RAMBAs for Breast Cancer Prevention and Treatment
Final rept. 15 Dec 2003-14 Dec 2008
MARYLAND UNIV BALTIMORE
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This is the final report of this project. We have made excellent progress and have obtained strong data that has enable licensing of our technologies by University of Maryland, Baltimore to Cancer Research UK, London, UK and Chesapeake BioDiscovery, Baltimore, MD, USA. Our studies show that the anti-tumor activity of our lead compound, VN14-1 is dependent on the presence of ER alpha andor RAR alpha receptors in the breast cancer cells. We have also determined that VN14-1 is a potent inhibitor of aromatase, and importantly, it is an exquisite inhibitor of the growth of human breast cancer cells and tumors that have become resistant to clinically used aromatase inhibitors AI or anti-estrogens, such as tamoxifen and faslodex. The agent could be developed for treatments of both endocrine-sensitive and endocrine-resistant breast cancers. In addition, we have also discovered that the combinations of retinoidsRAMBAs with histone deacetylase inhibitors HDACi or their corresponding mutual pro-drugs lead to additivesynergistic inhibition of growth of a variety of human breast cancer cells. We have also determined that although VN14-1 doses not bind to ER alpha, it behaves as a potent antiestrogen with potent anti-uterotrophic activity. We also show that VN14-1 is highly orally bioavailable and orally active. We have also synthesized novel mutual prodrugs of all-trans retinoic acid ATRA and histone deacetylase inhibitors HDIs with enhanced anticancer activities in a variety of breast cancer cell lines. Studies supported by this grant funds has also generated data that has led to other grant funds and technologies in prostate cancer. The data has also enabled us to apply for new grant funding to tackle challenges in the development of new treatments in neuroblastoma from PRMRP.
- Medicine and Medical Research