Effective Oral Benzimidazole Carbamates for the Treatment of Metastatic Breast Cancer
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women causing nearly 43,000 deaths per year in the U.S. The military active-duty women have a 20%-40% higher risk of BC than women in the general population.[1] According to Department of Defense data, women make up 20% of the Air Force, 19% of the Navy, 15% of the Army, and about 9% of the Marine Corps. Out of a total ~167,000 military women, nearly 900 will be diagnosed with BC this year. Moreover, among women Veterans, BC is the most commonly diagnosed cancer accounting for about 30% (292/989) of female cancers.[2] These statistics underscore the urgent need for novel, effective, and safe therapies for these military women as well as BC patients in the general population. The majority of deaths in patients diagnosed with BC occurs when metastatic breast cancer (mBC) develops. Median survival of patients diagnosed with mBC is just 3 years. In the past >20 years, there were no significant changes in this indicator. In majority of cases, mBC develops after a series of failed therapies and so, predictably, metastatic cancer cells acquire resistance to these therapies. mBC is the stage of BC that is the most difficult to treat and in ~90% of cases, it is a life-threatening progression. It is essential that new therapies are safe and effective in all BC patients and in particular, in mBC patients whose health and immunity are already compromised by multiple treatments. Moreover, in order to improve survival and successfully eradicate BC cells, new treatments must be able to overcome drug- and radioresistance. The central goal of our study is to develop and test novel safe drugs that can significantly impact survival of patients with mBC. To this end, we have synthesized a new category of promising drug candidates derived from benzimidazole carbamates (BCars), which have a clinically proven safety profile. Safe, oral drugs that can eradicate BC and are designed for personalized cancer therapy regimens represent a major advancement in the treatment of BC and mBC. BCars belong to a class of theranostics. They were designed to fulfill all prerequisites of the individualized treatment approach. The disease presence can be noninvasively detected with SPECT or PET allowing precise determination of the optimal treatment doses and alerting physicians to any anomalous distribution of the drug in normal organs and tissues before the therapy begins. When the dose is determined and risks identified, the patient can be treated with oral doses of BCars. Our BCars are excellent radiosensitizers, and so if brain metastases are present, BCars can be augmented with local doses of radiation therapy. BCars also open the possibility of alpha- and beta-particle molecular radiotherapies that can defeat even multidrug- and radio-resistant mBC. This notion is based on the overwhelming success of Xofigo used to treat metastatic prostate cancer. Our project addresses two overarching challenges: (1) Eliminate the mortality associated with metastatic breast cancer. (2) Revolutionize treatment regimens by replacing drugs that have life-threatening toxicities with ones that are more effective, less toxic, and impact survival. To lay the groundwork that will ultimately lead to the clinical trials, we will conduct systematic evaluation of BCars in vitro and in vivo to gather translational data. BCars activities will be tested in eight BC cell lines and two normal breast cell lines as controls. We will expend a significant effort to precisely define the mechanism by which BCars kill BC cells. These studies will be followed by the efficacy testing in mouse models of BC including transgenic mice that develop breast cancer lung metastases and the orthotopic mouse model of intracerebral mBC. At the conclusion of this study, we will have a good understanding of BCars’ role in the BC treatment. We will also assemble a considerable dataset that will be used in support of our Investigational N
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110700
Entities
People
- Ying Yan
Organizations
- United States Army
- University of Nebraska Medical Center