Seminar: David Cheresh, Ph.D., UC San Diego School of Medicine
Targeting cancer cell stress tolerance and drug resistance
Zoom link: https://umich.zoom.us/j/96343178582
The acquisition of tumor cell drug resistance represents a major obstacle in obtaining long term therapeutic benefit for a wide range of cancers. Cheresh's laboratory focuses on understanding how tumors acquire drug resistance at the molecular level with the goal of developing new strategies to target drug resistant tumor cells and thereby control tumor progression providing enhanced patient survival. Relative to drug sensitive tumors cells, those with acquired drug resistance often display stem like properties including distinct cell surface markers and gene expression profiles as well as increased tumor initiation, stress tolerance and anchorage independent growth. His research group has identified two mechanisms of lung, pancreas and breast cancer cell acquired drug resistance, both of which are induced by tumor cell exposure to nutrient stress, hypoxia or oxidative stress often found within the tumor microenvironment. In fact, many currently approved therapeutics themselves induce a stress response which in turn promotes the acquisition one or both of these mechanisms of drug resistance. Cheresh will discuss how these drug resistant tumor cells adapt to stress and therapeutic intervention at the molecular level and outline efforts to design new therapeutic strategies to target each of these pathways and thereby more effectively treat drug resistant cancers.
David Cheresh is a Distinguished Professor of Pathology at UC San Diego. A major goal of his current and past research is to understand the molecular mechanisms promoting angiogenesis, tumor progression, and metastasis in order to develop novel therapeutics for cancer. His group's efforts have led to the understanding of how growth factors, growth factor receptors and cell surface receptors (including integrins) drive signaling pathways leading to tumor cell invasion, migration, proliferation and survival. These findings have helped to delineate how these processes are regulated at the molecular level, and his group has identified downstream signaling events that play a critical role.
These studies have led to the development of integrin antagonists as novel therapeutics for cancer treatment that function to suppress the growth of angiogenic blood vessels. Two drugs that have developed from this work include Vitaxin (Abegrin), a humanized monoclonal antibody that targets αvβ3, and Cilengitide, a cyclic peptide antagonist of integrins αvβ3 and αvβ5. Both of these drugs showed clinical activity in cancer patients in Phase II trials. Cheresh was the scientific founder of TargeGen Inc., which developed a selective JAK2 inhibitor approved by the FDA in August of 2019 for patients with myelofibrosis.
Early in his career, Cheresh developed antibodies to tumor antigens and used these as both research tools and potential therapeutics. Among the antibodies he developed was one specific for the oligosaccharide portion of the GD2 ganglioside, expressed on tumors of neuroectoderm origin. This antibody was later humanized (named Unituxin) and tested clinically for its activity in patients with advanced neuroblastoma. Unituxin produced a significant survival benefit in a Phase III registration trial and in March of 2015 was approved by the FDA as a front-line therapy for patients with advanced neuroblastoma.
His recent work has focused on the intersection between cellular stress and the progression of lung and pancreatic cancers. He is particularly interested in evaluating how tumor cells become reprogrammed as an adaptation to stress or therapeutic intervention, giving rise to stress tolerance and drug resistance.