Patients with advanced (PR)-negative/HER-2-negative tumors present a therapeutic challenge for oncologists. Although advances in early detection and adjuvant therapy have made a favorable impact, there are currently no effective therapeutic cures. Treatment is primarily aimed at palliation of symptoms as well as improving overall survival. Hormonal, targeted and chemotherapeutic strategies largely depend on the expression of their cognate receptors and are often accompanied by intolerable toxicities [1]. New, effective and less toxic therapies for estrogen receptor negative (ER-) breast cancers are therefore urgently needed.BN107, a new oral drug candidate designed for the treatment of advanced breast cancer, is rich in oleanolic acid (OA) derivatives [1] and offers a novel mechanism of action by inducing apoptosis in estrogen receptor negative breast cancer cells via the mitochondrial apoptotic machinery. It causes rapid alterations in cholesterol homeostasis, resulting in rapid and specific inhibition of lipid rafts (LR-) mediated survival signaling of mTORC1 and mTORC2 activities, by decreasing the levels of the mTOR/FRAP1, RAPTOR and RICTOR. The drug is under development by Bionovo, Inc, a pharmaceutical company focusing on the discovery and development of safe and effective treatments for women’s health and cancer.mTORResults of a study, published today in the International Journal of Cancer, indicatets that BN107, a new anti-tumor drug candidate, shows dual mTOR inhibition for the treatment of breast cancer [2]. mTOR, mammalian target of rapamycin, is a kinase protein found predominantly in the cytoplasm of the cell that acts as a central regulator of many biological processes that are essential for cell proliferation, angiogenesis, and cell metabolism. These processes are abnormally activated in patients with many different types of cancer, resulting in deregulated cell proliferation, tumor angiogenesis, and abnormal cell metabolism [3.4,5]. The article in International Journal of Cancer describes the potential molecular mechanisms mediating the selective pro-apoptotic (cell death) effect induced by BN107 on estrogen receptor negative (ER-) breast cancer cells.Despite favorable advances that treatment options have had on survival, oncologists continue to face challenges in providing safe and effective treatment options for ER- breast cancer patients. In this patient population, the PI3K/Akt/mTOR pathway is often abnormally activated which allows cancer cells to grow uncontrollably and evade death. There are two mTOR protein complexes, mTORC1 and mTORC2, both of which are essential for the control of aberrant survival signals. Agents that can inhibit mTORC1 and mTORC2 at the same time might lead to effective suppression of the Akt/mTOR pathway and result in tumor cell death. The study showed that BN107 decreases the levels of proteins present in the mTORC1 and mTORC2 complexes, resulting in their demise specifically in ER- breast cancer cells. The mTOR pathway as a target for cancer therapies has been actively pursued by many pharmaceutical companies.Researchers at Bionovo believe that this is the first report demonstrating effective inhibition of both mTOR complexes concomitantly through a novel mechanism.According to Dr. Sylvia Fong, Research Scientist at Bionovo, the target selectivity of BN107 will result in a better tolerability and safety profile than conventional chemotherapy. Oral administration of BN107 is ideal for chronic treatment and will mark this targeted compound as a promising investigational drug for the treatment of metastatic breast cancer. ?The ability of BN107 to induce cancer cell death is selective. We demonstrate that breast cancer cells lacking estrogen receptors are highly sensitive to BN107. Our studies show that disruption of mTOR signaling mediated by both mTORC1 and mTORC2 complexes is most likely responsible for the anti-tumor effect of BN107. Simply put, BN107 has a unique way to target a specific sub-group of breast cancer cells that currently has no selective treatment. This is exciting.””It is critical to develop novel and safe strategies to effectively treat the patients with ER- breast cancers. We believe BN107 will result in better selectivity to hormone independent tumors based on its unique selectivity and mechanisms of action. Currently the only available treatment for this group, constituting 40% of women diagnosed with breast cancer, is chemotherapy. BN107, an oral drug candidate, should provide a chronic treatment option with a low toxicity profile,” said Dr. Isaac Cohen, Chairman and CEO of Bionovo.For more information:[1] Chu R, Shoemaker M, Tagliaferi M, Cohen I, et al. Molecular analysis of the selective pro-apoptotic effect of BN107 on estrogen receptor negative breast cancer cells. SABCS; Date/Time: Friday, December 12, 2008 – 5:00 PM Session Info: Poster Session III: Treatment: Alternative Therapies (5:00 PM-7:00 PM) Poster 3128[2]Campbell, M., Hamilton, B., Shoemaker, M., Tagliaferri, M., Cohen, I., Tripathy, D. Antiproliferative Activity of Chinese Medicinal Herbs on Breast Cancer Cells in Vitro. Anticancer Res 22: 3843-3852, 2002.[3] Chu, R., Zhao, X., Griffin, C., Staub, R., Shoemaker, M., Climent, J., Leitman, D.C., Cohen, I., Shtivelman, E., Fong, S. Selective Concomitant Inhibition of mTORC1 and mTORC2 Activity in Estrogen Receptor-Negative Breast Cancer Cells by BN107 and Oleanolic Acid. International Journal of Cancer. 2009 Article online 2009 Dec 21. [Epub ahead of print].[4] Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004 May;4(5):335-48.[5] Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006 May 25;441(7092):424-30.[6]Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006 Aug;5(8):671-88.
