***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance , which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation . Pre clinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib . We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma . We enrolled 25 patients , including 11 ( 44 % ) refractory to prior bortezomib . No protocol -defined dose-limiting toxicities occurred , and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with st and ard doses of bortezomib , at which we observed dose-related gastrointestinal toxicity and cytopenias . Of 22 patients evaluable for response , 3 ( 14 % ) had very good partial responses , 3 ( 14 % ) had minor responses , and 10 ( 45 % ) had a period of stable disease . Electron micrographs of bone marrow plasma cells collected at baseline , after a hydroxychloroquine run-in , and after combined therapy showed therapy-associated increases in autophagic vacuoles , consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity . Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy Pre clinical studies indicate autophagy inhibition with hydroxychloroquine ( HCQ ) can augment the efficacy of DNA-damaging therapy . The primary objective of this trial was to determine the maximum tolerated dose ( MTD ) and efficacy of HCQ in combination with radiation therapy ( RT ) and temozolomide ( TMZ ) for newly diagnosed glioblastoma ( GB ) . A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection . Patients received HCQ ( 200 to 800 mg oral daily ) with RT and concurrent and adjuvant TMZ . Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles ( AVs ) in peripheral blood mononuclear cells ( P BMC ) . Population pharmacokinetic ( PK ) modeling enabled PK-pharmacodynamic correlations . Sixteen phase I subjects were evaluable for dose-limiting toxicities . At 800 mg HCQ/d , 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia , 1 with sepsis .  HCQ 600 mg/d was found to be the MTD in this combination . The phase II cohort ( n = 76 ) had a median survival of 15.6 mos with survival rates at 12 , 18 , and 24 mo of 70 % , 36 % , and 25 % . PK analysis indicated dose-proportional exposure for HCQ . Significant therapy-associated increases in AV and LC3-II were observed in P BMC and correlated with higher HCQ exposure . These data establish that autophagy inhibition is achievable with HCQ , but dose-limiting toxicity prevented escalation to higher doses of HCQ . At HCQ 600 mg/d , autophagy inhibition was not consistently achieved in patients treated with this regimen , and no significant improvement in overall survival was observed . Therefore , a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ Blocking autophagy with hydroxychloroquine ( HCQ ) augments cell death associated with alkylating chemotherapy in pre clinical models . This phase I study evaluated the maximum tolerated dose ( MTD ) , safety , preliminary activity , pharmacokinetics , and pharmacodynamics of HCQ in combination with dose-intense temozolomide ( TMZ ) in patients with advanced solid malignancies . Forty patients ( 73 % metastatic melanoma ) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m2 daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed . An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ .  Common toxicities included grade 2 fatigue ( 55 % ) , anorexia ( 28 % ) , nausea ( 48 % ) , constipation ( 20 % ) , and diarrhea ( 20 % ) . Partial responses and stable disease were observed in 3/22 ( 14 % ) and 6/22 ( 27 % ) patients with metastatic melanoma . In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response , and prolonged stable disease , respectively . A significant accumulation in autophagic vacuoles ( AV ) in peripheral blood mononuclear cells was observed in response to combined therapy . Population pharmacokinetics ( PK ) modeling , individual PK simulations , and PK-pharmacodynamics ( PD ) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation . This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable , and is associated with autophagy modulation in patients . Prolonged stable disease and responses suggest antitumor activity in melanoma patients , warranting further studies of this combination , or combinations of more potent autophagy inhibitors and chemotherapy in melanoma Introduction : This investigator-initiated study explores the safety , maximum tolerated dose , clinical response , and pharmacokinetics of hydroxychloroquine ( HCQ ) with and without erlotinib in patients with advanced non – small-cell lung cancer . Methods : Patients with prior clinical benefit from an epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor were r and omized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema . Results : Twenty-seven patients were treated , eight with HCQ ( arm A ) and 19 with HCQ plus erlotinib  ( arm B ) . EGFR mutations were detected in 74 % of the patients and 85 % had received two or more prior therapies . Arm A had no dose-limiting toxicities , but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual . In arm B , one patient each experienced grade 3 rash , nail changes , skin changes , nausea , dehydration , and neutropenia ; one had grade 4 anemia ; and one developed fatal pneumonitis , all considered unrelated to HCQ . There were no dose-limiting toxicities , therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily . One patient had a partial response to erlotinib/HCQ , for an overall response rate of 5 % ( 95 % confidence interval , 1–25 ) . This patient had an EGFR mutation and remained on therapy for 20 months . Administration of HCQ did not alter the pharmacokinetics of erlotinib . Conclusions : HCQ with or without erlotinib was safe and well tolerated . The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg Autophagy enables cells to de grade and recycle cytoplasmic material s both as a housekeeping mechanism and in response to extracellular stress such as nutrient deprivation . Recent studies indicate that autophagy also functions as a protective mechanism in response to several cancer therapy agents , making it a prospect i ve therapeutic target . Few pharmacological inhibitors suitable for testing the therapeutic potential of autophagy inhibition in vivo are known . An automated microscopy assay was used to screen > 3,500 drugs and pharmacological agents and identified one drug , verteporfin , as an inhibitor of autophagosome accumulation . Verteporfin is a benzoporphyrin derivative used in photodynamic therapy , but it inhibits autophagy without light activation . Verteporfin did not inhibit LC3/Atg8 processing or membrane recruitment in response to autophagic stimuli , but it inhibited drug- and starvation-induced autophagic degradation and the sequestration of cytoplasmic material s into autophagosomes . Transient exposure to verteporfin in starvation conditions reduced cell viability whereas cells in nutrient-rich medium were unaffected by drug treatment . Analysis of structural analogs indicated that the activity of verteporfin requires the presence of a substituted cyclohexadiene at ring A of the porphyrin core but that it can tolerate a number of large substituents at rings C and D. The existence of an autophagy inhibitor among FDA -approved drugs should facilitate the investigation of the therapeutic potential of autophagy inhibition in vivo Autophagy is a lysosomal degradation process that may act as a mechanism of survival in a variety of cancers . While pharmacologic inhibition of autophagy with hydroxychloroquine ( HCQ ) is currently being explored in human clinical trials , it has never been evaluated in canine cancers . Non-Hodgkin lymphoma ( NHL ) is one of the most prevalent tumor types in dogs and has similar pathogenesis and response to treatment as human NHL . Clinical trials in canine patients are conducted in the same way as in human patients , thus , to determine a maximum dose of HCQ that can be combined with a st and ard chemotherapy , a Phase I , single arm , dose escalation trial was conducted in dogs with spontaneous NHL presenting as patients to an academic , tertiary-care veterinary teaching hospital .  HCQ was administered daily by mouth throughout the trial , beginning 72 h prior to doxorubicin ( DOX ) , which was given intravenously on a 21-d cycle . Peripheral blood mononuclear cells and biopsies were collected before and 3 d after HCQ treatment and assessed for autophagy inhibition and HCQ concentration . A total of 30 patients were enrolled in the trial .  HCQ alone was well tolerated with only mild lethargy and gastrointestinal-related adverse events . The overall response rate ( ORR ) for dogs with lymphoma was 93.3 % , with median progression-free interval ( PFI ) of 5 mo . Pharmacokinetic analysis revealed a 100-fold increase in  HCQ  in tumors compared with plasma . There was a trend that supported therapy-induced increase in LC3-II ( the cleaved and lipi date d form of microtubule-associated protein 1 light chain 3/LC3 , which serves as a maker for autophagosomes ) and SQSTM1/p62 ( sequestosome 1 ) after treatment . The superior ORR and comparable PFI to single-agent DOX provide strong support for further evaluation via r and omized , placebo-controlled trials in canine and human NHL We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase ( HDAC ) inhibitor vorinostat ( VOR ) through a cathepsin D-mediated mechanism . We thus conducted a first-in-human study to investigate the safety , preliminary efficacy , pharmacokinetics ( PK ) , and pharmacodynamics ( PD ) of the combination of the autophagy inhibitor hydroxychloroquine ( HCQ ) and VOR in patients with advanced solid tumors . Of 27 patients treated in the study , 24 were considered fully evaluable for study assessment s and toxicity . Patients were treated orally with escalating doses of HCQ daily ( QD ) ( d 2 to 21 of a 21-d cycle ) in combination with 400 mg VOR QD ( d one to 21 ) . Treatment-related adverse events ( AE ) included grade 1 to 2 nausea , diarrhea , fatigue , weight loss , anemia , and elevated creatinine . Grade 3 fatigue and /or myelosuppression were observed in a minority of patients . Fatigue and gastrointestinal AE were dose-limiting toxicities . Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen . One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease . The addition of HCQ did not significantly impact the PK profile of VOR . Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells . Based on the safety and preliminary efficacy of this combination , additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors 
    Output:
    
Pre clinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage .