Novel Targeted Therapy for Metastatic Triple-Negative Breast Cancer
Abstract
This research proposal will address the overarching challenges: (a) identify why some breast cancers become metastatic and (b) eliminate the mortality associated with metastatic breast cancer. An estimated 155,000 women in the US have metastatic breast cancer, and more than 40,000 women die of breast cancer every year in the US. Although there have been some improvements in the treatment of breast cancer in recent years, still many breast cancer patients die due to lack of effective therapies. Particularly, triple-negative breast cancer (TNBC), which is characterized by the absence of expression of estrogen, progesterone, and HER2 receptors, is the most aggressive form of breast cancer and associated with poor prognosis. The vast majority of TNBC-related deaths are due to metastasis to other vital organs. At present, TNBC patients are mainly treated with chemotherapies (e.g., docetaxel, doxorubicin, cisplatin). However, these chemotherapies eventually become ineffective due to the emergence of drug resistance. So, there is a critical need to develop novel therapies for metastatic TNBC. We have identified PIM1 and PIM2 kinases as potential therapeutic targets in metastatic TNBC. We have found that PIM1 and PIM2 expression is significantly increased in TNBC cells and tumors. PIM1 expression is also significantly increased in metastatic breast cancers. PIM1 and PIM2 belong to the PIM family of serine/threonine kinase that controls cell growth and survival. We have observed that depletion of PIM1 significantly inhibits tumor growth and blocks metastasis in animal model of metastatic breast cancer. We also have identified a highly efficacious novel PIM kinase inhibitor TP-3654 that significantly inhibits the growth of TNBC cells and markedly inhibits the tumor growth and metastasis in mouse breast cancer model without exhibiting any significant toxicity. Furthermore, TP-3654 treatment can overcome resistance to docetaxel chemotherapy in TNBC cells. Based on our strong preliminary data, we hypothesize that PIM1 and/or PIM2 may play an important role in the progression and metastasis of TNBC, and targeting of PIM kinase using TP-3654 in combination with chemotherapy might be useful for treatment of TNBC. The objectives of this proposal are to determine the roles of PIM1/PIM2 in TNBC tumor growth and metastasis and to test the efficacy of a novel second-generation PIM kinase inhibitor TP-3654 alone and in combination with chemotherapy drugs in cell and animal models of TNBC. We will also determine the mechanism by which inhibition of PIM kinase blocks TNBC tumor growth and metastasis, overcomes resistance to chemotherapy, and increases the effectiveness of chemotherapy. The translational impact of this study is very high. Our proposed studies will provide the first demonstration that targeting of PIM kinase using TP-3654 in combination with current chemotherapy is a useful strategy in treating metastatic TNBC. Moreover, the work proposed in this application will identify the potential biomarkers for such therapy in TNBC. We have assembled a strong research team that combines the expertise of mouse genetics, cancer biology, systems biology, biostatistics/bioinformatics, and medical oncology specializing in breast cancer. A Phase I, first-in-human trial of TP-3654 (ClinicalTrials.gov Identifier: NCT03715504) in patients with Advanced Solid Tumors has recently started at multiple clinical sites including the University of Virginia Medical Center. Early results from this trial are very promising, indicating that TP-3654 is well-tolerated in cancer patients. Results from our proposed studies could be the basis for further clinical development of PIM kinase inhibitor TP-3654 in metastatic TNBC. Successful completion of this project will lay the groundwork for clinical trials of TP-3654 in combination with current chemotherapy for treatment of metastatic TNBC. This study, therefore, can be expected to have a significant positive impact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110008
Entities
People
- Golam Mohi
Organizations
- United States Army
- University of Virginia