount that represented 15 percent of all state revenues. Codelco's pretax profits rose to $4.67 billion in the first half of this year, up slightly from $4.625 billion for the same period in 2006. Revenues rose 16 percent, to $7.85 billion. With soaring mineral prices leading to dramatic initiatives among competitors, Codelco seems to be moving at a glacial pace. If BHP Billiton succeeds with its current bid for Rio Tinto, it would create a company with a market value of $350 billion that would displace Codelco as the world's No. 1 copper producer. (In 2006, BHP Billiton and Rio Tinto had a combined copper output of 2 million metric tons versus 1.75 million tons for Codelco.) And although other mining giants are scouring the globe for new deposits, even in politically risky countries like the Congo and Pakistan, Codelco has confined itself to Chile. "The problem is that Codelco has such political and economic importance in Chile that any business decision it makes is placed under great scrutiny — and that leads to very cautious management," says Juan Carlos Guajardo, the executive editor at Centro de Estudios del Cobre, or Cesco, a copper industry think tank based in Santiago.
CODELCO IS THE CURIOUS by-product of left-wing radicalism and right-wing dictatorship. In 1971 the Marxist coalition government of President Salvador Allende expropriated the mines of Kennecott Corp. and Anaconda Copper Co. and refused to pay compensation, arguing that the U.S. companies had earned excess profits in Chile since the early 1900s. The move had broad popular support: Nationalization was approved unanimously by Chile's Congress.
Two years later the government was overthrown and Allende died in a bloody coup led by General Augusto Pinochet, the army commander who ruled the country with an iron hand for the next 17 years. The government reached compensation agreements with Kennecott and Anaconda but kept the mines under state control and grouped in a new entity, Codelco, which was created in 1976. Pinochet, a staunch advocate of privatization, did not want to risk nationalist ire by returning the mines to foreign ownership. The dictator also viewed Codelco as a lucrative source of income to ensure the loyalty of his troops: Under a 1976 law passed by the regime, 10 percent of the company's annual revenues are earmarked for the military.
Private sector competition, however, has forced Codelco to raise its game. The company doesn't suffer from the mismanagement, overstaffing, rising operational costs and diminishing output that have plagued government-owned oil companies such as Mexico's Petróleos Mexicanos and Petróleos de Venezuela. Codelco's newest mines, like Radomiro Tomic in the far desert north of the country, are among the most efficient in the world.
But state ownership has constrained Codelco's expansion, which lags that of its domestic rivals. The biggest impediment is a requirement that the company, after covering operational costs, turn over all its profits to the government. To fund new projects, it must negotiate with the Finance and Mining ministers for a share of those profits. "Codelco cannot go to the government and say, 'Look we would like to keep half of our profits this year because we have a lot of good investment opportunities,'" says John Tilton, a mining economist who teaches at the Colorado School of Mines and the Pontificia Universidad Católica de Chile.
Even before giving the government the vast bulk of its profits, Codelco is obliged to fork over a cut of its revenues to the armed forces. Military commanders concede that this bounty has induced lavish spending on new weapons and equipment that exceeds the country's defense requirements. The military's budget for 2007 is $5.19 billion, which is partly funded by the $1.7 billion it received from Codelco based on its 2006 revenues. The military budget has jumped more than a third since 2005, when spending amounted to $3.8 billion. "There is very broad agreement in Congress and the military that there is absolutely no justification to continue this arrangement," says Codelco CEO Arellano. The government has not yet formally proposed altering the 10 percent arrangement, nor has it been discussed in Congress. But given the political environment, Arellano predicts it will take at least two years to repeal the law.
The company has also turned to its biggest market for investment partners. In 2005, Codelco struck an agreement with China Minmetals Corp., a state-owned company, to develop the Gabriela Mistral, or Gaby, mine in Chile's Andes. The $900 million project is expected to produce 150,000 tons of copper a year, and is due to come on stream in the second half of 2008. China Minmetals invested $550 million and will have the right to buy the mine's output at market prices. "This allowed us to finance Gaby without having to go to the capital markets," says Juan Enrique Morales, Codelco's senior vice president for development. Under the accord Codelco will keep a 51 percent stake in Gaby and auction 49 percent of the mine at an unspecified date. Minmetals will have first option on 24 percent and the opportunity to purchase the remaining 25 percent if it matches the highest third-party bid.
The Gaby deal demonstrated the political clout that Codelco gives Chile. It set the stage for the signing in November 2005 of a free-trade agreement between the two countries — China's first and only with a Latin American nation — that opens up China's market for Chile's fruit, vegetable, fish and forestry exports. "We first had to show China, our biggest client, the benefits of a long-term arrangement for access to our copper," says Morales.
Even with such innovative financing arrangements, Codelco struggles to find the resources to fund its growth plans. The company has set a goal of raising its copper output to 2.5 million tons a year by 2020 — a 43 percent jump over current annual production. Most of this increase will come from mammoth expansions at existing mines. Codelco hasn't yet estimated the costs of this expansion, but the ambitious, high-tech transformation planned for El Teniente suggests that the price tag will be onerous.
El Teniente was considered a marvel of advanced mining when it began operations in 1905 under ownership of the Braden Copper Co., founded by William Braden, a young U.S. engineer. Today the mine, which descends to a depth of 3,300 feet, is a man-made wonder. Its underground tunnel network extends 1,428 miles — nearly the distance between New York and Houston. Explosives implanted high above these tunnels send 500-foot columns of copper ore crashing down into giant grinders. The ore is crushed and poured into the wagons of trains circulating through the tunnels. The loads are dumped outside the mine into vats where the ore is concentrated and mixed with water. The slurry then flows through a 53-mile-long concrete canal to a refinery, where it is turned into copper ingots and plates for export, mainly to Asia.
A science-fiction-like development of El Teniente by 2016 calls for replicating its entire tunnel network some 2,600 feet below the present contours of the mine, taking advantage of the same copper veins. By then the excavators, grinding equipment and trains will be fully automated and operated from distant control rooms. Copper experts don't doubt Codelco's technological prowess. "But given the financial and political handicaps under which it operates, a project like the expansion of El Teniente is very problematic," says Cesco's Guajardo.
Arellano is urging Congress to approve government-proposed reforms that would remove the two ministers and the military representative from the board and replace them with appointees with strong engineering and managerial experience in copper mining. He also suggests that the tenure of Codelco's board members be extended beyond the Chilean president's term and that some of them be appointed by a nongovernment commission to ensure a more nonpartisan, professional board.
The conservative opposition has stalled these reforms in Congress, however. Opposition politicians, who used to call for a nonpolitical, technocratic board of directors, are instead pressing the government to include representatives from the conservative parties on the board of Codelco.
The huge windfall from copper prices has also taken privatization off the table as a possible solution for Codelco's problems. Felipe Larraín, an economist at the Pontificia Universidad Católica de Chile who is on the short list of candidates for Finance minister if conservatives gain power in the 2009 elections, advocates the sale of a 10 percent stake, possibly to the country's six giant pension fund management companies. "Codelco would remain in the hands of the state, but that 10 percent sale could help finance a lot of Codelco's expansion projects," he says. In September the Chilean business lobby group Sociedad de Fomento Fabril called for the sale of as much as 20 percent of Codelco.
With major reforms stalled politically, Arellano is doing what he can to make Codelco more transparent. He gives financial analysts a detailed presentation of the company's financial picture every four months rather than merely releasing full-year results, as his predecessors had. "He has really opened up a debate on Codelco's strategy," says Leonardo Suárez, a mining industry analyst at LarrainVial, a leading Chilean investment bank.
That debate has revealed Codelco's struggle to contain operating costs, which have risen faster than those at private sector mines. Last year it cost Codelco $1.16 to produce a pound of copper; at Antofagasta Minerals, a private company that is the country's third-largest copper producer, it cost only 75 cents a pound.
Part of the differential reflects the fact that Codelco's mines are much older than those in the private sector. Chuquicamata, the world's largest open-pit copper mine, and El Teniente both date back at least a century. The grade of Codelco's copper ore has declined from 1.76 percent copper content in 1976 to 0.90 percent last year. "That means more ore has to be mined and removed — and more excavators and trucks have to be used," says Morales, Codelco's development chief. It also means that energy and equipment costs are rising faster at Codelco than at private sector companies.
Manpower was the one area where Codelco had been able to claim some success in containing costs, but that too has changed. Like private sector mining firms, Codelco began in the mid-1990s to hire thousands of contratistas — temporary workers subcontracted by the mining companies from labor-recruitment firms. By the beginning of this year, Codelco had 28,000 contratistas, or twice the number of its permanent employees. Such contract workers earn 30 percent to 40 percent less than their permanent counterparts. Codelco acknowledges it hasn't integrated its contratistas with its permanent work force as well as its competitors have. "Private sector mines began life with contratistas and fitted them in more easily than we did at Codelco," says Morales. Marcelo Awad, chief executive officer at Antofagasta Minerals, agrees. "Contratistas in the private sector share the same lodging, food, transportation, safety equipment and uniforms as permanent workers," he says.
Resentment among Codelco contratistas rose along with copper prices and finally exploded in late June in the violent strike that crimped output at El Teniente and at El Salvador, a smaller mine 650 miles north of the capital. The workers demanded a $4,775 bonus for 2007 but finally settled for the government's offer of $863. The median monthly salary of contratistas at Codelco's largest mines is $1,400.
The militancy of the contratistas has hardened attitudes among salaried miners. The 4,500 permanent miners at El Teniente agreed by only a 100-vote margin on October 15 to accept a 3.5 percent increase in salaries, which currently stand at about $2,000 a month, plus a one-time bonus of $14,208 reflecting the sharp rise in copper prices over the past three years.
In the past, rising copper wages have led to increased salary demands in other sectors. Chile's bulging export earnings are also putting additional pressure on President Bachelet to match the populist largesse of other Latin American leaders, such as Venezuela's Hugo Chávez. To her credit, Bachelet has stuck to the cautious save-and-invest approach that has guided Chilean economic policy since the mid-1970s. And she has done so at a painful political cost. According to a leading pollster, Adimark, her public support tumbled to 41.5 percent in November from a peak of 59.3 percent in March 2006, when she assumed office.
But it will take even more courage and determination to arrest Codelco's spiraling costs and promote reforms that will keep it at the forefront of global mining.
Chile is hardly alone in benefiting from the global surge in commodities prices. And as in many resource-rich countries, the government of President Michelle Bachelet has created two so-called sovereign wealth funds to preserve much of its copper windfall gains for the future rather than squander them in a burst of inflationary spending.
The Pension Reserve Fund and the Economic and Social Stabilization Fund have grown at a prodigious rate since they were launched in December 2006 and March 2007, respectively. The ESSF took over from the former Copper Stabilization Fund, from which it inherited $2.56 billion. By the end of September 2007, the ESSF had accumulated $11.15 billion and the PRF $1.42 billion. The Finance Ministry projects the two funds will reach a total of $17 billion by the end of 2007.
The ESSF accumulates any fiscal surplus exceeding 1 percent of GDP. The PRF — which was created to finance a minimum government pension for retirees who don't receive enough from the privatized pension fund system — collects up to 0.5 percent of annual GDP. Because of soaring mineral prices, copper revenues accounted for 34.2 percent of total government revenue in 2006 and are expected to reach about the same level in 2007. The two funds are broadly modeled after Norway's Government Pension Fund, which invests a portion of the country's oil revenues for current and future generations and has amassed some $328 billion since it was launched in 1990.
Policymakers hope that by mopping up excess copper revenues, the funds will help contain inflation and ease upward pressure on the peso. "In this way we will contribute to the stability and competitiveness of the economy," says Luis Felipe Céspedes, senior adviser to the Finance Ministry.
Officials have their work cut out for them to prevent the economy from overheating. Chile's annual growth rate accelerated to 6.1 percent in the second quarter, compared with 4.0 percent for all of 2006, and the inflation rate spiked to 6.5 percent in October from 2.1 percent a year earlier. Banco Central de Chile has raised its key short-term interest rate by 0.75 percentage points since July, to 5.75 percent. According to the Banking Association, inflation in 2007 is expected to reach 6.5 percent, but no new rise in the central bank's interest rate is predicted — though the association is forecasting a 0.5 percent interest rate hike in 2008. But higher interest rates may merely add to upward pressure on the peso, which has risen by 4.9 percent so far this year, to about 507 to the dollar.
The central bank is responsible for managing the two funds, and thus far it has adopted a conservative strategy. All of the monies are currently invested in fixed-income securities with credit ratings of single-A-minus or better: Some 70 percent is in government bonds, 6 percent in U.S. Treasury bills, 3.5 percent in Treasury Inflation-Protected Securities and the remainder mostly in certificates of deposit. Half of the funds are in dollar-denominated securities, 40 percent in euros and 10 percent in yen. The average duration of the securities is two-and-a-half years, and the portfolios have returned an annualized yield of 5.75 percent since the start of the year.
The government plans to eventually diversify the funds into stocks and other financial instruments and to appoint outside managers to run them. "In a second stage — and it hasn't been decided when — there will be a bidding process to determine the foreign money managers," says Céspedes.


My husband is not my Prince Charming. Never has been. Never will be. I'll never be like Sleeping Beauty, Cinderella, or Snow White. It's not the type of relationship we have. So why are we married? Well, I never wanted a Prince Charming husband, someone that sweeps me off of my feet and "rescues me." I want, a partner, someone who shares in my passion and works alongside me rather than in front of me. Thankfully, Darren is not my Prince Charming.
As our relationship flourished, we moved even further away from Prince Charming and Cinderella. We jumped at the chance to participate in extreme adventures together and I began my blogging journey, forging my own path as an independent person. We became equal partners in life and divided the roles based on likes and dislikes rather than gender expectations.
We have careers and independent directions that happily weave in the middle and compliment each other. Happily ever after isn't a fairy tale filled with princesses and princesses. It's a choice; a partnership; a lifelong commitment.
This entry was posted in Family, Family Travel and tagged bucket list, Bucket List Publications, bucketlist, Family, Lesley Carter, love, Marriage, relationships, travel by lesleycarter. Bookmark the permalink.
Love this! My husband isn't my Prince Charming, either. But I still think he's the most fantastic man I know, and there is no one else who would ever make me happier. We both work, both out of the home and at home. We both have hobbies. This is what 21st century relationships look like to me — mine and yours.
As a wise person once said, "A true friend does not bail you out of prison; they're sitting next you telling you how awesome last night was".
You obviously don't need someone to take care of you, Lesley. But, a true marriage is a partnership. My parents will mark 55 years of marriage this June. They've had their tough times, but there are thousands of more great times. My best to to the two of you in your continued life together.
Thank you, and congratulations to your parents. 55 years is a beautiful accomplishment.
Love this!! I am hoping to instill this in my daughter!
I really loved this. God bless you both. Partnership forever!
Awesomeness! Partnerships make happy marriages.
Well said, Lesley! A much needed sentiment to be shared in the 21st century.
Fairy tales are for kids and you have to grow out of them for your own good.
You took the words out of my mouth, Leslie. Love is a choice–one that needs to be affirmed every day. I believe falling in love is easy; it's the decision to be committed that's difficult for some. And when Athena gets older and starts watching Disney movies? You'll have to explain things to her in "realistic" terms.
We would agree 30 years plus…it's about sharing life and adventures. Lovely post Lesley.
Love your fishtail braid! Your husband could be my husband's brother!! And mine is definitely not a Prince Charming. Though, sometimes it'd be nice to see that side….not gonna lie! You guys are a gorgeous, adventurous family!
I think you mean in the Disney sense. And I think Kellisamson has a point. The fairy tales express a part of ourselves ('sometimes I'd like to see that side…-in her case she is talking about in her partner). We have a part of ourselves that is awakened like Snow White, but perhaps from within. I love the fairytales because they awaken our imagination. But really they don't give us answers but questions. I'm amazed about the journeys you both have foraged together as partners. Congratulations. In our day you can buy a princess costume, or dress up as a princess for a prom… but it is the personal discovery that allows us to shine with inner beauty every day.
You have a great relationship and partnership Lesley, with mutual respect and posibilities for both of you.
Thanks for sharing and I really hope, yours will be forever.
I couldn't agree more. Our relationship is the same way as yours and love it that way. Continued good wishes as you go through life together!
Prince Charming is the man who helps make your dreams come true. I think you found yours.
You really DO have a happily ever after…the best kind! Thanks for sharing.
Great post. I too decided after being independent in a previous relationship I needed to find a partner in this journey. Someone to walk beside me, not in front or behind. I have found my partner and equal other half.
Acquiescing to knights in shining armour on mounted steeds does take away one's independence. I did have to wean myself off the concept, however compelling.
Love this! I had a Prince Charming once and it was like a fairy tale, and I was swept off my feet, blah, blah, blah … It ended badly, of course. Fantasy can't merge with real life. I'm happier now with a partner, an equal, a non-Prince Charming (Prince Partner?). I love the last pic of you and your hubby and daughter on the bench. It's so languid yet it says so much. Big hugs to you all.
Sounds to me as though you have been swept off your feet by your prince, he just happens to look and act a little differently to Disney – a realistic view of happy ever after. Prince Charming and Happy Ever After don't exist as we are brought up to believe, reality looks and smells different, but what would we rather in the end? Happily ever after, or a future with someone real?
The mark of a real relationship is keeping a true sense of self, while creating a new, separate "couple" identity. Kudos to you and Darren for living a real fairytale, warts and all, as real happiness is experienced alongside sadness/stress. Wishing you many happy, healthy and prosperous years together.
Great post! I couldn't agree more–I even told my now-husband that if he surprised me with a proposal, I might be inclined to say "no." It's not that I hate surprises (I love 'em!), but I wanted the decision to get married to be a mutually-agreed upon one. I wanted to talk about it first. I wanted to make sure we were both going into a big decision like that as equal members of a team. Now our first baby is on the way, and I'm hoping that same mindset that we began cultivating four years ago will allow us to become fair, honest, and happy parents.
You are so lucky to have a true partner like that. The bond between you clearly shows in your photographs.
My husband is my best friend and I am his. That was always the number one thing I wanted from a relationship and marriage – someone who I could share my whole life with. I find the idea of someone coming in and "rescuing" me to be preposterous and there is nothing traditional about our marriage. I am the primary breadwinner and he runs a small business from home, while also doing all the house work. If anything, I am his Prince Charming. Lol!
I think Disney has messed up our ideas of what girls want in a relationship, but then along comes Brave–maybe they are starting to get it after all.
I feel exactly the same way about my marriage!
I feel the same way about my husband. He is my partner, which is something I always wanted from a spouse. We each have strengths, and I like that we balance each other out. We support each others dreams, but are building on a shared dream. I wouldn't have it any other way.
It is the same in my house with 2 exceptions! I don my armor to charge into battle to rescue her from giant spiders in the bathroom and creepy green covered left overs in the fridge. Otherwise we are right there with ya!
As much as I love your adventures, it's this writing that always really grabs me! It's the stuff I started following so very long ago! You two really make it look so wonderful… Way to go!
You've been such an active follower. I love seeing your photo show up in my feed. 🙂 I guess the visit will need to be in OC now. You're always welcome.
There are a lot worse places than OC! 😉 My guest room remains open. Headed to Belize at the end of March, and either Ireland/Iceland or Denmark/Iceland at the end of June… otherwise, here I am. Come visit!


Uploaded by SOLEH ISKANDAR in Springfield at Wednesday, November 6, 2013. The Amusing Indoor Furniture images on this page are the Amusing picture that we grabbed for you with a dimension of 588 x 344 pixels. Modern Fireplace Design With Blue Sofa And Rug Fur above are the same as what I saw when I visited my father in law�s private residence in Houston, United State of America. Don�t worry; you can also read the entire story in the Simple and Decorative Modern Gas Fireplace which contains picture that I took during a vacation to various states such as Iceland, Slovenia, and Honduras.
Feel free to use the corner gas fireplace picture that I served even though you are in tropical or desert states like Saudi Arabia, Cyprus, and Cape Verde. Download by right clicking your mouse right on the Amusing picture, then give this good resolution picture to your home decorator to be put on soon.


The past few days have been a little hectic but fun.
I was part of a panel that discussed science and science fiction last weekend over at the Science Discovery Center at the Mall of Asia, along with Queena Lee-Chua, Quark Henares, Emil Flores and host Karen Kunawicz. While scifi is not precisely my forte, I spoke about the genre in the context, of course, of speculative fiction. Highlights include my decision to throw poor Quark under the bus when a rather difficult question from the audience came our way (sorry Quark!), Queena and I exchanging whispers about time travel and Star Trek, and Emil and I arguing over the merits of Mazinger Z's Kouji Kabuto. Later, a Gundam question stumped the entire panel.
The Discovery Center is a very cool place, complete with a planetarium and lots of things to do. I plan on taking Sage there one day.
On Sunday, Nikki and I were godparents for the firstborn of Alex and Kate Osias - the handsome Hector Benjamin Osias. Hector and Rowan were born a week apart. The church was beautiful but the reception food was even better - nothing beats chicken and kare-kare at Aristocrat! Secretly, we actually arrived with time to spare and had adobo flying saucers.
We celebrated Kate's first Palanca Award (Short Story for Children) as well as Ian's first 1st Prize (Short Story - 4 to go for the Hall of Fame, Ian!) and got to share in everyone's happiness (and food, siyempre - combat buffet-style). This was when Butch recruited me for a new project early next year (and rather cleverly managed to foist responsibility on me - haha), Sarge and I ribbed each other as losers, and Jing and Tony gently exerted pressure on Nikki to submit her book to Milfores for publication. I was happy to see Marge Evasco and congratulate her for her Free Press win and join the marginalized smokers (old and new winners) in the adjacent smoking area. Everyone was hoping for a repeat of last year's outrageous door prizes - and we got our wish when P100k was raffled away, half of which went to Charlson Ong.
We had lunch with the winner of the Grand Prize for the Novel (English), Miguel Syjuco. Such a pleasant and well-spoken man, we were happy to find our poetics aligned in many ways. He wrote "Ilustrado" in the three years and cut down the 200,000 word monster in a more palatable 80,000 words (the same novel, by the way, is long-listed for the Man Asia). Over tapas and champagne we talked shop, and asked ourselves where everything is going, and what should be done, what we could do, and so on. We spoke about how, ultimately, we need to build upon (and then destroy) what has been done and construct new texts - killing our fathers, so to speak.
Yvette Tan, Wanggo Gallaga, Audrey Carpio and Tals Diaz were there for questions and revelations - and somehow, conversation swerved to "Twilight", and glittering vampires (gah), and how the LitCritters should be renamed GlitCritters or Gliterati (haha). The long lunch ended with open invitations for everyone to sit in with the LitCritters and/or play Upwords (we love this game).
Vin Simbulan's fantasy antho "A Time for Dragons" has been greenlit by Anvil, with cover and inner illustrationsby Andrew Drilon. Authors in the draconic antho include (to the best of my knowledge): Yvette Tan, Elbert Or, Cyan Abad-Jugo, Kate Aton-Osias, Alexander Drilon, Elyss Punsalan, Gabriela Lee, Nikki Alfar, Joseph Nacino, Apol Lejano-Massebieau, Vincent Michael Simbulan, Paolo Chikiamco-Recio, Dominique Cimafranca, Alexander Osias, Oscar Alvarez, Sarge Lacuesta and me.
Big, big thanks to Rochita Loenen-Ruiz (who blogs here and here) for sending me a surprise package: Interzone, Asimov's and stuff for Sage and Rowan! I am so happy - reading material!!!
Someday, I'll figure out how to get published in Interzone (Rochita recommended this lovely piece of spec fic by Aliette de Bodard, "Deer Flight").


Create your own interactive soundscapes inspired by literary bears and design playable, musical pictures to bring their story to life!
£3 per child. All children to be accompanied by an adult. Booking essential through Eventbrite.


5. Theme 1: You be the judge.
A lot of the deception in Much Ado About Nothing is all in good fun. But take note! Shakespeare's main theme in Much Ado About Nothing actually asks you to pass judgment on his characters' trickery. Find out more about Shakespeare's call to action when you press play.


Let's be real – building an app is no child's play. This particular venture demands time, money, dedication and foremost, perseverance. And, when done right, the effort most definitely pays off.
Successful platforms like Facebook, airG, King and Instagram that have created some of our favorite apps are the result of extensive hard work someone burning both ends of the candle to put forth something phenomenal.
According to Olson, while having an idea is paramount, the real work often lies in bringing it from conception to high-tech reality, which is exactly what this article will discuss.
Putting all your energy into the project of your dreams only to have a mediocre outcome is heartbreaking. Therefore, we've created here, a mini guide to aid you, so that the next 'most trending' app has your name in the headlines and you can steer clear of spammy apps.
Ask yourself the following questions: are there other apps offering similar services already? What features will your app have that will give it an edge over the others? What features are the previous apps lacking that yours would offer?
Validating your idea is another crucial step. You must identify the demand for your service. The Google Keyword Planner tool is an easy way to look at the number of people seeking out what you're planning to do. Having an insight into your potential future customers' needs is essential.
If you have yet to come up with a groundbreaking idea for an app, remember, observation is key. Look around yourself. People desire convenience. What sort of service could make life, in a personal or professional setting, simpler? Some of the most popular apps have been a result of a problem being solved, or a task being simplified.
"Try to find a way to easily solve a common problem. An app like Uber is so successful because it provides convenience and saves time. Anytime you can offer a convenience, you have the potential to be wildly successful," says Jonathan Long, founder of LAWYE.RS.
Building your app with an initially small audience gives you the opportunity to collect feedback, identify limitations and enhance your product before it reaches a broader market.
Facebook was built on this same principle.
When Mark Zuckerberg started making the platform, it was meant only for Harvard students. By the time it became popular amongst a larger population, Zuckerberg had enhanced it to be ideal for the market.
Entrepreneurs often tend to make the mistake of dismissing the design of an app as an insignificant detail. This mistake is a recipe for disaster – by some estimates, 80% of gamified apps fail because they are poorly designed. The experience a user has on an app depends largely upon its design.
Hence, when looking for a developer, make sure they focus on design. Finding the right developer is also important. You need to have the assurance that your developer shares your vision, listens to you, and keeps you in the loop throughout the entire process.
According to developer Mike Rundle, researching the competition is crucial and can determine what other apps in the space are doing right and wrong.
Ignoring the competition leads to the unfortunate downfall of 19% of startup failures.Therefore, do not ignore your competitors. Try to stay updated with what they are doing — whether it's marketing strategies or the latest products they might introduce. This will help keep your project up to date and also define your own USP.
Android and iOS are very different with regard to marketing apps. You must prepare your app for submission. Review the submission guidelines.
For Apple, this includes the iOS Human Interface Guidelines, the Apple Watch Human Interface Guidelines and the App Store Review Guidelines.
For Android, follow the Android launch checklist. Take time to understand Google play policies and agreements.
For iPhone and iPad apps, app creators must register with Apple for $99 a year. Apple's terms allow the company to collect 30 percent of an app's profit, with the creator taking in the remaining 70 percent. Both Google and Amazon have similar terms.
These steps are not sacrosanct, but act as a guideline to building your app in the most profitable manner. Once you're prepared to start, you must know that creating the mobile app is the easier part. Getting and retaining customers is the real challenge, which can only be accomplished with the right amount of time, patience and most importantly a strategy of trial and error.


This medium can be applied by brush directly to the screen printing screen to create a stylized, drawn image. Ideal for t-shirts, tote bags, prints, posters and more! Apply it full strength or dilute with water for areas with finer detail. Once dry, block out the entire screen surface with System 3 Removable Screen Block, using a squeegee. After drying, the drawn image is washed out in cold water to leave an open-mesh positive image ready for printing.


Handmade furniture from own carpentry!
Since we want to produce locally, we have opened our own carpentry. Our wood worker can handmake your dream piece. Diningtables, bartables, benches, mirrors, headboards and side tables are only a few examples of his creativity.
Our idea is that it should be easy to order what you want online. If you live on the other side of Mallorca you should not even have to come to Palma if you don´t want to. We will deliver for you. Many of our customers live abroad most of the time and like to decide on furniture from home. We can send you all the pictures you need in order to do so.
We use recycled wood when we work in order to be as sustainable as possible. You can choose from 2,5cm,4cm or 5cm thick wood. We have lots of colours to choose from and the finish can be more or less distressed. Here are our standard colours. We can make other ones upon request.
When we make furniture with a metal base we use 2x2cm, 3x3cm and flat 2x6cm is also used. On the picture we show our standard colours but we can make any colour upon request.
Let the pictures serve as inspiration! Any questions you might have, please Contact us. We are happy to help you out and give you a quote.


Click on the photos below for measurements & prices.
Add value to home by adding a built in desk. No job is too big or too small, from a little nook off your kitchen to entire home offices, contact us to discuss your ideas. Click on these photos for more inspiration.
Other configurations are available as custom orders. Prices on enquiry.
Solid Victorian Ash Timber with choice of stains available.
See our Finishes and Styles page.


The major advantage of satellite Internet is that you can receive broadband Internet signals from any location on Earth, regardless of how far you are from an Internet port for cable connection. This can be convenient for those who work or live in remote or rural locations where the only option for Internet connectivity is the very slow dial-up modem connection. It's practical and useful for maintaining Internet signals in varying locations, especially when you are travelling in a vehicle such as a ship or a train.
Satellite Internet can benefit many businesses because of the seamless communications it provides. For business continuity, particularly for situations wherein terrestrial providers of a signal may be disabled, damaged or simply nonexistent, people and organisations can still keep in touch with each other. Satellite Internet is a great solution for companies with offices located around the world.
Satellite Internet is more expensive than terrestrial connections. On average, as of 2010, it costs two or three times more than DSL service. Equipment required for satellite Internet, such as the satellite modem and satellite dish, ranges from £390 to £1,300.


• Pro-actively managing and developing relationships with a dedicated group of Partners in order to drive service renewals.
• To maximize revenue opportunities via phone and email to achieve sales targets.
• Identify new business opportunities.
• Manage the entire service sales cycle from start to finish.
Our client is a service company that specializes in 3rd party relationship management.
From their Multinational call center in Newcastle (UK), their teams work on behalf of some of the biggest International brands.
There are excellent career opportunities within the organisation!


text:
Facebook's Libra Cryptocurrency: A Technical Breakdown For Business Leaders
Michael del Castillo Forbes Staff
I cover enterprise adoption of blockchain and cryptocurrency.
Now that Facebook has finally published its plans for a new cryptocurrency, libra, Forbes takes a closer look at what makes it tick.
In spite of Facebook's attempts to look willing to play nice with others, there's much about the technology behind its new libra cryptocurrency that flies in the face of what many in the cryptocurrency world have been building for years.
Venture capital firm Union Square Ventures has been investing in cryptocurrency startups since 2011, and last year, Andreessen Horowitz changed its entire business model so it could invest more aggressively in the space. Both are now a part of Facebook's Libra Association, working to build the libra cryptocurrency and implement it as a way for merchants to accept payment for goods and for individuals to send remittances across borders.
Among the top-funded startups in cryptocurrency is another Libra Association member, Coinbase, which has raised $525 million venture capital, and even stablecoins, which are relatively new to the cryptocurrency ecosystem, and form the backbone of Facebook's work have caught significant investor attention.
Stablecoin startup Celo has raised $36.5 million , with New Jersey-based Basis raising $100 million before closing down operations citing regulatory concerns. Coinbase and cryptocurrency startup Circle, which have collectively raised almost $1 billion in venture capital, earlier this year launched USDC, a stablecoin with a market value of $343 million, designed to run across multiple blockchains and supported by Centre, a group of companies similar to Facebook's Libra Association.
When asked if Facebook had partnered with another stablecoin creator, Gemini, run by Tyler and Cameron Winklevoss, Facebook CEO Mark Zuckerberg's former Harvard classmates, as had been previously reported might occur, Facebook's head of blockchain, David Marcus, now the new head of cryptocurrency subsidiary, Calibra, responded indignantly: "Not in any way shape or form. Fake news."
Click here for a breakdown of what every business leader needs to know about Facebook cryptocurrency.
In spite of these investments in projects very similar to Facebook's, and a total of $5.8 billion having already been invested in the blockchain industry overall, according to industry news site CoinDesk, not a single existing solution met Facebook's technological demands, according to Marcus.
"I would have loved to have found the perfect solution. It would have made our lives much simpler," says Marcus, who was previously president of PayPal. "But unfortunately there wasn't, so we had to build something new." As a result, instead of working with one of the existing stablecoin projects, Facebook decided to establish its own group to build a new technology from the ground up.
So what is the libra blockchain? And how is it so different from what is already out there? In a sentence, it's a hybrid public-private blockchain, where anyone can build on the technology but only invited members can participate in helping the network reach consensus by running software, called a node.
While true public blockchains are much more decentralized than permissioned blockchains, they also tend to have lower transactions volumes. Bitcoin processes about seven transactions per second, compared to the 1,000 transactions Libra expects to need for its users. Which leads to another difference between Libra and more traditional public blockchains: It has to accommodate Facebook's 2.7 billion users, as well as the users of the other 27 association members.
Among the public blockchain features being designed into Libra, the transactions won't have names but will instead rely on a string of numbers and letters that will be visible to the general public. Which means that while the identities of the transactions might be known to the manufacturers of some wallets in which users store their libra coins, the public can see only the public key— or address—owned by each transaction counterparty.
While Facebook's new cryptocurrency wallet subsidiary, Calibra, will require users to go through an intensive anti-money-laundering (AML), know-your-customer (KYC) process, and will be reporting suspicious activity to the authorities, other wallet providers are not required to do so. Given concerns about how Facebook monetizes its users personal data, the company promises not to mingle transaction data collected by Calibra with Facebook's user data.
Perhaps most tantalizingly though, Marcus says libra will be able to be spent two different ways. One, the expected way, is by transacting on the blockchain. But another, yet to be clearly defined, is that the cryptocurrency is being designed so users can accept it using the existing payment rails.
In other words, while Facebooks' first attempt at creating its own form of payment, the mothballed Facebook Credits, which Marcus calls "funny money," was a truly closed system, libra appears to be even more open than some cryptocurrencies. "That's why we've got PayPal, Mastercard, Visa, Stripe and all of these players," Marcus says. "They're going to drive merchant acceptance of libra."
From a technical perspective, the consensus mechanism that helps Libra Association members with different interests come to an agreement on which transactions are valid, uses a modified version of the math behind bitcoin's Byzantine Fault Tolerance (BFT) algorithm, called BFTLibra. BFT in turn takes its name from a math problem that bitcoin solved for how a general is supposed to agree on a plan of attack when some of his commanders are known spies.
The solution to the problem in this case is an algorithm that lets groups reach consensus, even if some of the parties are dishonest. For bitcoin, only half of the network participants have to be honest. With BFTLibra, two thirds have to be honest, but since the participants have to be pre-approved, they already have some trust built in.
After testing many different consensus mechanisms, the founding members of the association decided on a modified version of the consensus mechanism created by Forbes Blockchain 50 member VMWare's consensus mechanism, called Hotstuff, which itself is an improvement on tendermint, an early upgrade to bitcoin's consensus mechanism, according to Tarun Chitra, CEO of technical Libra Association advisor and "silent founding member," Gauntlet Network.
While Gauntlet didn't pay the membership fee to be a full founding member, the company helps audit the libra blockchain code and ensures that the owners of Libra Investment Tokens (LIT) they will receive for their investmenet understand what they're voting for. "We're there to make sure all the other association members understand the possible decisions that are made," he says. "The goal is to ameliorate trust issues by having an informed populous."
Chitra further elaborated that the smart contract code, called Move, which lets coders write programs directly into the blockchain, is being designed to be more attractive to professional developers. "The thing I as a programmer have found is that the ethereum landscape [that popularized smart contracts] is a bit not quite professional-developer-friendly," Chitra says. "The tooling isn't very good, it's very haphazard, and Facebook has spent a lot of time making it developer-friendly."
Since the code is being open-sourced though, anyone who agrees with Chitra will be able to use it for free.
Introducing Forbes Blockchain 50: Learn about the companies investing in the tech that will speed up business processes, increase transparency and potentially save billions of dollars.
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Michael del Castillo
I report on how blockchain and cryptocurrencies are being adopted by enterprises and the broader business community. My coverage includes the use of cryptocurrencies su

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