Drug Discovery of Bax Activators for the Treatment of Breast Cancer
Abstract
Despite major advances over the last two decades, breast cancer remains the most common cause of cancer-associated death in women in the United States. Most breast cancers grow and progress in response to the hormone estrogen, so-called estrogen receptor (ER)-positive tumors. For approximately half of these patients, targeted treatments against estrogen or its receptor have resulted in a reduction in the recurrence of and mortality from these cancers. For the rest of these patients, whose tumors are resistant to such therapies, and for the almost 40% of breast cancers that lack a functioning estrogen receptor, no targeted therapies are currently available. Thus, there is an urgent need to revolutionize breast cancer therapy with safer treatments that are also effective against in these ER-negative patients. This is particularly true in light of the fact that the majority of these patients develop triple-negative breast cancer (TNBC), which lacks other key receptors and is prone to grow faster, spread or metastasize earlier, and recur more frequently, leading to worse prognosis. The majority of cancer therapies currently available depend on depend on activation of apoptosis in cancer cells. Apoptosis is a normal process by which cells that are no longer needed or are critically malfunctioning are destroyed and cleared. In many cancers, including TNBC, a critical protein in initiating apoptosis, Bax, is inactivated. As such, Bax is a promising target for cancer therapy if we can restore or reprogram Bax function in cancer cells. The novelty and the advantages by targeting Bax are discussed in detail in our recent paper entitled "Direct Activation of Bax Protein for Cancer Therapy" (Medicinal Research Reviews, 2016; 36(2), 313-341. DOI 10.1002/med.21379. PMID: 26395559). Our studies have identified several highly specific and potent molecules that irreversibly activate Bax in cells. We have shown that these new drug candidates specifically activate Bax by targeting a key serine amino acid to induce apoptosis in cancer cells with great potential to overcome therapy resistance. In the proposed work, we will improve and optimize our identified apoptosis-promoting Bax activators and develop these activators toward human clinical trials of breast cancer treatment. We will use various cancer cell and animal models to test the new molecules and select the best candidates for preclinical development. These efforts will allow us to develop innovative Bax activators as new treatment options for breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710072
Entities
People
- Qiang Shen
Organizations
- United States Army
- University of Texas at Austin