Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy

大手术和腹腔热化疗后 DNA 损伤的变化

• 批准号: 10677711
• 负责人: JOSEPH KIM
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677711
• 关键词: Adjuvant; Bathing; Blood specimen; Cell Line; Chemotherapy-Oncologic Procedure; Clinical; Cytotoxic Chemotherapy; Cytotoxic agent; DNA; DNA Damage; DNA Mismatch Repair Protein MLH1; DNA Repair Disorder; Data; Defect; Deposition; Disease; Disease Progression; Disseminated Malignant Neoplasm; Eligibility Determination; Excision; Exhibits; Genomic Instability; Greater sac of peritoneum; Heat shock proteins; Human; Hyperthermia; Immune System Diseases; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Inflammation; Inflammatory Response; MLH1 gene; MSH2 gene; Malignant Neoplasms; Measurement; Measures; Microsatellite Instability; Microscopic; Mismatch Repair; Mitomycin C; Monoclonal Antibodies; Multi-Institutional Clinical Trial; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Peritoneal; Phase; Physiological; Process; Prognosis; Progression-Free Survivals; Proteins; Randomized, Controlled Trials; Regimen; Relapse; Research; Resected; Safety; Site; Specimen; Stress; Testing; Therapeutic heat application; Tissue Sample; Tissues; Toxic effect; Tumor Debulking; anti-PD-1; cancer cell; cancer surgery; cancer survival; checkpoint therapy; chemotherapy; clinical predictors; colon cancer patients; cytokine; drug sensitivity; experience; improved; inhibitor therapy; intraperitoneal therapy; member; metastatic colorectal; neoantigens; operation; pembrolizumab; programmed cell death protein 1; response; tumor

ABSTRACT/SUMMARY Nearly 10% of patients with metastatic colorectal cancer (mCRC) have progression of disease involving the spread of metastatic cancer to the peritoneal cavity. These patients generally have the worst outcomes for all patients with mCRC. A recent phase III multicenter clinical trial has shown that single-agent immune checkpoint inhibitor (ICI) has greater efficacy and better safety profile than standard cytotoxic chemotherapy regimens for patients with mCRC. Importantly, indications to receive ICI therapy are dependent on the measurement of high tumor mutation burden (TMB), neoantigen burden, and microsatellite instability (MSI) status. These direct and indirect measures of genomic instability predict clinical response to ICIs, however, only 5% of patients are currently eligible to receive these therapies. Patients with mCRC with peritoneal spread of disease may undergo major cytoreductive surgery (CRS), during which all gross sites of disease are resected. CRS is combined with heated intraperitoneal chemotherapy (HIPEC) with mitomycin C at 43°C to eradicate microscopic disease. We hypothesize that major surgical inflammation from CRS and the heat and chemotherapy of HIPEC altogether increase genomic instability. Surgical inflammation is known to activate heat shock proteins (Hsps) which may destabilize its regulatory control over mismatch repair (MMR) proteins leading to deficient DNA repair. This condition combined with the DNA damaging effects of mitomycin c and heat may lead to high TMB, increased neoantigens, and altered MSI in occult microscopic mCRC cells. Our overarching hypothesis is that patients undergoing CRS/HIPEC will be eligible to receive and will benefit from ICI therapy. We propose to obtain blood samples and surgical tissues before and after CRS/HIPEC from patients with mCRC. These specimens will be assessed for changes in TMB and neoantigens (Aim 1) and MMR/MSI (Aim 2). From the surgical tissues, we will also create paired patient-derived organoids (PDOs) from which we will investigate Hsps, MMR proteins, and MSI. Our prior studies using PDOs from CRS/HIPEC patients support their use to assess sensitivities to ICI therapies before and after CRS/HIPEC. We propose the following specific aims: Specific Aim 1. To measure alterations in TMB and neoantigens as a result of the heat and DNA damaging effects of mitomycin C in mCRC patients undergoing CRS/HIPEC. Specific Aim 2. To determine whether surgical inflammation combined with heat and DNA damaging effects of mitomycin C from CRS/HIPEC disrupt Hsp-stabilization of MMR proteins to increase MSI.

摘要/摘要 近10％的转移性结直肠癌（MCRC）患者的疾病进展 转移性癌症传播到腹膜腔。这些患者通常对所有患者的结果最差 MCRC患者。最近的III阶段多中心临床试验表明，单药免疫切除点 抑制剂（ICI）比标准的细胞毒性化疗方案具有更高的效率和更好的安全性。 MCRC患者。重要的是，接受ICI疗法的适应症取决于高度测量 肿瘤突变伯嫩（TMB），新抗原伯恩和微卫星不稳定性（MSI）状态。这些直接和 基因组不稳定性的间接度量预测了对ICI的临床反应，但是，只有5％的患者是 目前有资格接受这些疗法。 疾病腹膜腹膜散布的MCRC患者可能会接受主要的细胞减少手术（CRS） 所有总体疾病部位均已切除。 CRS与加热的腹膜内化学疗法结合 （HIPEC）与丝裂霉素C在43°C下进行放射素微观疾病。我们假设主要手术 CRS的炎症和HIPEC的热和化学疗法完全增加了基因组不稳定性。 已知手术炎症会激活热休克蛋白（HSP），这可能破坏其调节控制 超匹配修复（MMR）蛋白质导致DNA修复不足。这种情况与DNA结合 丝裂霉素C和热量的破坏作用可能导致高TMB，新抗原增加并改变了MSI 神秘的微观MCRC细胞。我们的总体假设是，接受CRS/HIPEC的患者将是 有资格获得并将受益于ICI疗法。 我们建议从MCRC患者的CRS/HIPEC之前和之后获得血液样本和手术组织。 这些标本将用于评估TMB和新抗原（AIM 1）和MMR/MSI（AIM 2）的变化。从 手术组织，我们还将创建配对的患者衍生的类器官（PDOS），我们将从中调查 HSP，MMR蛋白和MSI。我们先前使用CRS/HIPEC患者PDO的研究支持他们的用途 评估CRS/HIPEC前后对ICI疗法的敏感性。我们提出以下具体目标： 特定目的1。测量由于热和DNA损害而导致TMB和新抗原的改变 丝裂霉素C在接受CRS/HIPEC的MCRC患者中的影响。 具体目的2。确定手术炎症是否与热和DNA损伤效应相结合 来自CRS/HIPEC的丝裂霉素C破坏MMR蛋白的HSP稳定化，以增加MSI。