MCM Helicase as a Novel Target for Pancreatic Cancer Treatment

描述（由申请人提供）：胰腺癌是最致命的癌症之一，并且很难用常规化疗方案治疗。因此，开发新的和创新的治疗方法是必要的。本研究的目的是探索一种新的可能性，即共同抑制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，MCM亚基的共同抑制增加了在s期产生应激的药物的细胞毒性作用（例如，阿希霉素和羟基脲）。不幸的是，这些有趣的研究仅限于非临床相关系统，特别是关于胰腺癌治疗。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适用性的潜力。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的治疗适用性。我们将确定MCM复合体成员的共同抑制是否可以增加两种用于胰腺癌治疗的药物，吉西他滨和5-FU的化疗敏感性。除此之外，我们还将使用一种创新的方法来确定MCM亚基（以及哪些亚基）的atp酶催化功能的丧失是否足以增加药物敏感性。这些探索性研究将采用创新的方法为三个与胰腺癌治疗相关的高度新颖的概念提供重要信息：(a)将作为MCM共抑制确实可以提高当前胰腺癌药物方案疗效的原理证明，(b)将为未来旨在灭活MCM的药物开发工作提供理由，(c)将表明MCM的atp酶间隙是否应该作为旨在加强胰腺癌患者临床管理的药物开发的重点。

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.