Targeted Therapy of Neuroendocrine Cancers Via the Notch Signaling Pathway

通过Notch信号通路靶向治疗神经内分泌癌

• 批准号: 9079433
• 负责人: SHAOQIN GONG
• 金额: $ 19.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079433
• 关键词: Abdominal Pain; Acids; Adverse effects; Affect; Animal Model; Antineoplastic Agents; Area; Award; Biology; Cancer Biology; Cancer Cell Growth; Cancer Patient; Carcinoid Tumor; Cells; Chemistry; Clinical; Development; Diarrhea; Disease; Distant Metastasis; Drug Compounding; Educational workshop; Elements; Encapsulated; Excision; Exhibits; Flushing; Goals; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Hormonal; Hormones; Human; In Vitro; Islet Cell Tumor; Knowledge; Lead; Ligands; Liver; Malignant Neoplasms; Maps; Mentors; Messenger RNA; Metastatic Neoplasm to the Liver; Micelles; Microscopic; Modality; Mus; Neuroendocrine Tumors; Neurosecretory Systems; Notch Signaling Pathway; Octreotide; Operative Surgical Procedures; Palliative Care; Patients; Permeability; Pharmaceutical Preparations; Production; Quality of life; Recurrence; Research; Research Institute; Research Personnel; Response Elements; Role; Rotation; Second Primary Cancers; Somatostatin Receptor; Somatotropin; Surgeon; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Tissues; Training; Treatment Efficacy; Tumor Tissue; Unresectable; Up-Regulation; Valproic Acid; airway obstruction; anticancer research; cancer cell; career; cell growth; curative treatments; disabling symptom; dosage; experience; improved; in vivo; materials science; medullary thyroid carcinoma; method development; mouse model; nanocarrier; nanomedicine; neoplastic cell; notch protein; novel; novel diagnostics; novel therapeutics; oncology; programs; promoter; response; skills; somatostatin analog; targeted treatment; tumor growth; uptake

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.

PI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，为癌症患者开发新的诊断和治疗模式。这个K25奖将为她提供受保护的时间，以接受癌症生物学的系统培训。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换，以快速扩展她的知识，并获得相关的生物实验室技能。拟议中的研究将开始在她的导师的实验室，并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计划。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）癌症研究人员。NE癌症如类癌、胰岛细胞瘤和甲状腺髓样癌是孤立性肝转移的第二常见原因，并且通常引起许多使人衰弱的症状。虽然手术是NE癌症患者唯一潜在的治愈性疗法，但大多数患者存在不可切除的疾病。目前，有非常有限的治愈性和姑息治疗可用于NE癌症患者，强调需要开发新的治疗形式。Chen博士的研究小组最近表明，组蛋白脱乙酰酶（HDAC）抑制剂激活人NE癌细胞中的Notch 1，在体外和体内均显著抑制肿瘤细胞生长和NE激素产生。在提案的目标1中，PI将研究以下机制： 通过定位Notch 1启动子内的HDAC转录因子-应答元件，通过HDAC抑制剂诱导NE癌症中的Notch 1 mRNA。鉴定HDAC反应元件将允许靶向该元件的其他分子的潜在开发，并且还可以允许开发预测NE癌症患者对HDAC抑制剂的临床反应的方法。在目标#2中，将使用复发性/持续性或转移性NE癌的鼠模型来确定使用HDAC抑制剂如丙戊酸（VPA）的Notch 1的药理学活化是否可以是NE癌患者的新治疗。VPA已经在临床上用于治疗其他疾病，因此使用VPA作为治疗NE癌症的可行治疗化合物的可能性既令人兴奋又可行。在目标#3中，将开发独特的奥曲肽（OCT）缀合的单分子胶束作为疏水性Notch 1活化化合物（例如，VPA）以增强其NE肿瘤靶向能力，从而大大提高其在NE癌症中的治疗功效，同时显著降低其各种有害副作用。总之，这项拟议的研究将导致更好地了解HDAC抑制剂在NE癌症中诱导Notch 1的机制，HDAC抑制剂可能用作治疗剂来治疗和减轻受影响患者的NE癌症。OCT偶联单分子胶束的开发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。