EGF receptor, DNA methylation and platinum resistance in ovarian cancer

描述（由申请人提供）：本研究提案的总体目标是更深入地了解控制卵巢癌铂类耐药发展的信号通路和机制。在卵巢癌研究领域，有必要更深入地了解铂类药物耐药性是如何发展的，因为这在卵巢癌患者中很常见，并且会妨碍临床疗效。迄今为止，由于缺乏对铂抗性的预防，防止获得铂抗性的努力受到限制。 关于它如何发展的机制的知识;而在它已经发展后逆转铂耐药性的努力只显示出部分应答率。本研究项目是作为一个5年的职业发展计划博士Samudio-Ruiz从博士后研究员过渡到研究助理教授，成为终身教职的长期目标。与分子生物学和表观遗传学相关的其他技术的具体培训将为Samudio-Ruiz博士在生物医学研究领域取得成功做好准备，特别是癌症和表观遗传学研究。临床和转化研究方面的额外培训将使Samudio-Ruiz博士能够将从基础生物医学研究中收集的信息传播到临床应用中;因此，可能会推动卵巢癌临床治疗的努力。这与国家癌症研究所支持可能导致癌症治疗进步的研究的目标不谋而合。这项工作的地点是新墨西哥州大学（UNM），该大学以致力于癌症研究，特别是妇女癌症研究而闻名，因为它是该州唯一的国家癌症研究所指定的癌症中心，也是新墨西哥州的官方癌症中心。UNM提供了一个支持性的环境，研究人员可以通过UNM癌症研究和治疗中心（CRTC）利用几个共享资源，Samudio-Ruiz博士将充分利用这些资源。这项拟议的研究将评估表观遗传机制，特别是DNA甲基化，及其在卵巢癌铂类耐药发展中的作用。特别关注的是表皮生长因子受体（EGFR），因为Samudio-Ruiz博士最近发现了EGFR和DNA甲基化之间的联系，这项工作刚刚被接受出版。总体研究设计是生成铂类耐药的体外模型，以评价与铂类耐药发生相关的DNA甲基化变化，并确定EGFR抑制是否可以预防耐药的发生。从体外模型产生的数据也将在铂耐药性产生前后的人体组织样本中得到证实;从而建立未来可用于体内和最终临床的实验。 模型

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to gain a deeper level of understanding of the signaling pathways and mechanisms that govern the development of platinum resistance in ovarian cancer. A deeper level of understanding for how platinum resistance develops is necessary in the field of ovarian cancer research as this is a common occurrence in patients with ovarian cancer and it prevents clinical effectiveness. To date, efforts at preventing the acquisition of platinum resistance have been limited due to lack of knowledge on the mechanism for how it develops; while efforts to reverse platinum resistance after it has already developed have only shown partial response rates. This research project is to serve as a 5 year career development plan for Dr. Samudio-Ruiz to transition from post doctoral fellow to research assistant professor with the long term goal of becoming tenure track faculty. Specific training in additional techniques related to molecular biology and epigenetics will prepare Dr. Samudio-Ruiz for a successful career in biomedical research with particular focus on cancer and epigenetics research. Additional training in clinical and translational research will allow Dr. Samudio-Ruiz to disseminate information gathered from basic biomedical research to clinical applications; thus, potentially advancing the efforts of ovarian cancer treatment in the clinic. This significantly coincides with the National Cancer Institute's goal of supporting research that could lead to the advancement of cancer treatment. The location for this work is the University of New Mexico (UNM) which is known for its commitment to cancer research, specifically women's cancer research, as a whole as it is the state's only National Cancer Institute-designated cancer center and the Official Cancer Center of the State of New Mexico. UNM offers a supportive environment where investigators can take advantage of several shared resources through the UNM Cancer Research and Treatment Center (CRTC) which Dr. Samudio-Ruiz will take full advantage of. The proposed research will evaluate epigenetic mechanisms, specifically DNA methylation, and its role in the development of platinum resistance in ovarian cancer. Particular focus will be paid to the Epidermal Growth Factor Receptor (EGFR) as Dr. Samudio-Ruiz recently found a link between EGFR and DNA methylation and that work was just accepted for publication. The overall research design is to generate an in vitro model of platinum resistance to evaluate changes in DNA methylation associated with the development of platinum resistance and determine if inhibition of the EGFR can prevent development of resistance. Data generated from the in vitro model will also be confirmed in human tissue samples both before and after the development of platinum resistance; thus setting up future experiments that can be taken to in vivo and eventually clinical models.