This proposal describes a 5-year plan to develop an independent clinician-scientist focused on the pharmacological manipulation of cancer cell metabolism to improve therapeutic responses. This project will be co-mentored by Dr. Craig Thompson, Director, Abramson Cancer Center, and Dr. Peter O'Dwyer, Director, Developmental Therapeutics at the University of Pennsylvania. Both mentors have an established record of successfully mentoring clinician-scientists to highly productive research careers in oncology. This award will allow Dr. Amaravadi to obtain didactic training in biostatistics, molecular techniques, and pharmacokinetic modeling. It will also provide protected time for mentored training that will enable the candidate to conduct a series of clinical trials and laboratory investigations. These studies are designed to elucidate the role of targetable components of cancer cell metabolism as critical determinants of therapeutic outcomes. An important problem for cancer care is that therapies developed on the basis of their ability to induce apoptosis are often ineffective for malignancies with defective apoptosis. Two non-apoptotic responses to cancer therapy are necrosis and autophagy. The fundamental characteristics of cancer cell metabolism provide the basis for why cancer cells preferentially undergo these processes in response to systemic therapy. This project is designed to establish the clinical significance of necrosis and autophagy in patients undergoing therapy through the completion of two specific aims 1) To correlate measurements of necrosis, apoptosis and autophagy to clinical outcomes in patients undergoing cancer therapy, and 2) To determine the antitumor activity of chloroquine as an inhibitor of autophagy. The first specific aim will be addressed by applying a serum ELISA, immunohistochemical, and EM methods to blood and tissue samples from patients enrolled on clinical trials for advanced melanoma.
The second aim will be the completion of the preclinical evaluation of hydroxychloroquine using xenograft tumor models followed by Phase I and Phase II clinical trials of hydroxychloroquine in patients with refractory malignancies. Multidisciplinary training during this award will allow Dr. Amaravadi to independently contribute to rational drug development, an important component of the NCI's initiative to incorporate state-of-the-art cancer treatments into clinical practice. ? ? ?
|Kraya, Adam A; Piao, Shengfu; Xu, Xiaowei et al. (2015) Identification of secreted proteins that reflect autophagy dynamics within tumor cells. Autophagy 11:60-74|
|Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice et al. (2014) Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10:1391-402|
|Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See et al. (2014) Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 10:1380-90|
|Ma, Xiao-Hong; Piao, Sheng-Fu; Dey, Souvik et al. (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124:1406-17|
|Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C et al. (2014) Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10:1369-79|
|Barnard, Rebecca A; Wittenburg, Luke A; Amaravadi, Ravi K et al. (2014) Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 10:1415-25|
|Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G et al. (2014) 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 10:1359-68|
|O'Connell, Michael P; Marchbank, Katie; Webster, Marie R et al. (2013) Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov 3:1378-93|
|Amaravadi, Ravi K (2013) PUMA: a puzzle piece in chloroquine's antimelanoma activity. J Invest Dermatol 133:2133-5|
|Leone, Robert D; Amaravadi, Ravi K (2013) Autophagy: a targetable linchpin of cancer cell metabolism. Trends Endocrinol Metab 24:209-17|
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