Integrating Epigenetic Modulation into DNA Damage Repair

将表观遗传调节整合到 DNA 损伤修复中

基本信息

批准号：
10446970
负责人：
Pamela N. Munster
金额：
$ 65.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-06 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446970
关键词：
Alternative Therapies BRCA mutations BRCA1 gene BRCA2 gene Back Biological Markers Biological Models Biopsy Biopsy Specimen Blood Blood specimen Breast Breast Cancer Risk Factor CHEK2 gene Cancer Therapy Evaluation Program Cancer cell line Cell Line Cells Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combination immunotherapy Communities Companions Complex Correlative Study DNA DNA Damage DNA Methyltransferase Inhibitor DNA Modification Methylases DNA Repair DNA Repair Inhibition DNA Repair Pathway DNA Single Strand Break DNA methyltransferase inhibition Data Decitabine Dose Drug Combinations Engineering Enrollment Epigenetic Process Gene Mutation Genes Genetic Genetic Engineering Genomics Hereditary Malignant Neoplasm In Vitro Individual Inherited Laboratories Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Modeling Molecular Mutate Mutation Organoids Pathway interactions Patient Selection Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Poly(ADP-ribose) Polymerases Randomized Refractory Regimen Resistance Risk Role Sampling Source Testing Therapeutic Tissues Toxic effect Translating Work Xenograft procedure brca gene cancer subtypes cell type chemotherapy clinically relevant comparative efficacy study follow-up functional status homologous recombination improved in vivo in vivo Model inhibitor insight interest lifetime risk malignant breast neoplasm patient derived xenograft model patient population patient response phase I trial predictive marker racial and ethnic recombinational repair repair function repaired resistance mechanism response screening side effect synergism therapeutic target therapy resistant treatment response tumor tumor DNA tumor progression tumor xenograft

项目摘要

Screening for hereditary DNA repair mutations in cancer has accelerated as Homologous Recombination Repair (HRR) deficient tumors respond well to DNA damaging agents and poly (ADP-ribose) polymerase inhibitors (PARPi). The most common HRD mutations include BRCA1, BRCA2, ATM, and CHEK2. Such mutations convey a 40-80% lifetime breast cancer risk across all racial and ethnic backgrounds, and pose elevated risks for ovarian, prostate and pancreatic cancer. While less toxic, responses to PARP inhibitors are still often short, despite a high initial response rate. Efficacy of PARP inhibitors in ATM and CHEK2 is mechanistically expected, but not yet established. Overlapping toxicities have significantly challenged the ability to combine PARPi with chemotherapy, and immunotherapy combinations remain of limited benefit in most breast cancer subtypes. In a quest to enhance PARPi efficacy, we studied strategies to increase DNA trapping and inhibition of DNA repair. DNA methyltransferases (DNMTs) directly modulate the DNA repair pathway and work in complex with PARP to repair single strand DNA breaks. As such, we hypothesize that DNMT inhibition would significantly improve the therapeutic benefit of PARP inhibition in HRD cancer. We found enhanced PARP trapping and promising synergistic efficacy with very low doses of the DNMT inhibitor, decitabine, and PARPi in preliminary in vitro and in vivo studies which was significantly enhanced in genetically engineered HRR mutated cancer cell lines and PDX models. Responsiveness to the combination varied by tumor (sub) tissue context and select HRD gene mutation. Preliminary data form our work has led to the approval of a dose finding phase I trial sponsored by the Alliance Network (A092003). In this application, we will explore biomarkers and mechanisms of sensitivity and resistance to combination PARP and DNMT treatment to provide deeper mechanistic insights and guide patient selection in the provisionally-approved large randomized ComboMatch trial (EAY191 A4) in three aims. Aim 1: Determine the mechanism of synergy and comparative effects of combined PARP and DNMT inhibition in isogenic cell lines bearing targeted mutation of 4 different HRR pathway genes, in vitro, in xenografts, and in comparison to established PDX with similar HRR mutations but different genetic backgrounds. Aim 2: Use pre- and posttreatment tumor biopsy and serial blood samples from patients in the Phase I Alliance Network (A092003) trial to generate a detailed understanding of patient’s HRR mutation, accompanying genomic landscape, and functional status of the HRR pathway. Establish Patient Derived Xenografts (PDX) from biopsy specimens for work in Aim 3 regarding resistance mechanisms. Assess circulating tumor DNA (ctDNA) for predictive biomarkers of therapeutic response. Aim 3: Translating from the clinic back to the bench, test the veracity of the therapeutic responses in PDX and organoid models compared to the source patient responses, identify PARPi+DNMTi therapeutic resistance mechanisms, test sensitivity to potential followup therapeutics.

筛查癌症中的胸腺DNA修复突变已加速作为同源重组修复（HRR）缺乏肿瘤对DNA损伤剂和聚（ADP-核糖）聚合酶抑制剂的反应良好（parpi）。最常见的HRD突变包括BRCA1，BRCA2，ATM和CHEK2。这样的突变传达在所有种族和种族背景下，终身乳腺癌风险为40-80％，对卵巢，前列腺和胰腺癌。虽然毒性较小，但对PARP抑制剂的反应仍然很短，但尽管初始响应率很高。 PARP抑制剂在ATM和CHEK2中的功效是机械预期的，但尚未确定。重叠的策略极大地挑战了将PARPI与在大多数乳腺癌亚型中，化学疗法和免疫疗法组合仍然有限。为了提高PARPI效率，我们研究了增加DNA捕获和抑制DNA的策略维修。 DNA甲基转移酶（DNMTS）直接调节DNA修复途径，并与 PARP修复单链DNA断裂。因此，我们假设DNMT抑制作用将显着提高PARP抑制在人力资源癌症中的治疗益处。我们发现增强的PARP捕获和具有非常低剂量的DNMT抑制剂的有希望的协同效率，在初步中决定和PARPI 体外和体内研究在一般设计的HRR突变癌细胞中显着增强线和PDX模型。对组合的响应能力因肿瘤（子）组织环境而异，然后选择HRD 基因突变。初步数据表格我们的工作导致了剂量查找I期试验的批准通过联盟网络（A092003）。在此应用中，我们将探索生物标志物和灵敏度机制以及对组合PARP和DNMT治疗的抵抗力，以提供更深的机械见解和指南在临时批准的大型随机组合试验（EAY191 A4）中，患者在三个目标中进行了选择。目标1：确定合并PARP和DNMT的协同作用和比较效应的机制在体外，异种移植物中，具有4种不同HRR途径基因的靶向突变的同基因细胞系的抑制作用，与具有相似HRR突变但遗传背景不同的已建立的PDX相比。 AIM 2：使用I阶段的患者的治疗前和治疗后肿瘤活检和连续血样联盟网络（A092003）试验，以产生对患者HRR突变的详细了解，涉及基因组景观和HRR途径的功能状态。建立从患者衍生的异种移植物（PDX）针对AIM 3工作的活检标本，涉及电阻机制。评估循环肿瘤DNA（CTDNA）用于治疗反应的预测生物标志物。 AIM 3：从诊所转移到长凳上，测试PDX和与源患者反应相比，类器官模型，识别PARPI+DNMTI治疗性抗性机制，对潜在随访疗法的测试敏感性。