ABSTRACT
Support is requested for a Keystone Symposia conference entitled Cancer Evolution and Combinatorial
Cancer Therapies: Concepts and Challenges, organized by Drs. William Sellers, Charles Swanton and Lillian
Siu. The conference will be held in Banff, Alberta Canada from January 19-23, 2020.
Progress in understanding the clonal and sub-clonal processes driving tumor evolution, tumor heterogeneity,
the mechanisms of therapeutic resistance, and in defining new cancer dependencies have converged to help
inform more rational approaches to achieving the development of transformative combination therapeutic
regimens in cancer. Nonetheless, examples of highly effective rationally elucidated combinations remain rare
and the pre-clinical and clinical development challenges to this goal are substantial. As an example, the
emergent role of immunotherapeutics having curative potential has led to tremendous excitement, yet
increased complexity. The broad swath of empiric based clinical trials attests to the continued and growing
need for improved pre-clinical means by which transformative combinations can be identified.
This conference will bring together evolutionary and computational biologists, experts in functional genomics,
translational scientists, drug discovery researchers and physician leaders in clinical development. The
conference program begins with how evolutionary processes drive the “natural” progression of cancer and how
such processes lead to the measured heterogeneous populations of cells resident in all tumors. These two
related forces, driven at least in part by ongoing mutational processes, then combine to give rise to therapeutic
resistance, which enables researchers to robustly identify mechanisms relevant to humans in pre-clinical
models. The deeper understanding of these forces can inform specific combination therapeutics, but
combination hypotheses are now being discovered though genome-scale functional screening approaches
(e.g. CRISPR, shRNA). Speakers have been invited to discuss the studies which are now taking place in both
the targeted and immuno-oncology (I/O) therapeutic fields. These talks filter into sessions on understanding
how I/O and targeted therapeutics are similar or distinct and to seek the lessons from the clinical trial outputs in
the I/O field that will emerge over the next year. Finally, clinical development paradigms for more rapidly
testing and developing combinations will be covered during the conference.