Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

Autophagy

Volumn 10, Issue 8, 2014, Pages 1391-1402

  Rangwala, Reshma ^a,f   Chang, Yunyoung C ^a,g   Hu, Janice ^a   Algazy, Kenneth M ^a   Evans, Tracey L ^a   Fecher, Leslie A ^a,h   Schuchter, Lynn M ^a   Torigian, Drew A ^b   Panosian, Jeffrey T ^b   Troxel, Andrea B ^c   Tan, Kay See ^c   Heitjan, Daniel F ^c   DeMichele, Angela M ^a   Vaughn, David J ^a   Redlinger, Maryann ^a   Alavi, Abass ^b   Kaiser, Jonathon ^d   Pontiggia, Laura ^e   Davis, Lisa E ^a,d   O'Dwyer, Peter J ^a   Amaravadi, Ravi K ^a   more..

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

^d UNIVERSITY OF THE SCIENCES   (United States)

^e UNIVERSITY OF THE SCIENCES   (United States)

^f MERCK RESEARCH LABORATORIES   (United States)

^g BOSTON UNIVERSITY   (United States)

^h INDIANA UNIVERSITY   (United States)

Author keywords

Autophagy; Clinical trial; Hydroxychloroquine; Melanoma; MTOR

Indexed keywords

ANTIBIOTIC AGENT; DIPHENHYDRAMINE; FLUORODEOXYGLUCOSE F 18; HYDROXYCHLOROQUINE; IPILIMUMAB; LACTATE DEHYDROGENASE; METFORMIN; TEMSIROLIMUS; ANTINEOPLASTIC AGENT; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE;

ADD ON THERAPY; ADULT; ADVANCED CANCER; AGED; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ANUS FISSURE; AREA UNDER THE CURVE; ARTICLE; ASPIRATION; AUTOPHAGY; BLOOD; BODY WEIGHT DISORDER; CANCER COMBINATION CHEMOTHERAPY; CANCER PROGNOSIS; CANCER SURVIVAL; CEREBROVASCULAR ACCIDENT; CHEMOTHERAPY INDUCED ANEMIA; CHOLANGITIS; CLINICAL ARTICLE; COMPUTER ASSISTED TOMOGRAPHY; CONSTIPATION; CREATININE BLOOD LEVEL; DIARRHEA; DIZZINESS; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG ERUPTION; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERANCE; DYSGEUSIA; ELECTRON MICROSCOPY; EVENING DOSAGE; FATIGUE; FEMALE; GALLBLADDER METASTASIS; GALLBLADDER TUMOR; HEAD AND NECK CANCER; HEMATURIA; HUMAN; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; LUNG DISEASE; LYMPHOCYTOPENIA; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MEDICAL HISTORY; METABOLIC STRESS; METASTATIC MELANOMA; MORNING DOSAGE; MULTIPLE CYCLE TREATMENT; ORAL DRUG ADMINISTRATION; OUTCOME ASSESSMENT; PATIENT; PATIENT PREFERENCE; PERIPHERAL BLOOD MONONUCLEAR CELL; PERIRECTAL ABSCESS; PET-CT SCANNER; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; PNEUMONIA; POSITRON EMISSION TOMOGRAPHY; PROGRESSION FREE SURVIVAL; PROSTATE CANCER; PULMONARY TUMOR ABSCESS; RECTUM DISEASE; SEPSIS; SIDE EFFECT; SINGLE DRUG DOSE; SOLID TUMOR; STOMATITIS; THROMBOCYTOPENIA; TREATMENT DURATION; TUMOR BIOPSY; TUMOR REGRESSION; TUMOR VOLUME; UVEA MELANOMA; VITILIGO; WEIGHT REDUCTION; WOUND HEALING; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CELL VACUOLE; CLINICAL TRIAL; DIAGNOSTIC USE; DOSE RESPONSE; DRUG EFFECTS; MELANOMA; METABOLISM; MIDDLE AGED; NEOPLASMS; PATHOLOGY; TREATMENT OUTCOME; ULTRASTRUCTURE;

ADULT; AGED; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; AUTOPHAGY; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; FLUORODEOXYGLUCOSE F18; HUMANS; HYDROXYCHLOROQUINE; MALE; MELANOMA; MIDDLE AGED; NEOPLASM STAGING; NEOPLASMS; POSITRON-EMISSION TOMOGRAPHY; PROTEIN KINASE INHIBITORS; SIROLIMUS; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME; VACUOLES;

EID: 84905826525     PISSN: 15548627     EISSN: 15548635     Source Type: Journal    
DOI: 10.4161/auto.29119     Document Type: Article

References (30)

1. Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012; 11:709-30; PMID:22935804; http://dx.doi.org/10.1038/nrd3802
2. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12:401-10; PMID:22534666; http://dx.doi.org/10. 1038/nrc3262
3. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT, White E. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011; 17:654-66; PMID:21325294; http://dx.doi.org/10.1158/1078-0432.CCR-10-2634
4. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009; 20:1992-2003; PMID:19225151; http://dx.doi.org/10.1091/mbc. E08-12-1249
5. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149:274-93; PMID:22500797; http://dx.doi.org/10.1016/j.cell.2012.03. 017
6. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 2011; 10:868-80; PMID:22037041; http://dx.doi.org/10.1038/nrd3531
7. Xie X, White EP, Mehnert JM. Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One 2013; 8:e55096; PMID:23383069; http://dx.doi.org/10.1371/journal.pone.0055096
8. Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, Chen J, Chen HY, Ghavami A, Stein M, DiPaola RS, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One 2012; 7:e41831; PMID:22848625; http://dx.doi.org/10.1371/journal.pone.0041831
9. Bukowski RM. Temsirolimus: a safety and efficacy review. Expert Opin Drug Saf 2012; 11:861-79; PMID:22861825; http://dx.doi.org/10.1517/14740338.2012. 713344
10. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, et al.; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271-81; PMID:17538086; http://dx.doi.org/10.1056/NEJMoa066838
11. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205-16; PMID:10655437; http://dx.doi.org/10.1093/jnci/92.3.205
12. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10:51-64; PMID:16843265; http://dx.doi.org/10.1016/j.ccr.2006.06.001
13. Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog 2012; 17:69-95; PMID:22471665; http://dx.doi.org/10.1615/CritRevOncog.v17.i1.60
14. Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A, Tan KS, Heitjan DF, Rodgers G, Gallagher M, et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 2014; 10:1369-79; PMID:24991839; http://dx.doi.org/10.4161/ auto.29118
15. Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, Rangwala R, Piao S, Chang YC, Scott EC, et al. Combined autophagy and proteasome inhibition: A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 2014; 10:1380-90; PMID:24991834; http://dx.doi.org/10.4161/auto.29264
16. Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, Wang D, Chang YC, Hu J, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014; 10:1359-68; PMID:24991840; http://dx.doi.org/10.4161/auto.28984
17. Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi RK, Davis LE, Mita AC, Curiel TJ, Espitia CM, Nawrocki ST, et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014; 10:1403-14; PMID:24991835; http://dx.doi.org/10.4161/auto.29231
18. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, Lynch JP, Uehara T, Sepulveda AR, Davis LE, et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci U S A 2012; 109:8253-8; PMID:22566612; http://dx.doi.org/10.1073/pnas.1118193109
19. Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH. Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 2014; 10:1415-25; PMID:24991836; http://dx.doi.org/10.4161/auto.29165
20. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 2005; 104:1045-8; PMID:16007689; http://dx.doi.org/10.1002/cncr.21265
21. Davies MA, Fox PS, Papadopoulos NE, Bedikian AY, Hwu WJ, Lazar AJ, Prieto VG, Culotta KS, Madden TL, Xu Q, et al. Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res 2012; 18:1120-8; PMID:22223528; http://dx.doi.org/10.1158/1078-0432.CCR-11-2436
22. Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010; 3:ra81; PMID:21062993; http://dx.doi.org/10.1126/scisignal.2001017
23. Mirzoeva OK, Hann B, Hom YK, Debnath J, Aftab D, Shokat K, Korn WM. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J Mol Med (Berl) 2011; 89:877-89; PMID:21678117; http://dx.doi.org/10.1007/s00109-011-0774-y
24. Lin Y, Shih WJ. Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials. Biostatistics 2001; 2:203-15; PMID:12933550; http://dx.doi.org/10.1093/biostatistics/2.2.203
25. Munster T, Gibbs JP, Shen D, Baethge BA, Botstein GR, Caldwell J, Dietz F, Ettlinger R, Golden HE, Lindsley H, et al. Hydroxychloroquine concentra-tion- response relationships in patients with rheumatoid arthritis. Arthritis Rheum 2002; 46:1460-9; PMID:12115175; http://dx.doi.org/10.1002/art.10307
26. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117:326-36; PMID:17235397; http://dx.doi.org/10.1172/JCI28833
27. Torigian DA, Lopez RF, Alapati S, Bodapati G, Hofheinz F, van den Hoff J, Saboury B, Alavi A. Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT. Hell J Nucl Med 2011; 14:8-14; PMID:21512658
28. Hofheinz F, Pötzsch C, Oehme L, Beuthien-Baumann B, Steinbach J, Kotzerke J, van den Hoff J. Automatic volume delineation in oncological PET. Evaluation of a dedicated software tool and comparison with manual delineation in clinical data sets. Nuklearmedizin 2012; 51:9-16; PMID:22027997; http://dx.doi.org/10.3413/Nukmed-0419-11-07
29. Kwee TC, Torigian DA, Alavi A. Overview of positron emission tomography, hybrid positron emission tomography instrumentation, and positron emission tomography quantification. J Thorac Imaging 2013; 28:4-10; PMID:23249967; http://dx.doi.org/10.1097/RTI.0b013e31827882d9
30. Oh JR, Seo JH, Chong A, Min JJ, Song HC, Kim YC, Bom HS. Whole-body metabolic tumour volume of 18F-FDG PET/CT improves the prediction of prognosis in small cell lung cancer. Eur J Nucl Med Mol Imaging 2012; 39:925-35; PMID:22270509; http://dx.doi.org/10.1007/s00259-011-2059-7