Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer

摘要 胰腺癌是一种毁灭性的疾病，五年存活率低于10%。其中一个主要因素是 突显这种低存活率的是缺乏有效的临床治疗。吉西他滨化疗是 最广泛使用的治疗胰腺癌的药物，因为它的耐受性很好，即使只治疗 略微延长了存活率。在其他癌症中，吉西他滨可能非常有效。的有限效用 吉西他滨治疗胰腺癌被认为是由于肿瘤中的非癌细胞产生了物理上的 限制药物输送的障碍。根据这个模型，化疗药物不能穿透 肿瘤并到达癌细胞。我们发现肿瘤相关巨噬细胞(TAMs)，一种非癌性的 免疫细胞类型，大量分泌核苷脱氧胞苷(DC)，这直接抑制细胞毒 吉西他滨的活性。在这项研究提案中，我们将定义TAMS和TAMS如何制作和释放DC 胰腺癌细胞如何获得和利用DC来促进吉西他滨耐药。我们还将测试 DC释放是属性的假设可以通过对表型的重新编程来逆转。 这些研究将使用代谢组学技术和抑制剂相结合来完成 代谢和信号转导。同时，我们将干扰-胰腺癌DC在人体内的串扰 确定患者来源的微肿瘤模型在同基因小鼠模型中的翻译价值。这个 将这些研究的见解应用于临床可能会对患者产生立竿见影的影响。一种手段 基于性质预测吉西他滨疗效和/或通过靶向提高吉西他滨疗效 的表型将增加这种耐受性良好的、主要的治疗方案对慢性阻塞性肺疾病患者的实用性 胰腺癌。

ABSTRACT Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors underscoring this low survival rate is the lack of effective clinical treatments. The chemotherapy gemcitabine is the most widely used agent for pancreatic cancer due to its well tolerated profile, even though treatment only marginally extends survival. In other cancers, gemcitabine can be very effective. The limited utility of gemcitabine in pancreatic cancer is thought to result from non-cancerous cells in the tumor creating a physical barrier limiting drug delivery. According to this model, chemotherapeutic agents are unable to penetrate the tumor and reach the cancer cells. We found that tumor associated macrophages (TAMs), a non-cancerous immune cell type, abundantly secrete the nucleoside deoxycytidine (dC), and this directly inhibits the cytotoxic activity of gemcitabine. In this research proposal, we will define how dC is made and released by TAMs and how dC is obtained and utilized by pancreatic cancer cells to promote gemcitabine resistance. We will also test the hypothesis that dC release is a TAM property that can be reversed by reprogramming the TAM phenotype. These studies will be accomplished using metabolomics techniques in combination with inhibitors of metabolism and signal transduction. In parallel, we will disrupt TAM-pancreatic cancer dC crosstalk in human patient-derived microtumor models and in syngeneic mouse models to determine the translation value. The clinical application of insights from these studies could have an immediate impact on patients. A means to predict gemcitabine response based on TAM properties and/or to enhance gemcitabine efficacy by targeting the TAM phenotype would increase the utility of this well-tolerated, mainstay treatment option for patients with pancreatic cancer.