The FDA has approved tamoxifen as the first breast cancer chemopreventive agent. SERM and aromataseinhibitor therapy is effective for estrogen receptor-positive (ER+) cancers, but they are not without limitationsand 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 Targretinthat 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- mammarycancers 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 arevery effective in vivo in mammary cancer chemoprevention. The least toxic UAB rexinoid, 9cUAB30, doesnot display common lipid toxicities that have plagued the clinical use of other retinoids, like 9cRA orTargretin, for cancer prevention. 9cUAB30 has finished preclinical development by the NCI RAPIDProgramas a new chemopreventive agent. The NCI RAPID Program will fund a phase I trial on 9cUAB30 todetermine human toxicity and pharmacokinetics. [In Specific Aim 1, we will design second-generationrexinoids based on x-ray crystallographic 3D structures of our active leads from two new classes of rexinoidsbound to RXR. Candidate rexinoids will be crystallized with RXR and evaluated in vitro. Potent andselective RXR agonists will then advance to in vivo testing (Specific Aim 2) using our new seven-day screenfor inhibition of tumor proliferation, and effects on triglyceride levels. Active rexinoids will be studied in twomammary cancer prevention models (MNU-initiated ER+ model and DMBA MMTV-erbB2 ER- transgenicmodel).
In Specific Aim 3, our first rexinoid candidate (9cUAB30) will enter a phase Ib trial as part of ourSPORE 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 breastcancer cells. Novel second-generation rexinoids will reach phase I trials in years 4 and 5 of the project. Adiverse team of scientists has been assembled with extensive expertise in retinoid research and clinicalchemoprevention 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.
Showing the most recent 10 out of 211 publications
