Cancer remains difficult to treat, even with the new generation of targeted cancer drugs. By far the most formidable obstacle is the rapid emergence of therapy resistance. Indeed, many of the new cancer drugs elicit powerful initial responses, leading to dramatic effects on progression free survival, but far less long-term benefit is seen in terms of overall survival.
Combination therapies can help fight therapy resistance, but with an arsenal of over 1000 cancer drugs in clinical development, the number of possible combinations seems nearly endless. In my laboratory we employ functional genetic screens to find powerful combinations of cancer drugs by exploiting the concept of "synthetic lethality". Using CRISPR/Cas9-based genetic screens focused on drugable gene families, we search for genes whose inactivation is particularly synergistic with clinically-relevant cancer drugs. Such screens can identify drug combinations that are far more powerful than the sum of the two single agents. We aim to understand the molecular rationale for the observed synergy between two cancer drugs. Once we have insight into the molecular mechanism, we aim to bring such rationally-designed combinations to the cancer clinic through collaboration with clinicians in our comprehensive cancer center.
We also use CRISPR based genetic screens to identify novel drug targets that are only toxic to cells having a defined genetic alteration. The prototypical example for this is the increased sensitivity of BRCA mutated breast and ovarian cancer cells to inhibitors of PARP. We use genetic screens to identify critical dependencies of tumors having recurrent mutations. Such dependencies can serve as cancer-specific vulnerabilities that can be exploited therapeutically.
A new research theme in my laboratory is the use of pro-senescence therapy for cancer, followed by a second therapy that selectively kills senescent cancer cells. This sequential “one-two punch” therapy for cancer begins to show promise in animal models of cancer.