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The Distinguished Seminar Series lectures below are held on Wednesdays, 9¨C10:30 a.m. in 4SCR1.1110.

John A. Benvenuto, Ph.D.

Born in Detroit, Michigan, on January 30, 1944, John A. Benvenuto received a bachelor of science degree in chemistry from Wayne State University. He went on to attend West Virginia University in Morgantown, West Virginia, earning a master of science degree and a doctor of philosophy degree, both in chemistry. Dr. Benvenuto joined MD Anderson Cancer Center in 1973 and received postgraduate training in medicinal chemistry and pharmacology in the Department of Developmental Therapeutics under Ti Li Loo, D.Phil., D.Sc. In 1975, he became a member of the MD Anderson faculty. Additionally, he was a faculty member of Â鶹ӳ»­ Graduate School of Biomedical Sciences in Houston.

Widely recognized in the scientific community for his expertise in clinical and biochemical pharmacology, Dr. Benvenuto published extensively on the mechanism of action of anticancer drugs. He was a member of the American Chemical Society, the American Association of Cancer Research, the American Society of Pharmacology and Experimental Therapeutics, the American Association for the Advancement of Science, the World Health Organization International Agency for Research on Cancer, Alpha Chi Sigma and Sigma Xi.

In 1986, Dr. Benvenuto learned he was afflicted with a metastatic carcinoid tumor. Through the efforts of staff at MD Anderson and his own indomitable spirit, Dr. Benvenuto made a miraculous recovery and returned to work in 1987. He continued to work full time until his
death on December 22, 1996 ¡ª nearly 10 years later. Often in pain and discomfort as he battled systemic cancer in the last years of his life, Dr. Benvenuto never complained. Indeed, his major concern was for the welfare of his friends and colleagues. A man of great dignity and personal warmth, Dr. Benvenuto left a lasting impression on all who knew him; his tremendous courage and unwavering optimism are an inspiration. Dr. Benvenuto¡¯s family and friends designed this lectureship as a tribute to perpetuate his memory.

PROTACs and Targeted Protein Degradation: A New Therapeutic Modality

Great strides have been made in identifying disease-causing proteins that should be targeted pharmaceutically. However, more than 70% of the proteome is not currently pharmaceutically vulnerable due to the lack of an inhibitor binding pocket. Fortunately, current clinical trials are demonstrating the potential of PROTACs as a novel therapeutic modality, which will hopefully expand the oncology Drug Target Space in the coming years.

Craig M. Crews, Ph.D.

Dr. Craig Crews is the John C. Malone Professor of MCDB and professor of Chemistry and Pharmacology at Yale University. He graduated from the University of Virginia with a B.A. in Chemistry and received his Ph.D. from Harvard University in Biochemistry. On the faculty at Yale since 1995, his laboratory has developed the use of small molecules to control intracellular protein levels. In 2003, he co-founded Proteolix, Inc., whose proteasome inhibitor, Kyprolis? received FDA approval for the treatment of multiple myeloma. The Crews¡¯ lab is also credited with founding the field of ¡®Targeted Protein Degradation¡¯ drug development technology, i.e., PROTACs, which has the potential to target currently ¡®undruggable¡¯ disease causing proteins. In 2013, Dr. Crews launched the New Haven-based biotech venture, Arvinas, Inc., which is testing the first PROTACbased drugs in clinical trials for prostate and breast cancer. Since then he had founded two additional biopharmas, Halda Therapeutics and Siduma Therapeutics. Dr. Crews has received numerous awards and honors, including the Ehrlich Award for Medicinal Chemistry (2014), a NIH R35 Outstanding Investigator Award (2015), the AACR Award for Outstanding Achievement in Chemistry in Cancer Research (2017), the Khorana Prize from the Royal Society of Chemistry (2018), the Pierre Fabre Award for Therapeutic Innovation (2018), the Pharmacia-ASPET Award for Experimental Therapeutics (2019), the Heinrich Wieland Prize (2020), the Scheele Prize (2021), an honorary doctoral degree from the Technische Universit?t Dortmund, Germany (doctor rerum naturalium honoris causa) (2021), the Connecticut Medal of Technology (2022), the inaugural Bristol Myers Squibb Award in Enzyme Chemistry (2023), the Gabbay Prize (2023), the Kimberly Prize (2024) and the IUPAC-Richter Prize (2024).

Tumor Plasticity

The presentation will address novel mechanisms of mitochondrial reprogramming in cancer associated with increased adaptation to cellular stress pathways, improved survival advantage, and greater cell motility and invasion, conferring heightened metastatic potential, in vivo.

Dario C. Altieri, M.D.

Dr. Dario C. Altieri is President, CEO and Director of the NCI-designated Ellen and Ronald Caplan Cancer Center at The Wistar Institute in Philadelphia. Born in Milan, Italy, and educated at the University of Milan School of Medicine, Altieri is a physician-scientist trained in internal medicine and holds a postgraduate degree in clinical and experimental hematology. In 1987, he joined the Scripps Clinic and Research Foundation in La Jolla, California, first as a research fellow and later as a faculty member. In 1994, Altieri became an associate professor at the Boyer Center for Molecular Medicine at Yale University School of Medicine, where he was named professor with tenure in 1999 and a member of the Yale Cancer Center executive committee. In 2002, Altieri became the founding chair of the Department of Cancer Biology at the University of Massachusetts Medical School and Director of the UMass Memorial Cancer Center. Altieri joined the Institute as the Wistar Cancer Center Director and its first Chief Scientific Officer in September 2010.

Altieri is interested in how mechanisms of cellular adaptation or ¡°plasticity¡± are universally exploited in cancer for disease maintenance and progression. A detailed, molecular, cellular, and genetic understanding of tumor plasticity could uncover new therapeutic targets and identify novel approaches to interfere with metastatic competence, which remains the primary cause of death for cancer patients. The Altieri laboratory studies the role of mitochondria in cancer. The lab pursues the overarching hypothesis that multiple mitochondrial functions in bioenergetics, buffering of reactive oxidative species (ROS), interorganelle communication with the endoplasmic reticulum (ER), and retrograde gene expression are invariably reprogrammed in malignancy and exploited to enable extraordinary plasticity and tumor heterogeneity for disease progression. Altieri¡¯s work has demonstrated that therapeutic targeting of mitochondrial reprogramming in cancer is feasible and may uniquely disable multiple mechanisms of disease progression, including metastatic competence across a broad spectrum of genetically heterogeneous tumors. Accordingly, a first-in-class, mitochondria-targeted small molecule inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90) was developed and characterized by the Altieri laboratory (Gamitrinib) and has recently entered a first-inhuman clinical trial in patients with advanced cancer (ClinicalTrials.gov NCT04827810).