Translational Development of MBQ-167 as Targeted Therapy for Metastatic Breast Cancer
Abstract
This proposal will further the development of a targeted therapeutic for metastatic breast cancer and address the following Fiscal Year 2022 (FY22) Breast Cancer Research Program (BCRP) overarching challenges: (i) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival, and (ii) eliminate mortality associated with metastatic breast cancer. Rationale: Breast cancer mortality is typically from metastatic disease. We are limited by targeted therapeutic options for metastasis, especially in triple-negative breast cancer (TNBC). Due to the inherent heterogeneity and lack of targetable receptors, a uniform therapeutic approach for TNBC has been challenging. Our solution is to target the related metastasis drivers Rac and Cdc42 proteins that drive metastatic TNBC and HER2 breast cancer, which until the development of our drug, have not been successfully targeted. The Principal Investigator (PI), a breast cancer biologist, in collaboration with medicinal chemists, has developed and characterized the drug MBQ-167 to target Rac and Cdc42. The PI and Partnering PI, breast cancer expert Dr. Robert J. Schneider, have clearly demonstrated the efficacy of MBQ-167 in preclinical mouse models: (i) MBQ-167 inhibits breast tumor growth and metastasis by ~90% to all organs from mice with breast tumors established from both human and mouse HER2-type and TNBC cells. (ii) MBQ-167 blocks direct establishment of metastases when TNBC cells are introduced into the blood vessels and allowed to colonize lungs. (iii) MBQ-167 chemosensitizes established TNBC metastases to Paclitaxel as well as those seeded during primary tumor growth. We were recently funded by the BCRP to investigate the mechanism of chemo-sensitization of breast cancer therapeutics including Paclitaxel, and that grant will end in 2022. Contracted by the company MBQ Pharma, Inc. (founded by the PI and collaborators with Dr. Schneider as chair of Scientific Advisory Board), MBQ-167 was shown to be completely safe in rat and dog models up to 1000 mg/kg BW, which is much higher than its effective concentration. Therefore, we recently submitted an Investigational New Drug (IND) application (IND148376) to the U.S. Food and Drug Administration (FDA) to conduct phase 1 clinical trials in metastatic breast cancer patients, independent of this application. The objective of the present application is to further the translational development of MBQ-167. Aim 1 will identify and characterize, for the first time, total expression and levels of biochemically active Rac, Cdc42, and their direct downstream effector p21-activated kinase (PAK) as well as cell proliferation regulator Cyclin D in breast cancer patient tissues from Puerto Rico and New York. We will correlate active Rac/Cdc42/PAK/Cyclin D status with breast cancer grade (I-IV), receptor status (ER, PR, HER2, TNBC), and ethnicity (Hispanic, non-Hispanic Caucasian, African American). The outcome of this aim will characterize the patient population that may best benefit from MBQ-167 therapy and aid in patient stratification for phase 2 clinical studies for MBQ-167 efficacy. Since available histopathological data do not have much information from Puerto Rican patients, we expect to obtain new data pertaining to the large underrepresented Hispanic and African American populations. Therefore, this study may elucidate a molecular basis for the health disparity of African American women in TNBC and identify a new drug that will forward personalized medicine for the medically underserved. Aim 2 will test the applicability of using active phosphorylated PAK (p-PAK) and Cyclin D expression as markers for MBQ-167 efficacy using mice with tumors from TNBC cells. MBQ Pharma, Inc. will then utilize a certified diagnostic development Research Organization to develop and validate a Clinical Laboratory Improvement Amendments (CLIA) certified diagnostic test for MBQ-167 patient selection
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310167
Entities
People
- Robert Schneider
Organizations
- Grossman School of Medicine
- United States Army