Rac and Cdc42 Inhibitors in Breast Cancer Metastasis Prevention
Abstract
Significance: Metastasis, when breast cancer cells move and establish tumors in distant, more vital organs, results in the death of 80% of metastatic patients. Therefore, this proposal will address the unmet need for targeted therapeutics to address current therapy failures in breast cancer due to resistance and metastasis. Overarching Challenges: (1) Revolutionizing treatment regimens by replacing them with ones that are more effective and less toxic. (2) Eliminating the mortality associated with metastatic breast cancer. The proposed research will impact breast cancer cure by testing the effect of a novel targeted therapeutic MBQ-167 in single and/or combination therapies for aggressive HER2 type and triple-negative breast cancer (TNBC), for which few targeted therapeutic options are available. Background and Rationale: The Principal Investigator (PI), a breast cancer biologist, in collaboration with medicinal chemists, is developing small molecule compounds targeting the closely related signaling proteins Rac and Cdc42. Rac and Cdc42 are pivotal regulators of migration and invasion of breast cancer cells, and thus promote metastasis to distant organs. Due to the inherent heterogeneity of TNBC, a uniform therapeutic approach has been challenging, and therefore, the standard of care for TNBC is chemotherapy with anthracyclines or taxanes. However, these non-targeted cytotoxic therapies can result in resistance, significant side effects, and increased metastasis, which is a recurring problem for successful breast cancer cure following chemotherapy. Especially in TNBC and HER2-type breast cancer, Rac and Cdc42 are overexpressed and (or) overactivated by oncogenic cell surface receptors such as epidermal growth factor receptors HER2 and EGFR, and consequently, Rac and Cdc42 overexpression is correlated with poor prognosis. The initial success of trastuzumab to target HER2-type breast cancers has been marred by development of resistance, which resulted in the development and Food and Drug Administration (FDA) approval of lapatinib for HER2/EGFR overexpressing breast cancer. However, patients may also develop resistance to lapatinib, due to mutations in the receptors, which needs to be overcome with therapies that target pathways downstream of HER2/EGFR, such as Rac/Cdc42 signaling. Therefore, we developed and licensed a new Rac and Cdc42 inhibitor called MBQ-167 that is 10 times more effective than currently available Rac/Cdc42 inhibitors. MBQ-167 is specific to metastatic breast cancer cells and inhibits both TNBC and HER2-type breast cancer cell growth, including stem cell growth, and mammary tumor growth by ~90% and metastasis by 100%. Therefore, the hypothesis is that MBQ-167 is effective in metastatic breast cancer in combination with current breast cancer therapeutics. Specific Aims: Aim 1 will test the efficacy of MBQ-167 in combination with current TNBC chemotherapy paclitaxel and doxorubicin. Preliminary data in a human TNBC mouse model showed that even though MBQ-167 and paclitaxel reduce primary breast cancer growth to the same level, paclitaxel alone actually increased metastasis to liver, lung, and spleen. This chilling increase in metastasis was completely abolished by MBQ-167 treatment, exemplifying its usefulness in combination therapy. Therefore, we will further analyze the potential of MBQ-167 to overcome metastasis exacerbated by doxorubicin and paclitaxel in four different subtypes of TNBC. The outcome of Aim 1 will demonstrate the utility of MBQ-167 to prevent metastasis in combination with chemotherapy in multiple types of TNBC. Aim 2 will demonstrate the efficacy of MBQ-167 in combination with HER2/EGFR-targeted therapeutics trastuzumab and lapatinib. Our published and preliminary data show that MBQ-167 inhibits growth and metastasis of trastuzumab-resistant HER2-type breast cancer. Moreover, lapatinib-resistant HER2 type cells overexpress Rac and are successfully inhib
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010041
Entities
People
- Suranganie Dharmawardhane
Organizations
- United States Army
- University of Puerto Rico