Improving response prediction to neoadjuvant therapy in pancreatic cancer

项目摘要 局限性胰腺癌（PC）的发病率正在上升，预计这一趋势将继续下去，因为越来越多的使用 成像模式和早期癌症检测的重点项目。虽然有可能治愈，但长期结果 本地PC仍然很差。这是由于早期微转移扩散和全身复发的风险， 使用全身化疗可降低。此外，手术前使用化疗可降低阳性率， 边缘和这些集体观察导致采用新辅助化疗（NAC），即在手术前 对于大多数患者，切除。NAC延长多个月（4-6个月），以便对缓解进行真实的时间评估 很危险然而，这仍然是一个很大的临床挑战，因为胰腺肿瘤的大小不会随着NAC的使用而改变很多， 肿瘤标志物缺乏特异性。手术切除标本对NAC的病理反应是高度的， 预后，但其分子预测仍然知之甚少。PC的转录亚型包括经典和 基础亚型;后者类似于三阴性乳腺癌，显示化疗耐药性，并富含 转移性疾病胰腺肿瘤的单细胞分析揭示了经典和基础之间的广泛异质性 亚型以及具有两种特征的共表达的细胞。在目标1中，我们使用了174名患者的机构队列， 在接受NAC治疗后接受胰腺肿瘤切除术，以确定使用前 治疗肿瘤标本。我们将使用经验证的多重检测来研究经典基底细胞状态异质性。 免疫荧光小组在初始诊断活检中的作用，以了解表现出以下特征的肿瘤之间细胞状态的差异： 主要反应与无病理反应。为了确定新的预测转录状态， 我们将使用Nanostring GeoMx平台进行数字空间分析。在目标2中，我们建议 研究高灵敏度ctDNA测定法在NAC期间跟踪肿瘤负荷和细胞状态变化的效用。我们 期望NAC期间的差异ctDNA动力学来预测结果。此外，使用基于新ctDNA的表观遗传学方法， 我们将评估肿瘤细胞状态是否在对更基础类型的治疗抗性出现期间演变。这 这项工作将导致识别新的预测生物标志物，可以帮助医生识别高风险病例， 不太可能对传统NAC有反应或在真实的时间内发现早期治疗耐药性，并促进早期转换为 替代化疗或考虑临床试验，改善患者的结局 本地化PC拟议的研究将在Dana-Farber癌症研究所进行，由Brian博士指导 作者声明：Andrew Aguirre.两者都是PC生物学领域公认的国际领导者。重要的是，这一研究战略是 一个全面的培训计划的一部分，以支持我过渡到一个独立的研究生涯在翻译 癌症生物学我的科学顾问（迈尔斯·布朗、瑞安·科科伦和埃利泽·货车艾伦博士）都是杰出的专家 具有与拟议研究高度相关的经验。我的长期目标是领导一个独立的学术研究 小组，专注于破译新的生物标志物和PC耐药的潜在机制。K 08奖 将为继续指导研究提供关键的保护时间，并使其成功过渡到独立。

PROJECT SUMMARY Localized pancreatic cancers (PC) are rising in incidence and this trend is expected to continue due to increased use of imaging modalities and focused programs on early cancer detection. Although potentially curable, long terms outcomes for localized PC remain poor. This is due to early micrometastatic spread and risk of systemic recurrence which has been reduced with use of systemic chemotherapy. In addition, use of chemotherapy prior to surgery lowers rates of positive margins and these collective observations have led to the adoption of neoadjuvant chemotherapy (NAC), i.e. prior to surgical resection, for majority of patients. NAC extends for multiple months (4-6 months) making real time assessment of response critical. However, this remains a big clinical challenge as pancreatic tumors don’t change much in size with NAC and use of tumor markers is marred by lack of specificity. Pathologic response to NAC on surgical resection specimens is highly prognostic, yet its molecular predictors remain poorly understood. Transcriptional subtypes of PC include classical and basal subtypes; the latter resembles triple negative breast cancer, displays chemotherapy resistance, and is enriched in metastatic disease. Single cell analysis of pancreatic tumors reveals extensive heterogeneity between classical and basal subtypes as well cells with co-expression of both features. In Aim 1, we use our institutional cohort of 174 patients who underwent pancreatic tumor resection after receiving NAC to identify predictors of pathologic treatment response using pre- treatment tumor specimens. We will investigate the classico-basal cell state heterogeneity using a validated multiplex immunofluorescence panel on initial diagnostic biopsies to understand differences in cell state between tumors which exhibit major response vs. no pathologic response. To identify novel predictive transcriptional states beyond classical-basal subtyping we will perform digital spatial profiling using the Nanostring GeoMx platform. In Aim 2, we propose investigating the utility of highly sensitive ctDNA assays to track changes in tumor burden and cell state during NAC. We expect differential ctDNA dynamics during NAC to predict outcomes. In addition using novel ctDNA based epigenetic assays we will assess whether tumoral cell state evolves during emergence of therapeutic resistance to more basal type. This work will lead to identification of novel predictive biomarkers which can help physicians identify high risk cases which are unlikely to respond to traditional NAC or identify early treatment resistance in real time and facilitate earlier switch to alternative chemotherapy or consideration of clinical trials leading to an improvement in outcomes for patients with localized PC. The proposed research will be performed at Dana-Farber Cancer Institute, under the guidance of Drs. Brian Wolpin and Andrew Aguirre. Both are recognized international leaders in PC biology. Importantly, this research strategy is one part of a comprehensive training program to support my transition to an independent research career in translational cancer biology. My scientific advisors (Drs. Myles Brown, Ryan Corcoran, and Eliezer Van Allen) are distinguished experts with experience highly relevant to the proposed research. My long-term goal is to lead an independent academic research group, focused on deciphering the novel biomarkers and mechanisms underlying therapy resistance in PC. The K08 award will provide pivotal protected time for continued mentored research and enable a successful transition to independence.