- Theme 1: Targeting signal transduction in cancer
- Theme 2: Targeting epigenetic modulation, cellular homeostasis, and the tumor environment
Theme 1: Targeting signal transduction in cancer
Kevan Shokat, PhD and James Wells, PhD collaborated to identify small molecules that irreversibly bind to a common oncogenic mutant, K-Ras. These compounds were discovered using the ‘disulfide tethering’ technology developed by Wells, and currently supported by the SMD directed by Michelle Arkin, PhD, that employs strategically placed cysteine residues to ‘tether’ cysteine containing small molecules from a designed small molecule library. The mutant cysteine in K-Ras. provided the tether for small molecule binding that does not affect the wild-type protein. These results led to the formation of Wellspring Biosciences, a company focused on the discovery and development of small molecule drugs that target signal transduction networks for the treatment of cancer such as the K-Ras inhibitors. They also resulted in NCI funding. to further probe the ability to drug the switch-II pocket of K-Ras.
In the previous grant cycle, Pamela Munster, MD in collaboration with multiple members of the BR Program (Mark Moasser, MD; Hope Rugo, MD; Jo Chien, MD; and Michelle Melisko, MD) demonstrated in preclinical models that HDAC2 inhibition reverts aberrant estrogen receptor signaling and independent action, thereby mitigating hormone therapy resistance. During the current grant cycle, this work was subsequently translated by Munster into two clinical trials: one as an institutional trial, and the second completed in collaboration with Syndax. Based on this work, the HDAC inhibitor entinostat received breakthrough status to reverse hormone therapy resistance in 2013. The benefits of entinostat in reversing hormonal therapy resistance is now being studied in a multicenter NCTN (Alliance) phase III registration trial). Munster is continuing laboratory investigations to define host factors that predict acetylation changes in tumors and in immune cells.
Theme 2: Targeting epigenetic modulation, cellular homeostasis, and the tumor environment
Jonathan Weissman, PhD played a central role in the development of CRISPRi/a technology systematically evaluating the rules by which dCas9 can effectively control the volume of expression of any transcript, when fused to transcriptional activation or repressor domains. He subsequently developed Perturb-seq, which pairs CRISPRi/a with advances in droplet-based single cell RNA-seq to enable the systematic exploration of gene function with ultra-rich phenotypic readouts.
Each of these technologies has been used to map out cancer vulnerabilities and led to the formation of KSQ Therapeutics, a platform technology company focused on screening the human genome to identify novel therapeutic targets associated with cancer. For example, a role of P97 in cancer therapy was identified that led to the inception of a first-in-human phase I trial studying p97 inhibitors in solid tumors (Munster) and hematologic malignancies (Jeffrey Wolf, MD). Subsequently, an NCI CTD renewal grant application that included Trever Bivona, MD, PhD; Weissman; Sourav Bandyopadhyay, PhD; Frank McCormick, PhD, FRS; and Alan Ashworth, PhD, FRS received a perfect priority score to build a technological and intellectual foundation that will allow for the systematic exploration of the functional roles of genetic lesions identified in large-scale cancer genome projects.