New effective therapeutic strategies are urgently needed to treat advanced breast cancer, especially triple-negative breast cancer (TNBC). We have identified a new therapeutic target, a protein called CECR2, that can be inhibited with small molecules for treatment of TNBC. Multiple pharmaceutical and biotech companies are developing CECR2 inhibitors for clinical use. We are in close contact with Genentech to plan for breast cancer clinical trials at Yale.

Our research team discovered that CECR2 allowed the breast cancer cells to evade immune surveillance by secreting macrophage chemoattractant. CECR2 targeting resulted in significant activation of T cells, and converted immunologically “cold” breast tumors into “hot” tumors. These “hot” tumors are more likely to be eliminated by the immune system and to respond to current immunotherapies, which had modest efficacy on breast cancer as monotherapies.

In this proposal, we plan to further elucidate and validate the specific roles of CECR2 in blocking antitumor immune response. As a critical step to translate our findings to the clinic, we will further validate the therapeutic potential of inhibiting CECR2, singly or in combination with a current immunotherapy in animal models.

Our proposed studies will address at least three overarching challenges, including determining how to stop breast cancer growth by boosting antitumor immunity; eliminating the mortality associated with metastatic breast cancer; and revolutionizing treatment regimens by replacing them with ones that are more effective, less toxic and impact survival.

It is expected that several CECR2 inhibitors will be available for oncology clinical trials within the next 2 years. In addition to the development of companion biomarker assays to predict response to CECR2 inhibition, these results could lay the groundwork for clinical trials in which CECR2 inhibitors are used singly or in combination with immune checkpoint blockade in 3 years. These results could also support the combination of CSF1/CSF1R inhibitor and CXCL1/CXCR2 inhibitor for TNBC treatment. These two classes of inhibitors are already in multiple clinical trials. As the PI collaborates closely with clinicians who run phase I breast cancer clinical trials, including Dr. Lajos Pusztai and Patricia LoRusso, this strategy could be translated directly to the clinic right away.

Therefore, our studies are expected to have major impact as this new paradigm-changing treatment strategy could be rapidly brought to the clinic for treating breast cancer patients within 3 years. Collectively, the results of our studies will have major impact on reducing breast cancer mortality and significantly advance the field toward the goal of ending breast cancer.