The Amaravadi Lab focuses on the role of autophagy in cancer therapy. Cancer therapy has made major strides in the past 20 years, but eventually most cancers have the ability to survive the stress of cancer therapy and recur, leading to suffering and death. We and others have demonstrated that autophagy, the process by which organelles such as mitochondria and proteins are internally digested and recycled, promotes cancer cell survival in advanced cancers, and is a potentially key resistance mechanism that cancers use to survive cancer therapy. Our lab collaborates closely with other basic scientists, clinical researchers, biotechnology and pharmaceutical companies so that we can test our hypotheses in cell lines, 3D culture, mouse models, and patients. We conduct basic laboratory research to understand fundamental aspects of autophagy in cancer biology, but we also have a translational focus. We are actively conducting innovative clinical trials intended to modulate autophagy to enhance effectiveness of existing therapies. Our funding comes largely from the National Cancer Institute, focused pharmaceutical collaborations, and private donations from patients and fundraising programs.
Can more potent and specific autophagy inhibitors be identified?
Working with the laboratory of Dr. Jeffrey Winkler (Merriam Professor of Organic Chemistry Department of Chemistry, School of the Arts and Sciences University of Pennsylvania) we have designed, synthesized and tested the first series of dimeric chloroquine derivatives. We call these compounds Lys01 derivatives (see Mcafee et al PNAS 2012). We have now identified dozens of potent derivatives and are using these new compounds to gain a better understanding of the molecular target of chloroquine derivatives. In parallel we are working with Presage Biosciences to develop clinical leads that can be tested in clinical trials.
Can we find the cancers and patient most likely to benefit from lysosomal autophagy inhibition?
Using genomic profiling methods we are investigating genetic and epigenetic determinants of sensitivity to chloroquine derivatives in a broad panel of tumor cell lines and patient tissues. This work is in collaboration with investigators from the the Abramson Family Cancer Research Institute and the Center for Clinical Epidemiology and Biostatistics.
Can proteins that are secreted in an autophagy dependent manner be used to develop bioamarkers of response to autophagy inhibitors?
Working with laboratory of Dr. David Speicher (Caspar Wistar Professor of Computational and Systems Biology, Wistar Institute), we have probed the secretome of melanoma cells grown in 3D culture and have identified autophagy dependent secreted proteins (Kraya et al Autophagy 2015). We are currently determining of effects of therapeutics that are known to modulate autophagy on secretome profiles. We are working on both small molecule targeted therapeutics and immunotherapies in imunocompetent mouse models.
How exactly does targeted therapy activate a cytoprotective autophagy response?
Working with the laboratory of Dr. Costas Koumenis ( Associate Professor and Vice Chair for Research Department of Radiation Oncology, University of Pennsylvania) we previously determined that BRAF inhibitors activate cytoprotective autophagy through an ER stress response( Ma et al JCI 2014). We are now probing the molecular mechanisms of this new pathway of resistance. Specifically we are leveraging our access to patient derived xenografts from patients that have progressed on BRAF inhibitors to determine the molecular underpinnings of the MAPK-ER stress-autophagy signaling. We anticipate we will uncover potential new combination therapies for BRAF mutant melanoma and other BRAF mutant cancers.
Can hydroxychloroquine (HCQ) improve the efficacy of currently available standard of care therapies in cancer?
In collaboration with dozens of investigators in the United States and abroad, we have completed the first 6 clinical trials involving HCQ in combination with a variety of anticancer therapeutics in diseases such as advanced glioma, refractory myeloma, advanced melanoma, and advanced solid tumors (see Publications for details). We currently have a second generation of HCQ clinical trials in colon cancer, renal cell carcinoma, melanoma, and pancreatic cancer. See Clinical Trials for more details about ongoing clinical trials.
Rani Ojha, PhD will be joining the Amaravadi Lab as a Post-Doctoral Fellow in the Fall of 2015. She completed in a PhD in Cell Biology from the Post Graduate Institute of Medical Education and Research Chandigarh, India.
Her thesis was focused on the role of autophagy as a resistance mechanism to therapeutics in urothelial cancer. Her work has resulted in a number of publications and recieved the Amir Chand Gold Medal award for best publication in translational research.