Beyond Apoptosis: Bcl-xL in Breast Cancer Metastasis
Abstract
This proposed study will address this overarching challenge: Eliminate the mortality associated with metastatic breast cancer. Breast cancer accounts for about 25% of all cancer in women. Currently, the chance of a woman being diagnosed with breast cancer is one in eight. Most breast cancer patients do not die of locally confined cancer, but rather from cancer that has spread, leading to diminished function of vital organs such as the lungs, liver, and brain. At the time of primary breast cancer diagnosis, tumor cells in 50% of patients have already spread to distant organs and will become metastatic disease if left untreated. Once metastatic disease is diagnosed, patients can no longer be cured with currently available targeted or non-targeted therapy. There is an urgent need to better understand drivers of breast cancer metastasis and to identify novel therapeutic targets. This proposed study will help breast cancer patients with primary tumors and those with metastatic tumors by preventing/treating metastatic tumors. In breast cancer, the gene that produces Bcl-xL is "overexpressed," leading to too much Bcl-xL protein. This protein is normally present in the mitochondrial compartment of a cell, and it has been known for its function in preventing a common, programmed form of cell death (apoptosis). When Bcl-xL is overexpressed in cancer, it helps cancer cells to survive. Several drugs have been developed to inhibit the anti-apoptotic function of BclxL. Unfortunately, these drugs have limited therapeutic value in clinical trials. We have a manuscript in press in a prominent scientific journal (Nature Communications) demonstrating that in cancer, Bcl-xL travels to the nucleus to promote metastasis independent of its anti-apoptotic function. This unexpected finding provides an explanation for why clinical trials using drugs to block anti-apoptosis roles of Bcl-xL have not been effective in halting cancer progression. Therefore, the overall goal of our proposed study is to investigate novel metastatic functions of the Bcl-xL protein in breast cancer progression and to assess the value of suppressing the nuclear function of Bcl-xL in preventing/treating metastasis. Importantly, we have designed an experimental approach to screen Food and Drug Administration-approved drugs and other chemical compounds (over 276,000 in total) for drugs that can block metastatic functions of Bcl-xL. Our specific hypothesis is that Bcl-xL promotes breast cancer metastasis via its nuclear functions and that blockade of Bcl-xL nuclear functions as well as its anti-apoptotic functions can prevent/treat metastatic breast cancer. Understanding the mechanisms of metastasis will lead to increased survival rates for cancer patients and decreased costs of medical care for the public and the military. The likely impact of this study on ending metastatic breast cancer is high. The proposed study, if successful, will have a major clinical application, because it will provide a strong mechanism- and evidence-based framework for the continued therapeutic development of blocking the metastatic function of Bcl-xL. We anticipate that the projected time to achieve a patient-related outcome is 3~5 years. The ultimate applicability of the research is to establish a new drug that blocks the metastatic function of Bcl-xL as well as its anti-apoptotic function in breast cancer, so as to offer a new and more effective modality for preventing/treating metastatic breast cancer. For testing our hypothesis, we have already assembled a strong research team. The Initiating Principal Investigator (PI), Dr. Du at Weill Cornell Medicine, has studied Bcl-xL and pancreatic cancer metastasis for years but is now poised to adapt her expertise for breast cancer metastasis. The Partnering PI, Dr. Li at Baylor College of Medicine, is an expert in mouse models of breast cancer. The two PIs collaborated closely to generate the strong preliminary data p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610620
Entities
People
- Yi Li
Organizations
- Baylor College of Medicine
- United States Army