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Dr. Evripidis Gavathiotis: Developing Medicines for Cancer and Aging-related Diseases

Dr. Gavathiotis is a Professor of Biochemistry and Medicine at Albert Einstein College of Medicine and Co-Leader of Cancer Therapeutics at Montefiore Einstein Cancer Center. He is also a member of the Institute for Aging Research and the Wilf Cardiovascular Research Institute at Montefiore Einstein.

The National Herald: Tell us about yourself.

Evripidis Gavathiotis: I was born and grew up in Athens, Greece, and earned my BSc in chemistry from the University of Crete. Then I moved to the UK and completed my PhD in biological chemistry at the University of Nottingham. I came to the United States in 2003 to pursue postdoctoral research training in structural biology at Rockefeller University in New York City and then to train in cancer chemical biology at Dana Farber Cancer Institute and Harvard Medical School in Boston. I returned to New York City as faculty of the Albert Einstein College of Medicine in 2011.

My overall goal is to understand how life-and-death decision-making proteins function and go awry in disease and to develop strategies to bring novel therapeutics to patients. My research focuses on applying innovative approaches to understand proteins that regulate cell death and cell survival mechanisms in cells but are dysregulated in cancer and other diseases. We use this knowledge to discover and develop new prototype therapeutics that restore the protein regulation in cells and kill cancer cells. In some cases, we aim to prevent the dysregulation of cells to extend cellular health.

My lab has made significant progress, and we have developed prototype therapeutics with the potential to treat various cancers and aging-associated diseases. These novel therapeutics are currently developed in collaboration with other scientists, clinicians, and biopharmaceutical companies to bring them to clinical trials to benefit patients.

Dr. Evripidis Gavathiotis with his postdoctoral trainee, Dr. Emmanouil Zacharioudakis, who received the 2022 Denis Shields Prize for outstanding postdoctoral research. (Photo Courtesy of Dr. Evripidis Gavathiotis)

TNH: Can you tell us about your research on cell death and protein BAX?

EG: A significant part of my research focuses on the physiological mechanism of cell death and how this is dysregulated in cancer cells and normal cells. More specifically, I have been studying a protein called BAX, which has a killer activity in cells and plays a critical role in determining whether the cell will die or survive. Cancer cells find ways to keep the BAX protein suppressed to survive and continue proliferating. Several years ago, my research led me to identify how BAX is regulated and discovered a switch to turn on and off the activity of BAX. Using this information, I have designed a drug to turn on the activity of BAX and cause cancer cells to die while sparing healthy cells. We have developed a targeted therapeutic and tested it in mouse models that developed various cancers such as AML leukemia, DLBC lymphoma, colorectal, pancreatic, and non-small cell lung cancers. We found that the drug has very promising efficacy, and we are now eager to bring this new therapy to cancer patients.

Furthermore, we have also understood how to shut off the activity of BAX and realized that we could use this information to avoid unnecessary cell death caused by BAX in neuronal and cardiac cells in neurodegeneration and heart diseases, respectively. With this information, we have developed another therapeutic that prevents cell death activity of BAX and used it in mice to prevent cardiomyopathy and thrombocytopenia that are induced by chemotherapeutic drugs as a side effect. We are very excited about this therapeutic strategy as well, and we are currently testing it in other diseases, as it could have a significant impact on various diseases associated with the death of vital cells.

Dr. Evripidis Gavathiotis in his laboratory at Albert Einstein College of Medicine, who has made a career out of studying proteins at the borderline of life and death and finding new prototype therapeutics to treat cancer and other aging-related diseases. (Photo Courtesy of Dr. Evripidis Gavathiotis)

TNH: Tell us about your research on autophagy.

EG: Autophagy is the process in our cells that recycles unwanted or dysfunctional proteins and organelles. It protects our cells from malfunctioning proteins and organelles and recycles them into nutrients to preserve healthy cellular function and our healthy aging. However, when autophagy is dysregulated, it can play an important role in the development of various aging-associated diseases and cancer as well. Our research has identified key proteins that regulate a selective mechanism of autophagy named chaperone-mediated autophagy. Based on this, we have developed small molecules that can turn on or off autophagy. We are currently developing these small molecules in models of lung cancer and AML leukemia where autophagy is highly active, and we aim to turn it off and lead cancer cells to their death.  Moreover, we have recently applied the small molecules that turn on autophagy in mouse models of Alzheimer’s disease and have shown that keeping the levels of autophagy at high levels can protect mice from symptoms of memory loss, depression, anxiety, walking ability, and reduction of relevant biomarkers that cause toxicity and neuronal cell loss. This novel therapeutic strategy has shown promising results in other neurodegenerative disease models and an overall increase in health span.

TNH: You won the Einstein Inaugural Therapeutics Venture & Pitch Competition, an amazing accomplishment. What work is involved in getting there?

EG: This prize was awarded for the best proposal with commercial interest for the development of a novel therapeutic strategy that has promising potential for the treatment of cancer. My proposal was considered worthy of investment and further development. It was awarded by New York City venture capital investment groups that found our project highly promising for further development into a therapeutic and establishing start-up company. It is often necessary that the translation of our discoveries in the lab into treatments that benefit patients requires investments and partnerships like this. The work awarded concerns an oncogenic gene whose mutations and alterations have been implicated in various cancers, including melanoma, colorectal, lung, thyroid, and pancreatic cancers. This oncogenic gene produces an enzyme named BRAF, which is critical in controlling the proliferation of many cancers. We have studied this protein and identified how it forms dimers, two BRAF molecules interacting together, and how they can be effectively inhibited. We have developed a new drug showing promising activity and selectivity for inhibiting BRAF and suppressing the growth of melanoma, colorectal, and non-small cell lung cancer cells. Additionally, our patented technology provides a framework to develop inhibitors for a range of solid tumors and blood cancers that do not respond or that develop resistance to existing FDA-approved cancer treatments.

Dr. Evripidis Gavathiotis with his team at Albert Einstein College of Medicine, from right to left: Emmanouil Zacharioudakis, Oi Wei Mak, Mericka McCabe, Nadege Gitego, Joanna Luo, Evangelia Matenoglou, Rajanya Bhattacharyya, Francisco Marques, Vladlena Kharchenko, Yazen Lehmeidi. (Photo Courtesy of Dr. Evripidis Gavathiotis)

TNH: What are you and your team developing now?

EG: Our lab constantly considers different mechanisms and proteins that become dysfunctional and causes vulnerable cells to succumb 0to stress or uncontrolled proliferation. We have recently explored other life-and-death decision-making proteins in healthy and malignant cells. We have also made significant progress with understanding a pair of similar proteins named mitofusins, which are responsible for regulating mitochondria – the energy powerhouse of our cells. Mitofusins enable mitochondria to fuse when the cell needs more energy to stay healthy or can cause the fragmentation and degradation of mitochondria when mitochondria appear dysfunctional. We have recently identified drugs that can activate or inhibit mitofusins and, subsequently, mitochondria in providing energy and necessary functions in the cell. This discovery has significant potential to treat mitofusin dysfunction-related diseases such as cancer, neurodegeneration, type 2 diabetes, and rare mitochondrial and neurological diseases. We have demonstrated recently how mitofusin inhibitors can have an important activity in cancer cells and we foresee that mitofusin-targeting therapeutics would be an important addition to the armamentarium for patients to combat various cancers and other diseases.

Dr. Evripidis Gavathiotis receiving the Einstein Inaugural Therapeutics Venture & Pitch Competition Award with lab members, from left to right: Francisco Marques, Rajanya Bhattacharyya, Nadege Gitego, Evangelia Matenoglou. (Photo Courtesy of Dr. Evripidis Gavathiotis)
Dr. Evripidis Gavathiotis in his laboratory at Albert Einstein College of Medicine, who has made a career out of studying proteins at the borderline of life and death and finding new prototype therapeutics to treat cancer and other aging-related diseases. (Photo Courtesy of Dr. Evripidis Gavathiotis)

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