Nucleoside Transporter-Connexin Interplay in Pancreatic Cancer Chemotherapy

描述（由申请人提供）：对核苷类似物药物的耐药性（例如，吉西他滨）是胰腺癌极差预后状态的主要潜在原因之一。虽然细胞核苷转运蛋白（NTs）和细胞间缝隙连接蛋白（Cxs）在决定肿瘤暴露的核苷类药物的关键作用已经开始出现，其功能的相互作用，在确定核苷类似物的化疗敏感性和其潜力预测化疗反应仍然未知。我们的长期目标是改善胰腺癌的化疗管理。这项R15申请的总体目标是研究NT-Cx在胰腺癌化疗中的相互作用。中心假设是表达的NT-Cx组合的类型将决定化学敏感性，并且然后可以靶向特定组合以增加抗肿瘤功效。这一假说是基于对NT和Cx的连续研究以及最近发现的胰腺肿瘤中NT和Cx亚型的非遗传功能改变而提出的。拟议研究的基本原理是，了解核苷类似物敏感性的确切决定因素将有助于预选适合这种类型治疗的患者，并确定临床策略，以提高疗效差的反应。具体目标1将定义NT-Cx组合在核苷类似物化学敏感性中的作用。工作假设是吉西他滨的细胞毒性在表达浓缩NT 1（hCNT 1）-Cx 32组合的细胞中将是上级的，并且由于一种组分的损失而导致的化学抗性可以被另一种组分有效地补偿。这一假说是基于胰腺肿瘤中NT和Cxs的表达和渗透特性。具体目标2将确定控制NT-Cx相互作用的调节剂以改善化学敏感性。工作假设是，通过操纵钙粘蛋白或microRNA可以实现NT-Cx组合的有利操纵以增加药物暴露。该假设基于申请人的研究，该研究显示钙粘蛋白控制Cx组装和microRNA作为hCNT 1的推定调节剂。具体目标3将研究使用NT-Cx组合的核苷类似物应答的体内可预测性。工作假设是，由特异性NT和Cx组成的复合指数将比现有的单一指数（即，单独的平衡NT 1（hENT 1））。这一假设是基于在培养的胰腺癌细胞中获得的初步体外结果的外推。这项工作的预期成果是描绘NT-Cx相互作用的核苷类似物的化疗敏感性，战略，以提高NT-Cx介导的药物靶向，并评估临床措施，用于预测胰腺癌亚型的化疗反应。这种方法是创新的，因为它侧重于一个综合指标来判断化疗反应。这一贡献是重要的，因为它将使后续的翻译研究，预计将改善胰腺癌患者的治疗和生存结果。

DESCRIPTION (provided by applicant): Chemoresistance to nucleoside analog drugs (e.g., gemcitabine) is one of the main underlying reasons for the extremely poor prognostic state of pancreatic cancer. While the pivotal roles of cellular nucleoside transporters (NTs) and intercellular gap junctional connexins (Cxs) in determining tumor exposure of nucleoside drugs have begun to emerge, their functional interplay in determining nucleoside analog chemosensitivity and their potential in predicting response to chemotherapy remain unknown. Our long-term goal is to improve the chemotherapeutic management of pancreatic cancer. The overall objective of this R15 application is to investigate NT-Cx interplay in pancreatic cancer chemotherapy. The central hypothesis is that the type of NT-Cx combination expressed will dictate chemosensitivity and that the specific combination(s) can then be targeted to increase anti-tumor efficacy. This hypothesis has been formulated on the basis of the continuum of studies on NTs and Cxs and the recent discovery of non-genetic functional alterations in NT and Cx subtypes in pancreatic tumors. The rationale underlying the proposed research is that understanding the precise determinants of nucleoside analog sensitivity will help in the preselection of patients suitable for this type of therapy and the identification of clinical strategies to increase efficacy in poor responders. Specific aim 1 will define the role of NT-Cx combinations in nucleoside analog chemosensitivity. The working hypothesis is that gemcitabine cytotoxicity will be superior in cells expressing the concentrative NT 1 (hCNT1)-Cx32 combination, and that chemoresistance due to the loss of one component can be effectively compensated by the other. This hypothesis is based on the expression and permeation characteristics of NTs and Cxs in pancreatic tumors. Specific aim 2 will determine the regulators governing NT-Cx interplay to improve chemosensitivity. The working hypothesis is that the favorable manipulation of NT-Cx combinations to increase drug exposure can be achieved by manipulating cadherins or microRNAs. This hypothesis is based on the applicant's studies showing cadherin control of Cx assembly and microRNAs as putative regulators of hCNT1. Specific aim 3 will investigate the in vivo predictability of nucleoside analog response using NT-Cx combinations. The working hypothesis is that a composite index comprising of specific NTs and Cxs will better predict in vivo gemcitabine response than with the existing single index (i.e., equilibrative NT 1 (hENT1) alone). This hypothesis is based on the extrapolation of preliminary in vitro results obtained in cultured pancreatic cancer cells. The anticipated outcomes of this work are the delineation of NT-Cx interplay in nucleoside analog chemosensitivity, strategies to improve NT-Cx-mediated drug targeting, and evaluation of clinical measures for predicting chemotherapeutic responses in pancreatic cancer subtypes. This approach is innovative because it focuses on a comprehensive index for judging chemotherapeutic response. This contribution is significant because it will enable subsequent translational studies that are expected to improve treatment and survival outcomes in pancreatic cancer patients.