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 和吉西他滨加白蛋白结合型紫杉醇 (GnP) 已成为患者的一线治疗 尚未在一线治疗中对这两种方案进行比较。 在患有转移性 PDAC 的患者中，治疗选择由医生选择指导。 对一线 FOLFIRINOX 没有反应的人，相当一部分人会对二线 GnP 产生强烈反应。 这强烈表明可能有一部分患者可能对药物有显着的临床反应 让患者接受最有效的一线治疗是 GnP 而不是 FOLFIRINOX 的关键，但尚未得到满足。 需要。 我们通过两项临床试验确定了稳健且可复制的 PDAC 分子亚型。 已表明基础亚型对基于 FOLFIRINOX 的疗法没有反应，并强调 最近的结果表明，基底肿瘤患者迫切需要确定替代疗法。 根据我们对亚型相关治疗的发现，与 FOLFIRINOX 相比，对 GnP 的反应更灵敏。 响应，我们开发了一个强大且可复制的单样本分类器 (PurIST)，现已获得 CLIA 批准 分析，并将使用该提案前瞻性地评估 PurIST 分类器是否可用于 直接治疗选择。 利用北卡罗来纳大学教堂山分校分子分型专业知识的优势和 威斯康星医学院胰腺癌项目拥有庞大的临床基础设施，我们 提出一项临床试验，其中 PurIST 亚型将用于指导初始化疗。 据了解，这将是第一个使用分子分型来指导新辅助治疗的试验。 该试验的结果将证明 PurIST 等精准肿瘤学方法是否有助于指导 治疗并改善可能对 FOLFIRINOX 或 FOLFIRINOX 反应较差的患者的结果 国民生产总值。 同时，我们将确定肿瘤和肿瘤微环境中的特定特征是否可以预测 最后，通过尖端试验的创新计算方法对不同的疗法做出反应。 通过我们新颖的蛋白质组学方法，我们发现基底肿瘤具有不同的激酶谱。 表明激酶抑制剂对 PDAC 的有效性可能被忽视，因为约 20% 的 PDAC 患者 是基础的，亚型特异性激酶可能是有希望的靶标。