Enhanced Targeting of Basal-like Breast Cancer Through 'Cooperation Response Genes'
Basal-like breast cancers (BLBCs) are known for rapid progression, high rates of metastasis and relapse, and poor long-term survival. BLBC cells are notoriously resistant to agents commonly used to treat breast cancer (chemotherapeutics, estrogen antagonists). We exploit differences between cancer and non-cancer cell gene expression to find new targets, and thus new treatment approaches against BLBC. We focus on a set of genes that regulate tumor formation capacity of multiple types of cancer, ‘cooperation response genes’ (CRGs). CRGs change in expression in cancer cells through the action of cooperating oncogenic mutations, but CRGs themselves are not mutated.
We recently discovered that changes in CRG expression control tumor formation capacity of BLBC cells. The role of CRGs is cancer specific, inhibiting cancer growth while sparing normal cell function. Through efforts to re-purpose FDA-approved drugs, we have identified multiple pharmacologic agents that modulate CRG expression and selectively inhibit growth of BLBC cells. Thus, CRGs represent new molecular therapeutic targets in BLBC, useful for developing novel therapeutic strategies.
Current efforts are directed at optimizing combination of CRG-modulating agents with existing anti-BLBC therapies, to identify effective, cancer selective combinations to drive into future clinical trials. We are also working to understand the molecular mechanisms of action of these CRG-modulating agents. Moreover, through collaborative efforts with colleagues in the laboratory of Dr. Mark Noble, we aim to develop combinations of novel agents that leverage independent discovery of critical regulators of BLBC tumor initiation, the redox/Fyn/Cbl pathway, discovered through work from the Noble laboratory, and the CRGs, identified through studies in my laboratory. In addition, we will examine how frequently and at what tumor stages CRGs are disregulated in BLBC transformation. Taken together, this work will enable development of new strategies for multi-drug combination targeting of BLBC to optimize anti-cancer effects while maximizing cancer selectivity.