A Platform for Identifying Druggable Targets of Cancer Persisters to Mitigate Tumor Recurrence

ASPIRE Award, PHASE II (2021-Present)

Steven Altschuler, PhD; Lani Wu, PhD,; Xiaoxiao Sun, PhD, University of California, San Francisco

One of the biggest hurdles in oncology is cancer recurrence. Although current therapies can be extremely effective in killing the vast majority of cancer cells, the failure to eradicate every last one will often lead to eventual regrowth of a tumor that is resistant to the initial therapies. Traditionally, researchers and clinicians have viewed this as a classical Darwinian process, with therapies driving selection for genetic changes that allowed for drug resistance. While this is certainly the case for many tumors, there is now a new appreciation for nongenetic mechanisms leading to a reservoir of drug-tolerant cancer cells, termed persisters. Pro-persistence signals can arise from a complex interplay between a drug’s mechanism of action, environmental signals received by the cancer cells, and their epigenetic states during the time of treatment. This has been difficult to study, as persistence emerges over a period that is longer than standard acute treatment regimens in traditional drug efficacy studies, and the fraction of surviving cells can be very small. Because of this, most current persister studies are low throughput and laborious.

Steven Altschuler, Lani Wu, and Xiaoxiaxo Sun have developed an in vitro method to study cancer cell persistence and screen for vulnerabilities in these cell populations. Their novel system allows them to study persisters over relatively long periods of time and how the presence of drugs and environmental factors influence the formation of persistent cells. They have already examined one cancer system: non-small cell lung cancer cells treated with erlotinib in the presence of interferon. These studies have revealed that an intricate signaling axis of STAT1 and arginine methyltransferases are areas of vulnerabilities for cancer persistence. In this project, they will examine if targeting this axis in mouse models will delay or prevent the development of persisters to determine whether targeting this pathway represents a viable therapeutic strategy for preventing relapse. They will also elaborate their screening platform to novel cancer systems under a battery of different environmental cues in order to uncover mechanism of persistence across diverse tumor types and find therapeutic vulnerabilities to target them. These studies will expand our understanding of cancer relapse and have the potential to increase our arsenal against tumor recurrence.