Maintenance therapy for ATM-deficient pancreatic cancer by multiple DNA repair pathway inhibition after platinum-based chemotherapy

343 Background: Germline single-nucleotide variations (SNVs) in DNA repair genes may have a role in response to platinum-based chemotherapy in bladder cancer (BC). As a pilot project we created a discovery cohort using an extreme phenotype model of BC response to neoadjuvant chemotherapy; we identified candidate SNVs in DNA repair genes via whole exome sequencing, and sought to replicate these findings in a validation cohort. Methods: We sequenced exomes of a discovery cohort with ≥ cT2 BC and neoadjuvant chemotherapy [6 complete responders (CR, pT0N0 and 1 year disease free interval) vs. 9 non-responders]. We identified SNVs within 377 DNA repair pathway genes. We filtered for SNVs with high impact effects, and moderate impact missense variants. The discovery phase resulted in 16 candidate SNVs which we genotyped (matrix-assisted laser desorption/ionization-time of flight) within a validation cohort of 303 BC patients treated with platinum-based neoadjuvant or first-line chemotherapy. Primary outcome was pathologic (neoadjuvant) or radiographic (first-line) CR, with secondary outcome CR+partial response (PR; RECIST criteria or pathologic downstaging). We used additive genetic model and logistic regression to analyze association between individual SNVs and both CR and CR+PR. Multivariate models included MSK risk score for CR or chemotherapy (cis- vs carboplatin) for CR+PR. Results: We included 303 patients (186 neoadjuvant, 117 first-line; 272 cisplatin, 31 carboplatin), median age 64, including 67 (22%) CR and 153 (50%) CR+PR. Genotyping was adequate for analysis in 14 of 16 SNVs—none were associated with CR. SNVs associated with CR+PR were rs2072454 (EGFR, p=0.031 unadjusted, p=0.035 adjusted for chemotherapy) and rs1805321 (PMS2, p=0.014 unadjusted, p=0.019 adjusted for chemotherapy). Findings were not significant after adjusting for multiple comparisons. Conclusions: Using an extreme phenotype model we identified SNVs in genes of the DNA repair pathway that may have an association with platinum-based chemotherapy response in BC. A larger validation study is required to increase power and reduce the impact of multiple testing prior to confirming significance.

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PDTM-41. INHIBITION OF DNA DOUBLE STRAND BREAK REPAIR PATHWAYS AS A PROMISING THERAPEUTIC TARGET IN DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)

Neuro-Oncology ◽

10.1093/neuonc/noz175.816 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi196-vi196

Author(s):

Sharmistha Pal ◽

Jie Bian ◽

Brendan Price ◽

Dipanjan Chowdhury ◽

Daphne Haas-Kogan

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Strand Break ◽

Repair Pathway ◽

End Joining ◽

Dsb Repair ◽

Dna Double Strand Break ◽

Repair Pathways ◽

Diffuse Intrinsic Pontine Gliomas ◽

Pathway Inhibition

Abstract New approaches to the treatment of diffuse intrinsic pontine gliomas (DIPGs) are desperately needed. DNA damage response is essential for cells to maintain genome integrity as DNA is damaged by both endogenous and exogenous stressors. Many cancer cells exhibit hyper-dependency on specific DNA repair pathways due to either defects in DNA repair mechanisms and/or high levels of endogenous stress leading to accumulation of DNA damage lesions. Identification of DIPG-specific DNA repair deficiencies and resultant dependencies may establish novel therapeutic strategies for DIPGs. METHODS To identify pathways critical for DIPG cell survival, genome wide CRISPR-Cas9 screen was performed on patient derived DIPG cell lines followed by gene set enrichment analyses. To monitor the effects of pathway inhibition on survival, apoptosis, DNA damage and repair, assays were performed to measure cell proliferation, cleaved-caspase3, gamma-H2AX and reporter based-DNA repair efficiency. RESULTS Our unbiased CRISPR approach to uncover vulnerabilities in DIPGs identified DNA double strand break (DSBs) repair pathways as essential for DIPG cell proliferation and survival. Further studies revealed high basal DSBs in DIPG cells compared to neural stem cells and primary astrocytes that suggest dependence of DIPG cell survival on specific DSB repair pathways. We confirmed the intrinsic reliance of DIPG cells on the specific DSB repair pathway of mutagenic end-joining, and defined a key role for DNA repair in suppressing endogenous DNA damage-induced apoptotic cell death. CONCLUSION DIPG cells have high endogenous DNA damage levels and escape catastrophic genomic instability and cell death by engaging DNA repair pathways, in particular the mutagenic end-joining DNA repair pathway. Inhibition of this specific DNA repair pathway represents a promising new avenue for the treatment of DIPGs.

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Abstract 09: Contribution of known and novel BRCA-mediated DNA repair pathway genes to pancreatic cancer susceptibility

10.1158/1538-7445.cansusc14-09 ◽

2014 ◽

Author(s):

Alyssa Smith ◽

Robert Grant ◽

Anita Hall ◽

Najmeh Alirezaie ◽

Spring Holter ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Repair ◽

Cancer Susceptibility ◽

Repair Pathway

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Multicentre randomized phase II trial of olaparib as maintenance therapy in platinum-sensitive advanced endometrial carcinoma: The GINECO-UTOLA study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6109 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6109-TPS6109

Author(s):

Florence Joly ◽

Pierre Emmanuel Brachet ◽

Sophie Abadie Lacourtoisie ◽

Bernard Asselain ◽

Anne Floquet ◽

...

Keyword(s):

Dna Repair ◽

Maintenance Therapy ◽

Phase Ii ◽

Phase Ii Trial ◽

Objective Response ◽

Primary Objective ◽

Small Cells ◽

Platinum Based Chemotherapy ◽

Patient Reported ◽

Eortc Qlq

TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.

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