Targeting the PIM Kinase Pathway to Eliminate Breast Cancer Metastasis
Abstract
Breast cancers that lack expression of the HER2, estrogen, and progesterone receptors, so called triple-negative breast cancers (TNBC), represent the tumor type with the poorest outcome and for which targeted agents are limited. Likewise, luminal B breast cancers represent a particularly aggressive subtype of ER+ tumors which have limited response to anti-hormone therapy. Both TNBC and luminal B are also associated with worse-response to existing therapies and increased risk of breast cancer metastasis. Our laboratory discovered that MYC is disproportionally expressed in the vast majority of triple-negative breast cancers and also in many luminal B tumors (Horiuchi, et al., Journal of Experimental Medicine, 2012). Likewise, increased MYC activity is associated with poor patient outcome across all subtypes of breast cancer (Horiuchi, et al., Journal of Experimental Medicine, 2012). Thus, MYC is a high-interest target for therapy of TNBCs, luminal B, and other aggressive breast cancers. Unfortunately, specific small-molecule inhibitors that directly target MYC are not available for clinical use. Furthermore, targeting MYC directly might be expected to cause substantial toxicity to rapidly-dividing normal cells, such as the intestinal cells, within a patient s body. Therefore, therapeutic strategies that target specific proteins that MYC-elevated tumors cannot live without might be an effective method to selectively kill the tumor cells. As part of the Breakthrough Award, our laboratory identified that the kinase PIM1 can selectively kill breast cancer cells that have high expression of MYC (Horiuchi, et al., Nature Medicine, 2016). This is important because loss of the PIM family of kinases does not appear to be toxic when these genes are lost in mice, suggesting that normal cells would not be significantly affected by PIM kinase inhibition. In our Department of Defense-supported Breakthrough studies, we have discovered that PIM kinase inhibitors developed for clinical studies blocked cancer metastasis and improved immunotherapies in advanced preclinical models of breast cancer. The Expansion Award proposal will build on these discoveries and address two overarching challenges: First, we seek to eliminate the mortality associated with metastatic breast cancer. Second, we intent to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. We seek a better understanding of the biology for how PIM inhibition eliminates metastatic colonization of the lung and other tissues. We have identified candidate molecules that are diminished by PIM inhibition and that may be critical for eliminating disseminated tumor cells (DTCs) and metastatic colonization. Our discoveries from the parent Breakthrough Award have also revealed that PIM inhibitors can be effectively combined with immune therapies. Since PIM inhibitors are an oral drug, this suggests that improved immune therapies may be achieved via oral and perhaps safer medications. As part of the proposal, a team of clinicians and physician-scientists, as well as experienced patient-advocates, will work together to test PIM inhibitors and move them forward to an early phase clinical trial. We have also received enthusiastic support of our ideas from pharma, who agree to provide novel drugs and look forward to collaborating on an investigator-initiated clinical trial of PIM inhibitors. This work will have direct and immediate clinical impact by determining if PIM inhibitors, already in clinical development, can block metastasis of TNBCs and luminal B breast cancers that overexpress MYC. Moreover, the proposed studies will determine if immunotherapies can be made more effective and less toxic for patients. Finally, the proposed studies will inform, guide, and accelerate clinical translation of PIM inhibitors to the clinic. The initiating PI, Dr. Andrei Goga, is a medical oncologist at the Unive
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310539
Entities
People
- Andrei Goga
Organizations
- United States Army
- University of California, San Francisco