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：
10675088
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/10675088
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 Immunologic Stimulation Immunology Immunotherapy In Vitro Individual 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) Polymerase Inhibitor Polymerase Polyps Predisposition Prevalence Prognostic Marker Property Public Health Research Personnel Resistance Role Sampling Scientist Site Specimen T-Lymphocyte Techniques Testing Therapeutic Thymine Tissue Microarray Training Translating Work Xenograft procedure anticancer research biomarker driven biomarker identification cancer type clinical trial implementation colon cancer cell line colorectal cancer progression colorectal cancer treatment design early phase clinical trial experience experimental study immune cell infiltrate immunogenicity immunoregulation immunostimulatory therapy 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理中都起着重要作用，并且鉴定异常的DNA修复途径已确定了靶向疗法的预测性和预后生物标志物。为了例如，O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）的启动子的表观遗传性高甲基化预测在多种癌症中对替莫唑胺（TMZ）的敏感性提高，可以提高患者的生存率，包括结直肠癌（CRC）。 TMZ是一种单官能烷基，由TMZ造成的DNA损伤为主要由MGMT修复，该MGMT被启动子高甲基化沉默。基础切除修复（BER）途径也是修复TMZ DNA损伤的关键途径。临床上，同时抑制用息肉ADP核糖聚合酶（PARP）抑制剂的BER进一步使MGMT缺乏肿瘤对TMZ敏感。但是，我们的初步发现揭示了一种替代和平行机制：TMZ损害导致急性复制应力和叉子崩溃，导致触发性共济失调和RAD3相关（ATR）依赖检查点激酶1（CHK1）的磷酸化。我们利用了这些发现和其他体内实验，通过两项研究者发起的临床试验将新型的TMZ组合推向诊所 MGMT沉默CRC：1）TMZ + Olaparib（PARP抑制剂）和TMZ + AZD 6738（ATR抑制剂）。注册会通过我们 CRC站在癌症（SU2C）梦中。此外，我们旨在开发新的生物标志物测定法包括评估MGMT异质性的生物标志物，以鉴定对TMZ组合最敏感的肿瘤，并执行基因组分析。利用DNA损伤另外代表了刺激的潜在工具免疫反应，以及通过辅助研究并使用从我们的试验中获得的标本，我们将研究影响TMZ组合对免疫微环境的效果，以增加支持免疫疗法将来。我是一名医学肿瘤学家，专注于治疗晚期胃肠道（GI）癌症重点是CRC的创新疗法。该奖项将促进我作为医生的发展 - 具有创新的科学家，能够设计和进行研究人员发起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用于肿瘤免疫学，临床试验实施的实践经验以及生物标志物的正式教学技术。为了实现这些目标，我组建了一个由我的小学领导的多学科指导团队导师Patricia Lorusso博士拥有成功指导初级教师和研究人员发起的临床试验中广泛的专业知识。在此奖项结束时，我将获得一般，专门针对临床试验设计的临床研究基础，有价值的技能，以及用于DNA修复和免疫学的生物标志物鉴定。这个奖项将帮助我确立独立的研究人员为CRC和其他GI癌进行了早期临床试验。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impact of early detection on cancer curability: A modified Delphi panel study.

DOI：
10.1371/journal.pone.0279227
发表时间：
2022
期刊：
PLOS ONE
影响因子：
3.7
作者：
Schwartzberg, Lee;Broder, Michael S.;Ailawadhi, Sikander;Beltran, Himisha;Blakely, L. Johnetta;Budd, G. Thomas;Carr, Laurie;Cecchini, Michael;Cobb, Patrick;Kansal, Anuraag;Kim, Ashley;Monk, Bradley J.;Wong, Deborah J.;Campos, Cynthia;Yermilov, Irina
通讯作者：
Yermilov, Irina

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

DOI：
10.1158/2767-9764.crc-23-0045
发表时间：
2023-06
期刊：
CANCER RESEARCH COMMUNICATIONS
影响因子：
0
作者：
Cecchini, Michael;Zhang, Janie Y.;Wei, Wei;Sklar, Jeffrey;Lacy, Jill;Zhong, Minghao;Kong, Yong;Zhao, Hongyu;DiPalermo, Jassim;Devine, Lesley;Stein, Stacey M.;Kortmansky, Jeremy;Johung, Kimberly L.;Bindra, Ranjit S.;LoRusso, Patricia;Schalper, Kurt A.
通讯作者：
Schalper, Kurt A.

Hybrid-control arm construction using historical trial data for an early-phase, randomized controlled trial in metastatic colorectal cancer.