Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer

新型替莫唑胺组合靶向 DNA 修复对结直肠癌的免疫调节作用

基本信息

批准号：
10462786
负责人：
Michael Cecchini
金额：
$ 26.1万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10462786
关键词：
ATR gene Acute Adenosine Diphosphate Ribose Alkylating Agents Alkylating Antineoplastic Agents Ancillary Study Apoptosis Award Base Excision Repairs Biological Assay Biological Markers CHEK1 gene Cancer Hospital Cancer Therapy Evaluation Program Cell Line Cells Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Colorectal Cancer Critical Pathways DNA Damage DNA Repair DNA Repair Pathway DNA replication fork Data Development Disease Disease Progression Dreams Enrollment Epigenetic Process Faculty Futile Cycling Future Gamma-H2AX Genomics Glioma Goals Grant Granzyme Health Heterogeneity Hypermethylation Immune Immune Targeting Immune response Immune system Immunofluorescence Immunologic Immunologic Markers Immunology Immunotherapy In Vitro Individual Infiltration Innovative Therapy Instruction Lesion Life MGMT gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Measures Medical Oncologist Mentors Mentorship Methods Mismatch Repair Mutation National Cancer Institute Oncology Pathogenesis Pathway interactions Patient Agents Patient-Focused Outcomes Patients Pattern Phase Ib/II Clinical Trial Phosphorylation Physicians Play Poly(ADP-ribose) Polymerases Polymerase Polyps Prevalence Prognostic Marker Property Public Health Research Personnel Resistance Role Sampling Scientist Site Specimen T-Lymphocyte Techniques Testing Therapeutic Thymine Tissue Microarray Training Translating Tumor-infiltrating immune cells Work Xenograft procedure anticancer research base biomarker identification biomarker-driven cancer type clinical trial implementation colon cancer cell line colorectal cancer progression colorectal cancer treatment design early phase clinical trial experience experimental study immunogenicity immunoregulation improved in vivo inhibitor innovation investigator-initiated trial multidisciplinary neoantigens new therapeutic target next generation novel novel marker novel therapeutic intervention novel therapeutics pre-clinical predictive marker promoter repaired replication stress response skills targeted treatment temozolomide therapeutic target tool tumor tumor heterogeneity tumor immunology tumor microenvironment tumor-immune system interactions virtual

项目摘要

ABSTRACT DNA repair plays an important role in the pathogenesis of virtually all cancer types, and the identification of aberrant DNA repair pathways has identified predictive and prognostic biomarkers to targeted therapies. For example, epigenetic hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT) predicts for better patient survival and increased sensitivity to temozolomide (TMZ) in multiple cancers, including colorectal cancer (CRC). TMZ is a monofunctional alkylator, and the DNA damage caused by TMZ is principally repaired by MGMT, which is silenced by promoter hypermethylation. The base excision repair (BER) pathway also serves as a critical pathway to repair TMZ DNA damage. Preclinically, the simultaneous inhibition of BER with polyp ADP ribose polymerase (PARP) inhibitors further sensitizes MGMT deficient tumors to TMZ. However, our preliminary findings reveal an alternative and parallel mechanism: TMZ damage causes acute replication stress and fork collapse leading to Ataxia Telangiectasia and Rad3 related (ATR) dependent phosphorylation of Checkpoint Kinase 1 (Chk1). We have leveraged these findings, and additional in vivo experiments, to advance novel TMZ combinations into the clinic with two investigator-initiated clinical trials for MGMT silenced CRC: 1) TMZ + olaparib (PARP inhibitor) and TMZ + AZD 6738 (ATR inhibitor). Enrollment will proceed at Yale Smilow Cancer Hospital with future opportunities expand to collaborating sites through our CRC Stand up to Cancer (SU2C) Dream Team. Furthermore, we aim to develop new biomarker assays including a biomarker assessing MGMT heterogeneity to identify tumors most sensitive to TMZ combinations, and perform genomic profiling. Leveraging DNA damage additionally represents a potential tool to stimulate an immune response, and through ancillary studies and using specimens obtained from our trials we will study the effects TMZ combinations on the immune microenvironment to lend support to the addition of immunotherapy in the future. I am a medical oncologist focusing on the treatment of advanced gastrointestinal (GI) cancers with an emphasis on innovative therapies for CRC. This award will facilitate my development as a physician- scientist equipped to design and conduct investigator-initiated early phase clinical trials based on innovative preclinical evidence regarding DNA repair and immunotherapies. My training will include didactic coursework for tumor immunology, practical experience of clinical trial implementation, and formal instruction in biomarker techniques. To achieve these goals, I have assembled a multidisciplinary mentorship team led by my primary mentor, Dr. Patricia LoRusso who has a proven track record of successfully mentoring junior faculty and extensive expertise in investigator-initiated clinical trials. At the conclusion of this award, I will have gained valuable skills into the underpinnings of clinical research generically, and specifically for clinical trial design, and biomarker identification for DNA repair and immunology. This award will help establish me as an independent investigator conducting early phase clinical trials for CRC and other GI cancers.

抽象的 DNA 修复在几乎所有癌症类型的发病机制中发挥着重要作用，并且识别异常 DNA 修复途径已经确定了靶向治疗的预测和预后生物标志物。为了例如，O6-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 启动子的表观遗传高甲基化预测多种癌症患者的更好的生存率和对替莫唑胺 (TMZ) 的敏感性增加，包括结直肠癌（CRC）。 TMZ是一种单功能烷基化剂，TMZ引起的DNA损伤是主要由 MGMT 修复，MGMT 因启动子高甲基化而沉默。碱基切除修复（BER）途径也是修复 TMZ DNA 损伤的关键途径。临床前，同时抑制息肉 ADP 核糖聚合酶 (PARP) 抑制剂的 BER 进一步使 MGMT 缺陷肿瘤对 TMZ 敏感。然而，我们的初步研究结果揭示了另一种平行机制：TMZ 损伤会导致急性复制压力和叉塌陷导致共济失调毛细血管扩张和 Rad3 相关 (ATR) 依赖性检查点激酶 1 (Chk1) 的磷酸化。我们利用了这些发现以及其他体内实验，通过两项研究者发起的临床试验将新型 TMZ 组合推进临床 MGMT 沉默 CRC：1) TMZ + olaparib（PARP 抑制剂）和 TMZ + AZD 6738（ATR 抑制剂）。报名将在耶鲁斯米洛癌症医院继续进行，未来的机会通过我们的合作扩展到合作地点 CRC 抗击癌症 (SU2C) 梦之队。此外，我们的目标是开发新的生物标志物检测方法包括评估 MGMT 异质性的生物标志物，以识别对 TMZ 组合最敏感的肿瘤，并进行基因组分析。另外，利用 DNA 损伤是刺激 DNA 损伤的潜在工具。免疫反应，并通过辅助研究和使用从我们的试验中获得的样本，我们将研究 TMZ 组合对免疫微环境的影响，为免疫治疗的添加提供支持将来。我是一名肿瘤内科医生，专注于晚期胃肠道 (GI) 癌症的治疗重点是 CRC 的创新疗法。这个奖项将促进我作为一名医生的发展- 科学家有能力设计和进行研究者发起的基于创新的早期临床试验有关 DNA 修复和免疫疗法的临床前证据。我的培训将包括教学课程肿瘤免疫学、临床试验实施的实践经验以及生物标志物的正式指导技术。为了实现这些目标，我组建了一个由我的校长领导的多学科指导团队导师帕特里夏·洛鲁索 (Patricia LoRusso) 博士在成功指导初级教师和在研究者发起的临床试验中拥有丰富的专业知识。在这个奖项结束时，我将获得一般临床研究基础的宝贵技能，特别是临床试验设计， DNA 修复和免疫学的生物标志物鉴定。这个奖项将帮助我成为一名独立研究者进行结直肠癌和其他胃肠道癌症的早期临床试验。