Perelman School of Medicine at the University of Pennsylvania

Amaravadi Lab

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Amphitheater (400 BC) Delos,Greece. The structure resembles an autophagolysosome degrading autophagy experts

Selected research publications

Selected Research Publications ( Complete list can be found at http://www.ncbi.nlm.nih.gov/pubmed?otool=upennlib&term=Amaravadi+RK)

Autophagy is a resistance mechanism to chemotherapy in vivo

Amaravadi, Ravi K.  Yu, Duonan.  Lum, Julian J.  Bui, Thi.  Christophorou, Maria A.  Evan, Gerard I.  Thomas-Tikhonenko, Andrei.  Thompson, Craig B.: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. Journal of Clinical Investigation 117(2): 326-36, Feb 2007.

Significance: This was one of the first papers to demonstrate autophagy promotes resistance to chemotherapy in vivo, and targeting autophagy with chloroquine enhances the efficacy of chemotherapy.

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Autophagy levels promote agressiveness and resistance to therapy in melanoma

Ma Xiao-Hong, Piao Shengfu, Wang Dan, McAfee Quentin W, Nathanson Katherine L, Lum Julian J, Li Lin Z, Amaravadi Ravi K: Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clinical Cancer Research 17(10): 3478-89, May 2011. PMCID: PMC3096713 http://www.ncbi.nlm.nih.gov/pubmed/21325076

Significance: This was the first paper to show autophagy is a resistance mechanism in melanoma

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Lys05, a dimeric chloroquine is a more potent autophagy inhibitor than HCQ

McAfee QM, Zhang Z, SamantaA, Levi S, MaXH, Piao S, Lynch J,Sepulveda AR, DavisLE, Winkler J,Amaravadi RK: The autophagy inhibitor Lys05 has single agent antitumor activity reproduces the intestinal phenotype of a genetic autophagy deficiency. Proceedings of the  National  Academy of Sciences 109(21): 8253-8, May2012. PMCID: 22566612 http://www.ncbi.nlm.nih.gov/pubmed/22566612

Significance:

First report of  dimeric chloroquine derivative that is more potent than monomeric chloroquine derivatives at autophagy inhibition. This agent had single agent antitumor activity in multiple xenografts models.

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Er stress-associated autophagy is a resistance mechanism to BRAF inhibitors in melanoma

Ma XH, Piao SF, Dey S, Mcafee Q,Karakousis G, Villaneuva J , HartLS, Levi S, Hu J, Lazova R, Klump V, Pawelek JM,Xu X, Xu W,Schuchter LM,Davies MA, Herlyn M, Winkler J,KoumenisC,Amaravadi RK.: Targeting ER stress induced-autophagy overcomes resistance to BRAF inhibition in melanomaJournal of Clinical Investigation .124(3):1406-17PMID:24569374 PMCID:PMC3934165 http://www.ncbi.nlm.nih.gov/pubmed/24569374

 

Significance:

Autophagy levels were increased in tumors that had grown resistant to BRAF inhibtors in patients. In sensitive and resistant cell lines, BRAF inhibitors, and the combination of BRAF and MEK inhibition induce cytoprotective autophagy through the engagment of the ER stress response.  Drug dependent engagement of mutant BRAF and the ER stress gatekeeper GRP78 was the mechanism by which ER stress is activated. Inhibition of autophagy enhanced the efficacy of BRAF inhibition in a BRAF inhibitor resistant mouse model of melanoma.

 

 

 

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Autophagy-dependent secreted proteins provide a snapshot of intratumoral autophagy dynamics

Identification of secreted proteins that reflect autophagy dynamics within tumor cells.Kraya AA1, Piao S, Xu X, Zhang G, Herlyn M, Gimotty P, Levine B, Amaravadi RK, Speicher DW.Autophagy 2015;11(1):60-74 PMID:25484078 PMCID:PMC4502670 http://www.ncbi.nlm.nih.gov/pubmed/25484078

Significance: Comparison of the secretomes by unsupervised label free proteomics from three dimensional spheroids generated from a pair of isogenic melanoma cell lines with either high versus low autophagy levels identified a subset of inflammatory cytokines that were secreted in an autophagy dependent manner. These candidate biomarkers of intratumoral autophagy dynamics were elevated in the serum of patients with high levels of autophagy in their tumors.

 

 

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First Clinical Trials of HCQ in cancer patients

  • Rosenfeld MR, Supko JG, Grossman SA, Brem S, Mikkelson T,  Wang D,  Chang C, Hu J, McAfee Q, Troxel A, Piao S, Hetjian D, Tan KS, Pontiggia L, O’Dwyer PJ, Davis LE, Amaravadi RK.  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; Aug;10(8):1359-68 PMID: 24991840 PMCID: PMC4203513
  • Rangwala R, Chang C,  Hu J, Algazy K, Evans T, Fecher L, Schuchter LM, Torigian D, Troxel A, Tan KS, Hetjian DF,  Demichele A, Vaughn D, Redlinger M,  Alavi A, Kaiser J, Pontiggia L, Davis LE, O'Dwyer PJ, Amaravadi RK.  Combined mTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma  Autophagy 2014; 10 (8). Aug;10(8):1391-402 PMID: 24991838 PMCID: PMC4203516
  • Rangwala R, Leone R, Chang YC, Fecher L, Schuchter L, Kramer A, Tan KS, Heitjan DF, Rodgers G, Gallagher M, Piao S, Troxel A, Evans T, Demichele A, Nathanson KL, O'Dwyer PJ, Kaiser J, Pontiggia L, Davis LE, Amaravadi RK.: Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma   Autophagy 10(8), August 2014.PMID: 24991839 PMCID: PMC4203514
  • Vogl DT, Stadtmauer EA, Heitjan DF, Tan KS, Rangwala R, Piao S, Chang C, Scott EC, Paul TM, Nichols CW, Porter DL, Kaplan J, Mallon G, Bradner JE, Davis LE, Pontiggia L, Amaravadi RK.  Combined autophagy and proteasome inhibition: Phase I trial of hydroxychloroquine with bortezomib in patients with relapsed refractory multiple myeloma. Autophagy 2014; Aug;10(8):1380-90 PMID: 24991834  PMCID: MC4203515

The PDFs can be found here:

 http://www.ncbi.nlm.nih.gov/pubmed/24991834

http://www.ncbi.nlm.nih.gov/pubmed/24991840

http://www.ncbi.nlm.nih.gov/pubmed/24991838

http://www.ncbi.nlm.nih.gov/pubmed/24991836

http://www.ncbi.nlm.nih.gov/pubmed/24991835

http://www.ncbi.nlm.nih.gov/pubmed/24991839

Significance: Six phase I/II trials were performed in human patients diagnosed with glioblastoma multiforme, relapsed/refractory myeloma , and melanoma in addition to other advanced tumors. One additional clinical trial was published wherein pet dogs diagnosed with spontaneously occurring lymphoma were also treated with HCQ-based combination therapies. Each trial involved a combination therapy that had preclinical studies to justify clinical translation. The major finding from these trials is that, based on electron microscopy-based pharmacodynamic assays, autophagy can be modulated therapeutically with chloroquine derivatives. Remarkably, across all of the trials <10% of patients had severe non-hematological toxicity. Specifically, there was no evidence of extensive metabolic toxicity, liver injury or neurologic impairment in these trials despite some evidence that chronic modulation of autophagy was achieved in patients, as seen by accumulation of autophagic vesicles in peripheral blood mononuclear cells and tumor cells. When combined with radiation therapy and concurrent and adjuvant temozolomide, HCQ produced dose-limiting myelosuppression at doses above 600 mg HCQ. At these doses only a subset of patients had evidence of autophagy modulation detectable in their peripheral blood mononuclear cells (PBMC), which may be one reason there was no significant improvement in overall survival compared to historical controls of temozolomide and radiation alone. Significant therapy-associated increases in AVs and LC3-II were observed in PBMCs in a concentration-dependent manner, demonstrating HCQ could modulate autophagy in vivo. Combined treatment with the proteasome inhibitor bortezomib and HCQ resulted in a greater perturbation of tumor cell autophagy compared to PBMC autophagy, arguing HCQ may selectively accumulate in tumor cells. Similar results were observed in the phase I trial of vorinostat and HCQ and in the canine lymphoma trial using doxorubicin with HCQ. Although these phase I studies were not powered to determine efficacy, response rates in unselected patient populations were generally low. However, there were a number of striking responses and prolonged stable disease observed in patients with melanoma, renal cell carcinoma, colon cancer and myeloma, that suggest a specific subset of cancers may be susceptible to regimens containing chloroquine-based autophagy inhibitors.

 

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Reviews

  • Amaravadi RK, Thompson CB.: The survival kinases Akt and Pim as potential therapeutic targets.  Journal of Clinical Investigation 115(10): 2618, 2005
  • Amaravadi RK, Thompson CB: The roles of therapy-induced autophagy and necrosis in cancer treatment. Clinical Cancer Research 13(24): 7271-9, Dec 15 2007
  • Amaravadi RK, Lippincott-Schwartz J,Yin XM, Weiss WA, Takebe N,Timmer W,  DiPaola RS, Lotze M,  White E. Principles and Current Strategies for Targeting Autophagy for Cancer Treatment. Clinical Cancer Research 2011 Feb 15;17(4):654-666 PMID: 21325294 PMCID: PMC3075808
  • Robert Leone, Ravi Amaravadi : Autophagy: a targetable linchpin of cancer cell metabolism. Trends in Endocrinology and Metabolism  Cell Press,(4), 209-17, Apr 24 2013.
  • Rebecca VW, Amaravadi RK : Emerging Strategies to effectively target autophagy in cancer  Oncogene. Apr 20. doi: 10.1038/onc.2015.99. [Epub ahead of print] PMID:25893285

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Commentaries

  • Amaravadi, Ravi K.: Autophagy-induced tumor dormancy in ovarian cancer. Journal of Clinical Investigation 118(12): 3837-40, Dec 2008. PMCID: PMC2582935
  • Amaravadi RK. Autophagy in tumor immunity, Science 334(6062): 1501-2 2011 Dec 16PMID:22174234 PMC n/a
  • Amaravadi RK, Debnath J : Mouse models address key concerns about autophagy inhibition for cancer therapy  Cancer Discovery  4(8): 873-5, August  2014
  • Amaravadi RK. Transcriptional regulation of autophagy in Ras-driven cancers. J. Clin Investigation.  2015 Apr 1;125(4):1393-5. doi: 10.1172/JCI81504. Epub 2015 Mar 23.PMID:25798614

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