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UAB Rexinoids for Breast Cancer Prevention

UAB Rexinoids 用于预防乳腺癌

基本信息

批准号：
7680145
负责人：
DONALD D MUCCIO
金额：
$ 37.89万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7680145
关键词：
Agonist Apoptosis Apoptotic Appendix Aromatase Inhibitors Bexarotene Binding Biological Availability Biological Markers Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Bromodeoxyuridine Cell Proliferation Chemoprevention Chemopreventive Agent Cholesterol Class Clinic Clinical Clinical Chemoprevention Clinical Research Clinical Trials Combined Modality Therapy Decision Making Development Disease Dose Dose-Limiting Drug Design Drug Kinetics Drug or chemical Tissue Distribution End Point Ensure Estrogen Antagonists Estrogen receptor negative Estrogen receptor positive Evaluation Funding Future Gene Expression Gene Targeting Generations Goals Homologous Gene Human Human Volunteers Hypertriglyceridemia In Situ Nick-End Labeling In Vitro Industry Investments LGD1069 Lipids Malignant Neoplasms Mammary Neoplasms Mammary gland Methylnitrosourea Modeling Morbidity - disease rate Names Nuclear Nuclear Receptors Numbers Oral Patients Phase Phase I Clinical Trials Phase II Clinical Trials Plague Prevention Preventive Principal Investigator Protocols documentation Public Health Purpose RXR Randomized Controlled Clinical Trials Rate Rattus Reproduction spores Research Retinoid Receptor Retinoids Risk Schedule Scientist Selective Estrogen Receptor Modulators Series Serum Structure Structure-Activity Relationship Surrogate Endpoint Tamoxifen Testing Tissues Toxic effect Transgenic Model Transgenic Organisms Translating Triglycerides United States Food and Drug Administration Vorozole Woman Work alitretinoin anastrozole anticancer research base cancer prevention day design dimethylbenzanthracene drug development drug efficacy experience in vivo indexing malignant breast neoplasm mortality mouse model novel pre-clinical prevent programs receptor receptor binding research clinical testing three dimensional structure tumor volunteer

项目摘要

The FDA has approved tamoxifen as the first breast cancer chemopreventive agent. SERM and aromatase inhibitor therapy is effective for estrogen receptor-positive (ER+) cancers, but they are not without limitations and risks. New less-toxic chemopreventive agents are needed for the prevention of ER+ and ER- cancers (for which no suitable preventive agent is available). 9-cis-Retinoic acid (9cRA) and rexinoids like Targretin that selectively interact with nuclear retinoid X receptors (RXRs) are effective in the prevention of ER+ cancer either alone or in combination with anti-estrogens. Additionally, Targretin prevents ER- mammary cancers in transgenic mouse models. At UAB, we designed and synthesized two new classes of RXR- selective retinoids, named UAB rexinoids. We identified several different low-toxicity UAB rexinoids that are very effective in vivo in mammary cancer chemoprevention. The least toxic UAB rexinoid, 9cUAB30, does not display common lipid toxicities that have plagued the clinical use of other retinoids, like 9cRA or Targretin, for cancer prevention. 9cUAB30 has finished preclinical development by the NCI RAPIDProgram as a new chemopreventive agent. The NCI RAPID Program will fund a phase I trial on 9cUAB30 to determine human toxicity and pharmacokinetics. [In Specific Aim 1, we will design second-generation rexinoids based on x-ray crystallographic 3D structures of our active leads from two new classes of rexinoids bound to RXR. Candidate rexinoids will be crystallized with RXR and evaluated in vitro. Potent and selective RXR agonists will then advance to in vivo testing (Specific Aim 2) using our new seven-day screen for inhibition of tumor proliferation, and effects on triglyceride levels. Active rexinoids will be studied in two mammary cancer prevention models (MNU-initiated ER+ model and DMBA MMTV-erbB2 ER- transgenic model). In Specific Aim 3, our first rexinoid candidate (9cUAB30) will enter a phase Ib trial as part of our SPORE project (this will follow the NCI sponsored phase la trial in normal volunteers). In the phase Ib trial, we will evaluate whether 9cUAB30 alters proliferation, apoptosis or RXR downstream target genes in breast cancer cells. Novel second-generation rexinoids will reach phase I trials in years 4 and 5 of the project. A diverse team of scientists has been assembled with extensive expertise in retinoid research and clinical chemoprevention experience to move promising second-generation UAB rexinoids to phase I clinical trials.] This SPORE project impacts public health by the development of drugs that may prevent breast cancer.

FDA已经批准他莫昔芬作为第一种乳腺癌化学预防药物。SERM和芳香化酶