Targeted Therapy of Neuroendocrine Cancers Via the Notch Signaling Pathway

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DESCRIPTION (provided by applicant): The PI's long-term career goal is to become an independent and interdisciplinary researcher with a combined expertise in materials science/chemistry and cancer biology in order to develop new diagnostic and treatment modalities for cancer patients. This K25 award will provide protected time for her to receive systematic training in cancer biology. She will attend a number of biology and oncology courses/workshops and conduct lab rotations in three reputable cancer biology labs to quickly expand her knowledge and gain relevant biology lab skills. The proposed research will begin in her mentor's lab and gradually be transitioned to her own lab, where she will establish an independent cancer biology program. Her principle mentor, Dr. Chen, is a renowned surgeon and researcher in neuroendocrine (NE) cancers. NE cancers such as carcinoid, islet cell tumors, and medullary thyroid cancer are the second most common cause of isolated hepatic metastases and often cause many debilitating symptoms. While surgery is the only potentially curative therapy for patients with NE cancers, most patients present with unresectable disease. Currently, there are very limited curative and palliative treatments available to patients with NE cancers, emphasizing the need for the development of new forms of therapy. Dr. Chen's group has recently shown that the activation of Notch1 in human NE cancer cells by histone deacetylase (HDAC) inhibitors markedly suppresses tumor cell growth and NE hormone production both in vitro and in vivo. In Aim #1 of the proposal, the PI will study the mechanism of Notch 1 mRNA induction in NE cancers via HDAC inhibitors by mapping the HDAC inhibitor-response element(s) within the Notch 1 promoter. Identifying the HDAC-response element(s) will allow for the potential development of other molecules that target this element and may also permit the development of methods to predict the clinical response of patients with NE cancer to HDAC inhibitors. In Aim #2, whether pharmacologic activation of Notch1 using HDAC inhibitors such as valproic acid (VPA) could be a novel treatment for NE cancer patients will be determined using a murine model of recurrent/persistent or metastatic NE cancer. VPA is already used clinically in humans for treating other diseases, hence the possibility of using VPA as a viable therapeutic compound to treat NE cancers is both exciting and viable. In Aim #3, a unique octreotide (OCT)-conjugated unimolecular micelle will be developed as a nanocarrier for hydrophobic Notch 1 activating compounds (e.g., VPA) to enhance its NE tumor-targeting abilities, thereby greatly improving its therapeutic efficacy in NE cancers while significantly reducing its various detrimental side-effects. In summary, this proposed research will lead to a better understanding of the mechanism of Notch 1 induction in NE cancers by HDAC inhibitors, which can potentially be used as therapeutic agents to treat and palliate NE cancers in affected patients. The deve- lopment of OCT-conjugated unimolecular micelles can further enhance treatment efficacy. UW-Madison is one of the top cancer research institutes in the world, thereby making it possible for the PI to achieve her goals.