MCM Helicase as a Novel Target for Pancreatic Cancer Treatment

MCM 解旋酶作为胰腺癌治疗的新靶点

基本信息

批准号：
8027488
负责人：
Mark G. Alexandrow
金额：
$ 21.79万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8027488
关键词：
ATP Hydrolysis ATP phosphohydrolase Address Antineoplastic Agents Aphidicolin Apoptotic Biological Assay Boxing Cancer Patient Catalytic Domain Cells Chemosensitization Chromosomes Cleaved cell Clinical Management Colon Carcinoma Complex Development Dose Drug usage Etoposide Fluorouracil Future Goals Individual Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Modeling Mutate Pancreatic carcinoma Pharmaceutical Preparations Proteins Publishing Rana Regimen Resistance S Phase Small Interfering RNA Stress System Therapeutic Therapeutic Index Time Walkers cancer cell cancer therapy cancer type cell type chemotherapeutic agent clinical application combinatorial cytotoxic disorder control drug development drug sensitivity gemcitabine helicase hydroxyurea indexing innovation member mutant neoplastic novel oxaliplatin pancreatic cancer cells research study success tumor

项目摘要

DESCRIPTION (provided by applicant): Pancreatic carcinoma is one of the deadliest forms of cancer, and one that is very difficult to treat with conventional chemotherapeutic regimens. As such, the development of new and innovative therapeutic approaches is necessary. The goal of this proposal is to explore the novel possibility that co-suppression of the replicative MCM helicase complex can enhance the anti-proliferative effects of chemotherapeutic agents used in pancreatic cancer treatment. Recent published studies have shown that co-suppression of MCM subunits increases the cytotoxic effects of drugs that produce stress during S-phase (e.g., aphidicolin and hydroxyurea). Unfortunately, these intriguing studies have been limited to non-clinically relevant systems, particularly with regard to pancreatic cancer treatment. We present preliminary studies showing that the MCM co-suppression concept does indeed have the potential for direct clinical applicability. Using these precedents from our own studies, we propose to extend these concepts to pancreatic cancer treatment applicability. We will determine if co-suppression of members of the MCM complex can increase the chemosensitivity of two drugs used for pancreatic cancer treatment, gemcitabine and 5-FU. Complementary to this, we will also use an innovative approach to determine if loss of the ATPase catalytic function of MCM subunits (and of which subunits) is sufficient to increase drug sensitivity. These exploratory studies will use innovative approaches to provide important information for three highly novel concepts related to pancreatic cancer treatment: (a) will serve as a proof of principle that MCM co-suppression can indeed increase the efficacy of current pancreatic cancer drug regimens, (b) will offer justification for future drug development efforts aimed at inactivating MCMs, and (c) will indicate whether the ATPase cleft of MCMs should serve as the focus for drug development aimed at enhancing clinical management of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: Pancreatic carcinoma is one of the deadliest forms of cancer, and one that is highly resistant to most current forms of chemotherapeutic treatment. Thus, the development of new and innovative therapeutic approaches is necessary. The goal of this proposal is to explore the novel possibility that co-suppression of proteins involved in basic aspects of copying our chromosomes can enhance the anti-tumor effects of chemotherapeutic agents used in pancreatic cancer treatment. Success with this proof of principle study will support the future development of novel drugs that will enhance our ability to control this disease.

描述（由申请人提供）：胰腺癌是最致命的癌症之一，并且使用常规化学治疗方案很难治疗。因此，必须开发新的和创新的治疗方法。该提案的目的是探索复制性MCM解旋酶复合物的共抑制可以增强用于胰腺癌治疗中化学治疗剂的抗增殖作用的新颖可能性。最近发表的研究表明，MCM亚基的共抑制增加了在S期间产生应激的药物的细胞毒性作用（例如，蚜虫和羟基脲）。不幸的是，这些有趣的研究仅限于非链式相关系统，特别是在胰腺癌治疗方面。我们提出了初步研究表明，MCM共抑制概念确实具有直接临床适用性的潜力。使用我们自己研究的这些先例，我们建议将这些概念扩展到胰腺癌治疗的适用性。我们将确定MCM复合物成员的共抑制是否可以增加两种用于胰腺癌治疗，吉西他滨和5-FU的药物的化学敏度。对此互补，我们还将使用一种创新的方法来确定MCM亚基（以及哪个亚基）ATPase催化功能的丧失是否足以提高药物敏感性。这些探索性研究将采用创新方法为与胰腺癌治疗相关的三种高度新颖概念提供重要信息：（a）将作为原则证明，表明MCM的同事确实可以提高当前胰腺癌药物方案的疗效旨在增强胰腺癌患者的临床管理。公共卫生相关性：胰腺癌是最致命的癌症之一，并且对大多数当前形式的化学治疗形式具有高度抵抗力。因此，必须开发新的和创新的治疗方法。该提案的目的是探索新的可能性，即复制染色体的基本方面的蛋白质的共抑制可以增强用于胰腺癌治疗中化学治疗剂的抗肿瘤作用。这项原则研究证明的成功将支持未来的新药物发展，这将增强我们控制这种疾病的能力。