Targeted Therapy of Neuroendocrine Cancers Via the Notch Signaling Pathway

简介(由申请人提供)：国际癌症研究所的长期职业目标是成为一名独立的跨学科研究人员，拥有材料科学/化学和癌症生物学方面的综合专业知识，以便为癌症患者开发新的诊断和治疗方法。这项K25奖项将为她提供受保护的时间，让她接受癌症生物学方面的系统培训。她将参加多个生物学和肿瘤学课程/工作坊，并在三个著名的癌症生物实验室进行实验室轮换，以迅速扩大她的知识并获得相关的生物实验室技能。这项拟议的研究将在她导师的实验室开始，并逐渐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。她的主要导师陈博士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是孤立肝转移的第二大常见原因，通常会导致许多衰弱的症状。虽然手术是治疗NE癌症患者的唯一可能的治愈方法，但大多数患者都患有无法切除的疾病。目前，对东北癌症患者的治疗和姑息治疗非常有限，强调了开发新的治疗形式的必要性。陈博士的团队最近发现，在体外和体内，组蛋白脱乙酰酶(HDAC)抑制剂激活人NE癌细胞中的Notch1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，国际和平倡议将研究 通过将HDAC抑制-反应元件(S)定位在Notch 1启动子内，通过HDAC抑制剂诱导NE癌症中的Notch 1mRNA。确定HDAC反应元件(S)将允许针对该元件的其他分子的潜在开发，并可能允许开发预测NE癌症患者对HDAC抑制剂的临床反应的方法。在目标2中，使用丙戊酸(VPA)等HDAC抑制剂对Notch1的药理激活是否可能成为NE癌症患者的一种新疗法，将使用复发/持续性或转移性NE癌症的小鼠模型来确定。VPA已经在人类临床上用于治疗其他疾病，因此使用VPA作为一种可行的治疗化合物来治疗NE癌症的可能性是令人兴奋和可行的。在Aim#3中，将开发一种独特的奥曲肽(OCT)偶联的单分子胶束，作为疏水Notch 1激活化合物(例如VPA)的纳米载体，以增强其对NE肿瘤的靶向能力，从而大大提高其对NE癌症的治疗效果，同时显著减少其各种不良副作用。综上所述，这项拟议的研究将有助于更好地理解HDAC抑制剂在NE癌中诱导Notch 1的机制，这些抑制剂可能被用作治疗和缓解受影响患者的NE癌的药物。OCT共联单分子胶束的发展可以进一步提高治疗效果。威斯康星大学麦迪逊分校是世界上最顶尖的癌症研究机构之一，从而使PI有可能实现她的目标。

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.