BLR&D Research Career Scientist Award Application

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications & trials

Abstract

Project Summary/Abstract: The primary focus of our research group is to elucidate the underlying molecular mechanisms of pancreatic (PDAC) and breast cancer (BC) pathogenesis. The overarching goal of our research is to investigate how the cellular pathways (i.e., circuits) are dysregulated and can lead to uncontrolled cell growth (i.e., cancer). The ultimate goal is to develop and use small molecules to target the dysregulated proteins to mitigate pancreatic and breast cancers. Our laboratory has been working with novel protein kinases with a short-term goal to define their physiological functions (in cancer) and, in the long term, to identify their inhibitors or activators. We have been working on kinases called Mixed Lineage Kinases (MLKs) and MAP4K4. The roles of MLKs and MAP4K4 in cancer are an emerging area. Especially the inhibitor of the MLK family, CEP-1347, has gone through a clinical trial for Parkinson’s disease, demonstrating no collateral toxicity. We have shown that inhibitor of MLKs can be repurposed to treat Triple Negative breast cancer (TNBC) and PDAC in animal models. Our recent results (previous VA-Merit) demonstrated that one of the MLK family members, MLK3, was significantly overexpressed in human pancreatic cancer tumors and was necessary for cancer cell growth. Moreover, MLKs inhibitor ameliorated PDAC tumor burden and extended the life of animals than vehicle treated group in an aggressive animal model of PDAC (KPC). We plan to explore how MLK3 and MAP4K4 crosstalk with other regulatory proteins and promote pancreatic cancer to determine the rationale for combination therapy to mitigate PDAC. We recently reported (current VA-Merit) that another kinase, MAP4K4, is also overexpressed in PDAC, and its inhibitor, GNE-495, similarly ameliorated the PDAC tumor burden in animals. However, in these animals, the T cell co-stimulatory molecule, 4-1BB (CD137), was elevated, and thus combining GNE-495 and agonistic-4-1BB antibody significantly reduced the tumor burden and extended the life of animals than the single agent, (GNE-495) treated animals. The other three projects [one NCI (no cost) and 2 DOD funded grants] are on breast cancer. We reported earlier that suppression of MLK3 activity by estrogen and HER2 amplification was necessary for ER+ and HER2+ breast cancer cell survival and growth. Therefore, we developed a novel nanoparticle loaded with MLK3 activator ceramide (PPP-CNP) that induced significant cell death in HER2+ and ER+ breast cancer cells. In animal models of HER2+ breast cancer, the PPP-CNP was able to reduce tumor burden and overcome Trastuzumab (first-line therapy for HER2+ BC) resistance (published in PNAS 2023). In human TNBC tumors, the activity of MLK3 was very high compared to ER+ breast cancer tumors. We identified that another kinase, Pak1, is overexpressed in TNBC and blocks the pro-apoptotic activity of MLK3. Based on our mechanistic data, the animals bearing TNBC tumors (i.e., PDXs) were sensitive to MLKs inhibitors, dependent on TrkA expression in the tumors (published in Oncogene 2023). The other two grants from the DOD are on breast cancer. The first grant is focused on elucidating the roles of the MLK3-CD70 axis in mesenchymal BC. The Second grant focuses on understanding the crosstalk between TrkA fusion proteins and MLK3 in BC. Our comprehensive published and unpublished results corroborate that MLKs and MAP4K4 are viable targets in breast and pancreatic cancers. Our results also suggest that activators of MLK3/MLKs could be useful to treat ER+ and HER2+ breast cancer. In contrast, the inhibitors of MLK3/MLKs could serve as a therapeutic intervention for TNBC and pancreatic cancer. Our comprehensive studies also suggest that understanding the detailed roles of any given protein before considering it for targeted therapy is of utmost importance. We plan to continue working on these clinically important kinases and take their inhibitors/activators for future clinical trials.