Our primary research interest is to elucidate the molecular mechanisms of erbB receptor tyrosine kinase (RTK) family members-mediated signal transduction in breast cancer formation and progression. By understanding the cancer biology of erbB2/erbB3 receptors and the protein-protein interactions among RTKs, we hope to identify novel molecular targets and develop small molecules with therapeutic potential for cancer patients.
While numerous studies demonstrate that erbB2 is one of the most well characterized oncogenes involved in breast carcinogenesis and more recently used as a therapeutic target, there is relatively little study on erbB3 as a molecular target for cancer treatment.In the last 2-3 years, our laboratory has focused on studying the unique biologic features of erbB3 receptor, and published a series of articles indicating that erbB3 may be an important molecular target and novel therapeutics targeting erbB3 may enhance the efficacy of erbB2-targeted therapies.
There are currently three areas of investigation in my laboratory:
Project 1: The role of erbB3 receptor in erbB2-mediated therapeutic resistance.We have reported that specific knockdownof erbB3 expression abrogates erbB2-mediated tamoxifen resistance (Int J Cancer, 120: 1874-1882, 2007). Our recent studies reveal that elevated expression of erbB3 upregulates Survivin to confer paclitaxel resistance in erbB2-overexpressing breast cancer cells, and erbB3 receptor interacts with both erbB2 and insulin-like growth factor-1 receptor (IGF-1R) to form a heterotrimeric complex in Herceptin-resistant breast cancer cells (Cancer Res,in press, 2009). Modern molecular and cellular biological techniques are applied to determine the mechanisms by which erbB3 contributes to erbB2-mediated therapeutic resistance.
Project 2: Identification of novel erbB3-targeted therapeutics. We have considered the unique biologic features of erbB3 receptors and successfully discovered that the selective class I HDACi SNDX-275 (Syndax Pharmaceuticals, Inc., San Diego, CA) modulates expression of erbB3-targeting miRNAs, and induces apoptosis in erbB2-overexpressing breast cancer cells via downregulation of erbB3 (Cancer Res, 69: 8403-8411, 2009). The ongoing experiments aim to determine whether the potential therapeutics targeting erbB3 (blocking antibodies and SNDX-275) may abrogate or attenuate erbB2-mediated resistances to tamoxifen, paclitaxel, and enhance erbB2-targeted therapies, such as Herceptin and lapatinib.
Project 3: Epigenetic regulation of Multiple Myeloma (MM). In collaboration with Dr. Choon-Kee Lee (Division of Medical Oncology, Department of Medicine), we are exploring the combinational effects of Bendamustine and SNDX-275 on MM. Bendamustine, a hybrid molecule of purine analog and alkylator, is known to induce cell death by activation of DNA-damage stress response, and induction of mitotic catastrophe and apoptosis. The study proposes combination of bendamustine with SNDX-275 to enhance cell death of MM cells, in particular of the resistant ones to conventional chemotherapeutic agents and to bortezomib.