Developing a patient derived model platform to treat BRCA1/2-mutant pancreatic cancers

摘要 高达17%的胰腺癌（PDAC）患者的肿瘤含有易受肿瘤生长抑制的突变。 通过DNA损伤反应和修复（DDR）抑制策略进行开发。事实上，近10%的 BRCAPDAC携带BRCA 1/2突变，并且在高风险人群中存在较高的患病率（例如， 20%的德系犹太人）。这项研究的科学依据是携带BRCA 1/2的PDAC患者 突变对基于铂和/或聚ADP核糖聚合酶抑制剂（PARPi）的 由于合成致命性的治疗。先前研究的严谨性与我们努力利用一个有前途的， 针对BRCA 1/2突变的PDAC的个性化方法，其中已经建立了先例， 研究者的集体临床前和临床工作。虽然目前最好的个性化 治疗BRCA 1/2改变的PDAC的方法是有希望的，它限制了耐药范围 机制等我们的建议的主要和转化影响是，我们正在采取第一步， 开发和验证一个离体平台，将确定新的治疗策略，从而可以告知 BRCA 1/2突变PDAC患者的个性化治疗方法。我们的国际团队 专家，专注于PDAC的这一子集是独特的定位，以开发这个平台，利用我们的病人， 从已建立的BRCA-PANC联盟获得的癌症衍生模型（PDMC）（由 每个机构），并通过我们正在进行的一套资助的临床试验。我们将开始与一个大面板的良好- 经验证的患者源性细胞系（PDCL），来自对以下药物具有耐药性或敏感性的患者： 奥拉帕尼在目标1中，我们将评估BRCA 1/2改变的PDCL中网络的功能完整性， 我们来确定PDCL中的DDR能力是否与耐药性或敏感性一致。我们将进一步 在功能性DDR的背景下，利用该平台筛选一组可用的FDA批准的药物 能力。一旦完成，我们将确定BRCA 1/2缺陷PDAC的新药物敏感性 具有已知DDR能力的肿瘤。在目标2中，我们将扩展我们的2D研究，并采用已建立的3D 生物打印模型，以确定肿瘤微环境对药物敏感性和耐药性的影响。 此外，我们将描述和识别肿瘤微环境中驱动药物的成分。 阻力最后，我们验证了我们的体外模型在一个试点临床前，在体内实验。总的来说，我们计划 实现以下里程碑：1）评估BRCA 1/2缺陷PDCL的DDR能力以及如何做到这一点 2）确定FDA批准的药物，可用于靶向这种耐药的子集 PDAC;以及3）确定肿瘤微环境的重要性及其元素如何影响 药效这项工作将为一种新的离体平台提供框架，该平台可以： 为迫切需要新疗法的PDAC患者子集进行药物发现，和B）最终a 我们的精准医学试验中加入了互补检测。

ABSTRACT Up to 17% of pancreatic adenocarcinoma (PDAC) patients' tumors harbor mutations that are vulnerable to exploitation through DNA-damage response and repair (DDR) inhibitory strategies. In fact, nearly 10% of unselected PDACs harbor BRCA1/2 mutations, and a higher prevalence exists in high-risk populations (e.g., up to 20% of Ashkenazi Jews). The scientific basis for this study is that PDAC patients who harbor BRCA1/2 mutations are exquisitely sensitive to platinum- and/or poly ADP ribose polymerase inhibitor (PARPi)-based therapies due to synthetic lethality. The rigor of prior research relates to our efforts to leverage a promising, personalized approach to targeting BRCA1/2-mutated PDACs, where a precedent has been established by the investigators' collective pre-clinical and clinical work. Although this current best-in-class personalized approach for the treatment of BRCA1/2-altered PDACs is promising, it is limited a range of resistance mechanisms. The primary and translational impact of our proposal is that we are taking the first steps in developing and validating an ex vivo platform that will identify novel therapeutic strategies and thus may inform personalized therapeutic approaches for patients with BRCA1/2 mutant PDACs. Our international team of experts, focused on this subset of PDACs is uniquely positioned to develop this platform, utilizing our Patient- Derived Models of Cancer (PDMCs) obtained from an established BRCA-PANC consortium (supported by each institution), and through our ongoing suite of funded clinical trials. We will begin with a large panel of well- validated, patient-derived cell lines (PDCLs) from patients with documented resistance or sensitivity to olaparib. In Aim 1, we will assess the functional integrity of the network in BRCA1/2-altered PDCLs, allowing us to determine whether DDR competence in PDCLs aligns with drug resistance or sensitivity. We will further utilize this platform to screen a panel of available FDA-approved drugs in the context of functional DDR competence. Once completed, we will have identified novel drug sensitivities of BRCA1/2-deficient PDAC tumors with known DDR capabilities. In Aim 2, we will expand our 2D studies and employ an established 3D bioprinted model to determine the influence of the tumor microenvironment on drug sensitivity and resistance. Moreover, we will depict and identify components of the tumor microenvironment that are driving drug resistance. Finally, we validate our in vitro models in a pilot pre-clinical, in vivo experiment. Overall, we plan to deliver the following milestones: 1) evaluate the DDR competence of BRCA1/2-deficient PDCLs and how this relates to innate resistance; 2) identify FDA-approved drugs that may be used to target this subset of resistant PDACs; and 3) determine the significance of the tumor microenvironment and how its elements may impact drug efficacy. This work will provide the framework for a novel ex vivo platform that could be: a) utilized for drug discovery for a subset of PDAC patients in desperate need of new therapies and b) ultimately a complementary assay plugged into our precision medicine trials.