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.

随着同源重组修复技术的发展，癌症中遗传DNA修复突变的筛查已经加速