Project 3: Transcriptomic subtypes, response predictions, and therapy selection

项目 3：转录组亚型、反应预测和治疗选择

• 批准号: 10334085
• 负责人: Jen Jen Yeh
• 金额: $ 47.16万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334085
• 关键词: Aftercare; Biological Assay; Biopsy; CLIA certified; Cancerous; Cells; Cellularity; Characteristics; Classification; Clinic; Clinical; Clinical Trials; Coculture Techniques; Computing Methodologies; Consensus; Data; Data Set; Desmoplastic; Devices; Ecosystem; Effectiveness; Epidermal Growth Factor Receptor; Evaluation; Fibroblasts; Genes; Immune; Immunooncology; Infrastructure; KPC model; Letters; Libraries; Light; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Methodology; Methods; Neoadjuvant Therapy; Normal Cell; North Carolina; Organoids; Outcome; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phosphotransferases; Physicians; Prediction of Response to Therapy; Proteins; Proteomics; Regimen; Resistance; Risk; Sampling; Selection for Treatments; Signal Transduction; Treatment outcome; Tumor Subtype; Universities; Validation; Wisconsin; alternative treatment; base; cell stroma; chemotherapy; clinical infrastructure; cohort; combinatorial; differential expression; gemcitabine; improved outcome; inhibitor; innovation; kinase inhibitor; malignant breast neoplasm; medical schools; molecular subtypes; nano-string; novel; novel strategies; pancreatic cancer patients; patient derived xenograft model; patient subsets; precision oncology; predicting response; programs; prospective; response; therapy resistant; transcriptomics; treatment response; tumor; tumor microenvironment

PROJECT 3: ABSTRACT FOLFIRINOX and gemcitabine plus nab-paclitaxel (GnP) have emerged as the first-line treatment for patients with metastatic pancreatic cancer (PDAC). These two regimens have not been compared in the first-line setting, and treatment selection is guided by physician choice. Among patients with metastatic PDAC who do not respond to first-line FOLFIRINOX, a substantial proportion will have a robust response to second-line GnP. This strongly suggests that there may be a subset of patients who may have significant clinical response to GnP but not FOLFIRINOX. Matching patients to the most effective first-line therapy is a critical and unmet need. We have identified molecular subtypes of PDAC that are robust and replicable. Analysis from two clinical trials has shown that the basal subtype does not respond to FOLFIRINOX-based therapies and emphasizes the critical need to identify alternative treatments. Recent results have shown that patients with basal tumors are more responsive to GnP compared to FOLFIRINOX. Based on our findings of subtype associated treatment response, we developed a robust and replicable single-sample classifier (PurIST) that is now a CLIA-approved assay, and will be used this proposal to prospectively evaluate whether the PurIST classifier can be used to direct treatment selection. Leveraging the strength of molecular subtyping expertise at the University of North Carolina at Chapel Hill and the tremendous clinical infrastructure at the Medical College of Wisconsin’s Pancreatic Cancer Program, we propose a clinical trial where PurIST subtyping will be used to direct the initial chemotherapy. To our knowledge this will be the first trial to use molecular subtyping to direct treatment in the neoadjuvant setting. Results from this trial will demonstrate if precision oncology approaches such as PurIST may help direct treatment and improve outcome for patients that may otherwise be less responsive to either FOLFIRINOX or GnP. In parallel, we will determine if specific characteristics in the tumor and tumor microenvironment may predict response to different therapies through innovative computational approaches of cutting edge trials. Finally, through our novel proteomic approaches we have found that basal tumors have differential kinase profiles. We show that effectiveness of kinases inhibitors in PDAC may have been overlooked as ~20% of PDAC patients are basal, and that subtype-specific kinases may be promising targets.

项目3：摘要 FOLFIRINOX和吉西他滨联合NAB-紫杉醇(GNP)已成为患者的一线治疗方案 患有转移性胰腺癌(PDAC)。这两种方案还没有在一线进行比较。 设置，治疗选择由医生选择指导。在转移性PDAC患者中 如果不对一线的FOLFIRINOX做出反应，相当大一部分人将对二线的GNP做出强有力的反应。 这强烈地表明，可能有一部分患者可能对 GNP而不是FOLFIRINOX。将患者匹配到最有效的一线治疗是一个关键和未得到满足的问题 需要。 我们已经确定了PDAC的分子亚型是健壮的和可复制的。两项临床试验的分析 已经表明基本亚型对基于FOLFIRINOX的治疗没有反应，并强调 迫切需要确定替代治疗方法。最近的研究结果表明，基底肿瘤患者 与FOLFIRINOX相比，对GNP的反应更快。根据我们对亚型联合治疗的发现 作为回应，我们开发了一个健壮且可复制的单样本分类器(Purist)，它现在是CLIA批准的 化验，并将利用这一建议来前瞻性地评估纯粹主义分类器是否可以用于 直接选择治疗方法。 利用北卡罗来纳大学教堂山分校的分子分型专业知识 威斯康星医学院胰腺癌项目的巨大临床基础设施，我们 建议进行一项临床试验，其中将使用纯粹主义亚型来指导最初的化疗。致我们的 知道这将是第一次在新辅助治疗环境中使用分子亚型来指导治疗的试验。 这项试验的结果将证明，精准肿瘤学方法，如Purist，是否有助于指导 对对FOLFIRINOX或FOLFIRINOX反应较差的患者进行治疗并改善结果 国民生产总值。 同时，我们将确定肿瘤的特定特征和肿瘤微环境是否可以预测 通过前沿试验的创新计算方法，对不同的治疗方法作出反应。最后， 通过我们新的蛋白质组学方法，我们发现基底肿瘤具有不同的激酶图谱。我们 显示约20%的PDAC患者可能忽略了激酶抑制剂在PDAC中的有效性 是基础的，亚型特异的激酶可能是有希望的靶点。