The Role of HBP1 in Controlling Breast Cancer Dormancy Reawakening
Abstract
In the past two decades, improved abilities to detect subsets of breast cancers (BrCa) have facilitated increased patient survival by the development of drugs that target the cancer driver mechanisms in a patient-specific manner. However, as many as 22% of BrCa cases exhibit disease recurrences, typically at distant sites such in the bones, lungs, or brain. Patient survival rates drop precipitously with evidence of multiple sites of recurrence. However, recent studies have shown that the seeding of these recurrent, metastatic tumors occurs early during primary tumor growth in the breast, and thus, even after these initial tumors are removed surgically, and patients are treated with radiation, immunotherapy and/or chemotherapy, many if not most of these patients have dormant tumor cells that have already disseminated to sites such as the bone. Our research has identified a specific gene, HBP1, that is turned on in dormant BrCa growing in the bone and that prevents these cells from reawakening and becoming an actively growing metastasis. Our research has identified pathways that HBP1 controls to induce dormancy. We have identified a drug, cyproheptadine, originally used clinically as an antihistamine, that turns on the production of HBP1 in BrCa cells. Importantly, a literature of 71,000 liver cancer cases in Taiwan showed that those also taking cyproheptadine had significantly increased overall survival rates, suggesting that this drug has long-term effects on cancer. We propose to determine whether this drug can suppress the reawakening of dormant BrCa cells in the bone. Our research strongly suggests that HBP1 controls BrCa dormancy in both estrogen receptor-positive and triple-negative BrCa patients. Therefore, this target, as well the use of cyproheptadine, would likely benefit a broad population of BrCa cases to prevent disease recurrence, and therefore improve long-term survival. Because cyproheptadine has been used clinically for years as an antihistamine, it could be repurposed quickly for fast-tracked clinical trials in BrCa patients. Benefits for these patients would include decreased frequencies of disease recurrences and increased time-to-recurrence, both of which are parameters of increased long-term survival. Because cyproheptadine is U.S. Food and Drug Administration-approved, successful preclinical data from our study could quickly trigger a phase 2 clinical trial within 6 months if the doses used for BrCa is the same as for its antihistamine dose, i.e., not requiring further phase 1 toxicity trials. There is a high likelihood that the current proposal will impact BrCa patient survival, specifically, by using cyproheptadine to target HBP1, thereby decreasing the reawakening of dormant BrCa cells and the formation of recurrent disease – a direct mission goal of the Breast Cancer Research Program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110619
Entities
People
- Irwin H Gelman
Organizations
- United States Army