In the developed world, cancer is currently the number one cause of death, primarily due to ageing populations. Survival rates are reduced for patients whose cancer undergoes metastasis to another site in the body and metastases to the brain have a particularly poor prognosis, with average survival being less than six months. It is estimated that brain metastases characterise 8.5-9.6% of all cancer diagnoses and are ten times more common than primary brain tumours, with most of these secondary tumours originating from primary lung, breast, skin (melanoma) and colorectal cancer, and malignant melanoma.
Like most cancers, treatment of brain metastasis involves three options; surgery, radiotherapy or chemotherapy. While these approaches can extend the survival of patients and improve quality of life, the prognosis for sufferers remains disheartening. Surgical resection has high rates of recurrence, and both chemotherapy and radiotherapy are non-specific and have poor safety profiles. Most chemotherapeutics are further complicated by the limited access of circulating drugs to the brain parenchyma. Temozolomide (TMZ) is one drug that can enter the brain, however it is still limited by a lack of efficacy (Minniti G et al, (2014) J Neurooncol 118(2):329-34). As such, there is a need for targeted drugs that can firstly enter the brain environment, but also limit their toxicity to cancer cells, and in particular the tumorigenic subpopulation.
The treatment of brain tumours is complicated by the presence of the blood-brain barrier (BBB), which isolates the brain microenvironment from the systemic circulation by strictly regulating the passage of molecules. As such, chemotherapeutic drugs are scarcely able to enter the brain, although they can still do damage elsewhere in the body.
Brain tumours as small as 1 mm can compromise the permeability of the BBB. However, this effect is not homogenous throughout the BBB, and as such, does little to improve the administration of sufficient quantities of drugs (Huse J T et al, (2010) Nature Reviews Cancer 10(5):319-31). One technique employed to avoid the problem presented by the BBB, direct cranial injection, is quite invasive and harmful (Lassaletta A et al, (2009) 95(1):65-9). While this approach has been shown to be effective, it carries the risk of infection and other side effects. Other methods involve increasing the permeability of the BBB through osmotic or chemical means. Again, these are risky treatment options, and have the potential to induce seizures and other neurological side effects.
The transferrin receptor 1 (TfR) is a membrane glyocoprotein involved in iron homeostasis. It is expressed strongly on the surface of the BBB, as well as on many cancer cell lines (Wilner S E et al, Mol Ther Nucleic Acids 2012; 1:e21) and has been identified as an effective target for receptor-mediated transcytosis (RMT) of drug conjugates through the BBB. While the TfR is saturated in most cell types where it is expressed, such as red blood cells, hepatocytes, intestinal cells, macrophages and the brain itself, it is not saturated on the BBB, where its expression is considerably higher.
It has been proposed that the growth of cancers is driven by the presence of a unique subpopulation of cells with self-renewal properties. These cancer stem cells (CSC) are relatively quiescent and drug-resistant, and there is evidence suggesting that they may arise from normal stem cells or from epigenetic modifications resulting in the de-differentiation of other cells. Furthermore, it seems that inter-conversion is possible between CSCs and progenitor cells, which some have suggested can be characterised as a dynamic equilibrium.
The first line of evidence pointing to the existence of CSCs were studies involving the xenotransplantation of serial dilutions of cancer cells into immunodeficient mice. These have found that it takes a large number of cells to develop cancer in the animal model, suggesting that only some cells have the ability to do so.
Given the role that CSC play in tumour development, there is a need for novel targeted therapeutics that can be directed towards specifically eliminating this population of cells (which can be refractory to treatment with conventional therapy) in addition to the tumour, and which further are capable of crossing the BBB to treat brain tumours and brain metastasis, including inoperable brain tumours.