Pharmaceutical Reactivation of p53 for Breast Cancer Treatment
Abstract
Significant advances in breast cancer treatment have dramatically improved survival of patients with early-stage primary breast carcinomas. However, prognosis for patients with recurring metastatic breast cancer remains bleak. Patients do not die of cancer confined to the breast or lymph nodes but because the cancer has spread to vital organs such as liver, brain, or lung. With no breakthrough in therapy or prevention for recurring metastatic breast cancer, an estimated 747,000 women will die from this disease in 2030. Novel therapeutic approaches for recurring metastatic breast cancer are therefore desperately needed. In addition to the general difficulties in treating breast cancer that has spread to other organs, many of these cancers originate from a subgroup of breast cancer, known as triple negative, which is unresponsive to the most effective breast cancer therapies available. This most lethal and therapy-resistant form of breast cancer has the highest prevalence of mutations in the body s own potent protection from cancer, the tumor suppressor protein p53. We propose to develop drug leads that restore p53 activity as a novel therapy for currently therapy-resistant forms of breast cancer. Similar to other cancers, breast cancer can only develop when growth-promoting pathways in normal cells become overactive (e.g., oncogene expression), and when the cells own protection against uncontrolled cell proliferation becomes inactivated. The latter is mediated by tumor suppressor proteins, which prevent normal cells from becoming tumor cells. Most notably is the tumor suppressor protein p53, which is thought to be inactivated or bypassed in all tumors. Tumors depend on keeping p53 inactive, because reintroduction of active p53 in animal models by genetic tricks leads to tumor cell death and rapid tumor regression. However, reintroducing active p53 into human tumors is technically not feasible. Nevertheless, restoring p53 activity in human breast cancer could lead to the development of radically different breast cancer therapeutics with potentially dramatic effects on breast cancer survival rates. Indeed, such therapeutics that restore the body s own defense against cancer, namely, the tumor suppressor p53, may be feasible goals for many recurring metastatic breast cancers. Interestingly, a large fraction of aggressive breast cancers (between 60% and 88% for triple-negative breast cancer) typically express high levels of p53, but its tumor-preventing activity is blocked by single amino acid mutations. These mutations change the three-dimensional structure of p53 and inactivate its cancer preventing function. We discovered several small, drug-like molecules that help the mutated p53 to regain its active three-dimensional conformation. When added to cancer cells, these small molecules restore p53 activity and induce cancer cell death. Thus, these molecules can serve as drug leads for a novel class of "p53 reactivation" therapeutics. We propose to select the most active p53 reactivation molecules based on their effect on breast cancer cells with common p53 mutations and use a computer-guided chemical synthesis strategy to improve efficacy of these compounds in animal models. Success of this proposal will lead to small molecule drug leads for pharmaceutical reactivation of p53 mutants in breast cancer and set the foundation for translation to the clinic for targeted treatment of breast cancer patients with p53 mutations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510022
Entities
People
- Peter Kaiser
Organizations
- Naval Information Warfare Center Pacific
- United States Army