MCM Helicase as a Novel Target for Pancreatic Cancer Treatment

描述(申请人提供)：胰腺癌是最致命的癌症之一，也是一种很难用传统化疗方案治疗的癌症。因此，开发新的和创新的治疗方法是必要的。该提案的目的是探索一种新的可能性，即共同抑制复制的MCM解旋酶复合体可以增强用于胰腺癌治疗的化疗药物的抗增殖作用。最近发表的研究表明，共抑制MCM亚单位会增加在S期产生应激反应的药物(如除草剂和羟基脲)的细胞毒效应。不幸的是，这些有趣的研究一直局限于非临床相关的系统，特别是关于胰腺癌的治疗。我们提出的初步研究表明，MCM共抑制概念确实具有直接临床应用的潜力。利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。我们将确定共同抑制MCM复合体成员是否可以增加用于胰腺癌治疗的两种药物-吉西他滨和5-FU的化疗敏感性。作为补充，我们还将使用一种创新的方法来确定MCM亚单位(以及哪些亚单位)的ATPase催化功能的丧失是否足以增加药物敏感性。这些探索性研究将使用创新的方法，为与胰腺癌治疗相关的三个非常新的概念提供重要信息：(A)将证明MCM共抑制确实可以提高当前胰腺癌药物方案的疗效，(B)将为未来旨在灭活MCM的药物开发工作提供理由，以及(C)将表明MCM的ATPase裂解是否应作为旨在加强胰腺癌患者临床管理的药物开发的重点。 公共卫生相关性：胰腺癌是最致命的癌症之一，对目前大多数形式的化疗都具有高度耐药性。因此，开发新的和创新的治疗方法是必要的。这项建议的目的是探索一种新的可能性，即共同抑制参与复制我们的染色体的基本方面的蛋白质可以增强用于胰腺癌治疗的化疗药物的抗肿瘤效果。这项原则证明研究的成功将支持未来新药的开发，这些新药将增强我们控制这种疾病的能力。

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.