Targeted Therapy of Neuroendocrine Cancers Via the Notch Signaling Pathway

描述（由申请人提供）：PI的长期职业目标是成为一名独立的跨学科研究人员，具有材料科学/化学和癌症生物学的综合专业知识，为癌症患者开发新的诊断和治疗方法。此次K25奖将为她接受系统的癌症生物学培训提供有保障的时间。她将参加一些生物学和肿瘤学课程/研讨会，并在三个著名的癌症生物学实验室进行实验室轮转，以迅速扩展她的知识并获得相关的生物学实验室技能。拟议中的研究将从她导师的实验室开始，逐步过渡到她自己的实验室，在那里她将建立一个独立的癌症生物学项目。她的主要导师陈医生是一位著名的外科医生和神经内分泌（NE）癌症的研究人员。类癌、胰岛细胞瘤和甲状腺髓样癌等NE癌是孤立性肝转移的第二大常见原因，通常会引起许多衰弱症状。虽然手术是NE癌患者唯一可能治愈的治疗方法，但大多数患者存在不可切除的疾病。目前，可用于NE癌患者的治愈性和姑息性治疗非常有限，这强调了开发新疗法的必要性。Chen博士的研究小组最近发现，在体外和体内，组蛋白去乙酰化酶（HDAC）抑制剂激活人NE癌细胞中的Notch1可显著抑制肿瘤细胞的生长和NE激素的产生。在提案的目标1中，PI将研究的机制

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.