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

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形式之一,并且是非常难以用常规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共抑制复制型MCM解旋酶复合物可以增强胰腺癌治疗中使用的化疗剂的抗增殖作用的新的可能性。最近发表的研究表明,MCM亚基的共抑制增加了在S期产生应激的药物的细胞毒性作用(例如,阿非迪霉素和羟基脲)。不幸的是,这些有趣的研究仅限于非临床相关的系统,特别是关于胰腺癌治疗。我们目前的初步研究表明,MCM共抑制的概念确实有直接的临床应用的潜力。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MCM复合物的共同抑制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。这些探索性研究将使用创新方法,为与胰腺癌治疗相关的三个高度新颖的概念提供重要信息:(a)将作为MCM共抑制确实可以增加当前胰腺癌药物方案的功效的原理证明,(B)将为旨在灭活MCM的未来药物开发工作提供理由,以及(c)将表明MCM的ATP酶裂缝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,也是对大多数当前形式的化疗具有高度耐药性的癌症。因此,开发新的和创新的治疗方法是必要的。该提案的目标是探索新的可能性,即共同抑制参与复制我们染色体的基本方面的蛋白质可以增强胰腺癌治疗中使用的化疗药物的抗肿瘤作用。这项原理证明研究的成功将支持未来新药的开发,从而提高我们控制这种疾病的能力。

项目成果

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Mark G. Alexandrow其他文献

Mark G. Alexandrow的其他文献

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{{ truncateString('Mark G. Alexandrow', 18)}}的其他基金

Direct Control of the human CMG Helicase by Myc and Rb
Myc 和 Rb 直接控制人 CMG 解旋酶
  • 批准号:
    10094948
  • 财政年份:
    2021
  • 资助金额:
    $ 18.16万
  • 项目类别:
Direct Control of the human CMG Helicase by Myc and Rb
Myc 和 Rb 直接控制人 CMG 解旋酶
  • 批准号:
    10413807
  • 财政年份:
    2021
  • 资助金额:
    $ 18.16万
  • 项目类别:
Direct Control of the human CMG Helicase by Myc and Rb
Myc 和 Rb 直接控制人 CMG 解旋酶
  • 批准号:
    10624906
  • 财政年份:
    2021
  • 资助金额:
    $ 18.16万
  • 项目类别:
Inhibition of the CMG Helicase as Novel Anti-Neoplastic Approach
抑制 CMG 解旋酶作为新型抗肿瘤方法
  • 批准号:
    9189594
  • 财政年份:
    2016
  • 资助金额:
    $ 18.16万
  • 项目类别:
Inhibition of the CMG Helicase as Novel Anti-Neoplastic Approach
抑制 CMG 解旋酶作为新型抗肿瘤方法
  • 批准号:
    8993839
  • 财政年份:
    2016
  • 资助金额:
    $ 18.16万
  • 项目类别:
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
  • 批准号:
    8027488
  • 财政年份:
    2011
  • 资助金额:
    $ 18.16万
  • 项目类别:
Chromatin Remodeling by Cdt1: Role in DNA Replication and Tumorigenesis
Cdt1 的染色质重塑:在 DNA 复制和肿瘤发生中的作用
  • 批准号:
    8658391
  • 财政年份:
    2010
  • 资助金额:
    $ 18.16万
  • 项目类别:
Chromatin Remodeling by Cdt1: Role in DNA Replication and Tumorigenesis
Cdt1 的染色质重塑:在 DNA 复制和肿瘤发生中的作用
  • 批准号:
    8090409
  • 财政年份:
    2010
  • 资助金额:
    $ 18.16万
  • 项目类别:
Chromatin Remodeling by Cdt1: Role in DNA Replication and Tumorigenesis
Cdt1 的染色质重塑:在 DNA 复制和肿瘤发生中的作用
  • 批准号:
    8458596
  • 财政年份:
    2010
  • 资助金额:
    $ 18.16万
  • 项目类别:
Chromatin Remodeling by Cdt1: Role in DNA Replication and Tumorigenesis
Cdt1 的染色质重塑:在 DNA 复制和肿瘤发生中的作用
  • 批准号:
    8241092
  • 财政年份:
    2010
  • 资助金额:
    $ 18.16万
  • 项目类别:
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