PIM Kinase Inhibition as a Novel Therapy for Aggressive Breast Cancers
Abstract
Breast cancers that lack expression of the ERBB2, estrogen and progesterone receptors, so-called "triple-negative" breast cancers (TNBCs), represent the tumor type with the poorest outcome and for which no targeted agents are currently available. Therapy for patients with TNBCs is thus limited to various types of chemotherapy, which are associated with substantial toxicity for patients. Our laboratory previously discovered that the MYC cancer gene is overexpressed in the vast majority of TNBCs. Likewise, increased MYC activity is associated with poor patient outcome across all subtypes of breast cancer. Thus, MYC is a high-interest target for therapy of TNBCs and other aggressive breast cancers. Unfortunately, no specific small molecule inhibitors are available for clinical use that directly target MYC. Furthermore, targeting MYC directly might be expected to cause substantial toxicity to rapidly dividing normal cells within a patient s body. Our laboratory recently identified that the kinase PIM1, and perhaps other kinases in this family, can selectively kill breast cancer cells that have high expression of MYC. This is important because loss of the PIM family of kinases does not appear to be toxic when these genes are lost in mice. Furthermore, we have shown that using PIM kinase inhibitors, we can kill breast tumor cells and block the growth of patient-derived tumors in mice. Patient-derived tumors are among the most stringent and authentic means to verify if a new therapy is likely to work in patients. Based on our exciting results, we have partnered with pharma and received access to clinically relevant PIM inhibitors that are already in early phase clinical trials for blood cancers. These inhibitors have proven to be generally well tolerated and safe in patients. In this proposal, we seek to test these new clinically relevant PIM inhibitors in a large variety of patient-derived tumors. This will inform our research team how best to use these drugs when designing a clinical trial for TNBCs. Finally, we have discovered that MYC is especially elevated in early tumor metastasis. Thus, we hypothesize that PIM inhibitors may not only block the growth of TNBC tumors, but also help to eradicate early tumor metastasis. Thus, our proposal seeks to address two overarching challenges for breast cancer. First, we seek to revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Second, we seek to eliminate the mortality associated with metastatic breast cancer. 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, which agreed to provide novel drugs and look forward to collaborating on an investigator-initiated clinical trial of PIM inhibitors. Impact: This work will have direct and immediate clinical impact by determining if PIM inhibitors, already in clinical development, can selectively kill the majority of TNBCs that overexpress MYC. Moreover, the proposed studies will determine if tumor metastasis can be block by PIM kinase inhibition. Finally, the proposed studies will inform, guide, and accelerate clinical translation of PIM inhibitors to the clinic. The Initiating Principal Investigator, Dr. Andrei Goga, is a medical oncologist at the University of California, San Francisco (UCSF) Breast Oncology Program. In collaboration with Dr. Hope Rugo and other oncologists at UCSF, we anticipate results from this proposal will rapidly inform clinical translation of PIM inhibitors to clinical trials for breast cancer patients within the next few years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610603
Entities
People
- Andrei Goga
Organizations
- United States Army
- University of California, San Francisco