Our long-term objective is to cure cancer by combining conventional therapeutics that targeting on proliferative cells with novel therapy targeting dormant cancer cells. Currently, almost all anticancer drugs used in the clinic target proliferative cancer cells. While these effective anticancer treatments can lead to cancer dormancy – a state of cancer inactivity that is considered beneficial to the patient – it also renders them unresponsive to additional conventional treatments. As such, these dormant cancer cells can be considered the most resistant form of cancer. Unfortunately, they can eventually become reactivated in patients, causing cancer relapse and metastasis that kills. Our specific goal is to comprehensively understand the mechanisms understanding behind how dormant cancer cells relapse and progress into metastatic castration resistant prostate cancer (mCRPC). This will enable us to develop therapeutics that delay or prevent such occurrences. (Insights gained from studying prostate cancer can also be broadly applied to other cancer types given commonly shared mechanisms.)
Hypothesis: Therapy induces a heterogeneous, but definable, repertoire of mechanisms (e.g. lineage plasticity, transdifferentiation, and dormancy) that gives rise to lethal treatment-resistant CRPC. These mechanisms can be modeled and studied in patient-derived xenografts (PDXs), which are unique tools for discovering critical drug targets and testing novel anticancer therapies. By comprehensively understanding the mechanisms underlying cancer dormancy and reactivation, novel therapies can be developed.
Program significance: We anticipate that our research will build a new paradigm of cancer drug discovery and development by using evidence-based precision oncology and employing novel strategies that focus on eliminating dormant precursors of CRPC. Through our research program, we also hope to equip a next generation of scientists and clinical fellows to appreciate team science and interdisciplinary approaches. They will deepen their expertise in cancer modeling, molecular biology, and drug development. Using this combinatory approach, they will improve our understanding of the dynamic processes driving treatment resistance and develop the clinical tools necessary to impede cancer progression. Thus, our team’s synergy will significantly advance the knowledge of cancer biology and translate it to improving patient outcomes and quality of life.