CLP Seminar Speaker: Stuart Schreiber, PhD

June 29, 2017 - 3:30pm - 5:00pm

Talk Title: Chemical biology-based approach to understanding and overcoming cancer therapy resistance

Venue: Pancoe Hall, Abbott Auditorium
Refreshments: Cupcakes, Coffee & Appetizers will be served at 3:30PM, seminar starts at 4:00PM

During the past several decades there have been several transformational advances in the treatment of cancers, including surgery, radiation, chemotherapy and immune­therapy. The latter are based upon the discovery of two types of cancer vulnerabilities. The first was the discovery that many cancers are dependent on the cancer genes from which they arise – and the consequential rise of ‘targeted therapeutics’. The second was the discovery that many cancers are dependent on their ability to mute the body’s immune response to cancers – and the consequential rise of ‘immuno therapies’. Nevertheless, even responsive cancers have revealed their powerful ability eventually to resist these therapeutic attacks on their dependencies, and so these otherwise impressive responses are rarely durable.

Much attention has therefore been focused on the resistance problem. One approach is to understand the mechanism of resistance on a case-by-case basis, searching for specific therapeutic combinations that might overcome resistance to specific agents in the context of specific cancers. Another approach is predicated on the hypothetical existence of a common and conserved cancer-resistant state that extends across these case-by-case cancer-resistant contexts. A hint of such a common therapy-resistant state comes from the observation that many cancer cells are able to transition to one or more quasi-stable cell states having mesenchymal characteristics. A key feature of these increased mesenchymal states appears to be a reduced capacity to undergo apoptotic cell death, which is a common response to cancer drug treatments and could provide the molecular basis for a common cancer resistant state.

To explore this concept, we first used small-molecule sensitivity to deeply characterized cancer cell lines to identify targets that when inhibited selectively kill cells with high mesenchymal states. This analysis and follow-up experiments suggest that a lipid hydroperoxide dissipation pathway constitutes a vulnerability of a common cancer-resistant state. This state is associated with one specific apoptotic-resistant mesenchymal state, and indeed this state also appears to be associated with certain sarcomas – cancers of tissues having a mesenchymal or embryonic mesenchymal origin. Small molecules can target key nodes in this cell state, suggesting a therapeutic strategy towards resistance to cancer therapeutics in the future.