Integrating Epigenetic Modulation into DNA Damage Repair

将表观遗传调节整合到 DNA 损伤修复中

• 批准号: 10632128
• 负责人: Pamela N. Munster
• 金额: $ 64.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10632128
• 关键词: Acceleration; Aftercare; 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; Combined Modality Therapy; 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; Epigenetic Process; Ethnic Origin; 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) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Race; 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; follow-up; functional status; homologous recombination; improved; in vivo; in vivo Model; insight; interest; lifetime risk; malignant breast neoplasm; participant enrollment; patient derived xenograft model; patient population; patient response; phase I trial; predictive marker; 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

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.

随着同源重组修复，癌症遗传性 DNA 修复突变的筛查已加速 (HRR) 缺陷的肿瘤对 DNA 损伤剂和聚 (ADP-核糖) 聚合酶抑制剂反应良好 (PARPi)。最常见的 HRD 突变包括 BRCA1、BRCA2、ATM 和 CHEK2。 所有种族和民族背景的终生乳腺癌风险为 40-80%，并且对以下人群构成较高风险： 虽然卵巢癌、前列腺癌和胰腺癌的毒性较小，但对 PARP 抑制剂的反应通常仍然很短。 尽管 ATM 和 CHEK2 中 PARP 抑制剂的初始缓解率很高，但从机制上来说，这是预期的。 但尚未确定重叠的毒性对 PARPi 与 PARPi 结合的能力提出了重大挑战。 化疗和免疫治疗组合对大多数乳腺癌亚型的益处仍然有限。 为了增强 PARPi 功效，我们研究了增加 DNA 捕获和 DNA 抑制的策略 DNA 甲基转移酶 (DNMT) 直接调节 DNA 修复途径并与之复合发挥作用。 PARP 修复单链 DNA 断裂因此，我们追求 DNMT 抑制会显着。 提高 PARP 抑制对 HRD 癌症的治疗效果 我们发现增强的 PARP 捕获和 初步研究显示低剂量 DNMT 抑制剂、地西他滨和 PARPi 具有非常有前景的协同功效 体外和体内研究在基因工程 HRR 突变的癌细胞中显着增强 线和 PDX 模型对组合的反应因肿瘤（子）组织背景而异，并选择 HRD。 我们工作的初步数据已导致我们赞助的剂量发现一期试验获得批准。 由联盟网络 (A092003) 提供。在此应用中，我们将探索生物标志物和敏感性机制。 以及对 PARP 和 DNMT 联合治疗的抵抗力，以提供更深入的机制见解和指导 临时批准的大型随机 ComboMatch 试验 (EAY191 A4) 中的患者选择的三个目标。 目标 1：确定 PARP 和 DNMT 组合的协同作用机制和比较效果 在体外、异种移植物中对携带 4 个不同 HRR 途径基因的靶向突变的同基因细胞系进行抑制 并与具有相似 HRR 突变但遗传背景不同的已建立的 PDX 进行比较。 目标 2：使用治疗前和治疗后的肿瘤活检以及 I 期患者的连续血液样本 Alliance Network (A092003) 试验旨在详细了解患者的 HRR 突变，并伴随 建立患者来源的异种移植物 (PDX) 的基因组景观和功能状态。 用于目标 3 评估循环肿瘤 DNA (ctDNA) 工作的活检标本。 用于治疗反应的预测生物标志物。 目标 3：从诊所回到实验室，测试 PDX 治疗反应的准确性和 类器官模型与源患者反应进行比较，确定 PARPi+DNMTi 治疗耐药性 机制，测试对潜在后续治疗的敏感性。