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Ref Type abstract
Authors Victor Ng; Sonali Sinha; Ardijana Novaj; Jennifer Ma; Niamh McDermott; Ana Longhini; Rui Gardner; Ezra Rosen; Simon Powell; Diana Mandelker; Atif Khan; Jeremy Setton; Anne Roulston; Stephen Morris; Maria Koehler; Nancy Lee; Jorge Reis-Filho; Nadeem Riaz
Title Abstract A002: Genotype-directed synthetic cytotoxicity of ATR inhibition with radiotherapy
Abstract Text The DNA damage response is crucial for the efficacy of radiotherapy (RT), prompting efforts to target this pathway with radiosensitizers to improve outcomes. Early clinical trials evaluating this approach, however, have failed to yield evidence of benefit in unselected populations. Here we demonstrate that a genotype-directed combination of DNA repair inhibition and RT can unleash the significant therapeutic benefit of this approach in pre-clinical models and present first experience from a Phase I/II trial (NCT05566574) testing this concept. Using CRISPR/Cas9, we created isogenic murine models (Atm-/- and WT) in 4T1 breast and CT26 colorectal cancer models, and then studied the synergy between camonsertib and RT across genotypes. In vitro, camonsertib radio-sensitized both Atm-/-and WT models, but was more potent and synergistic in Atm-/- models. In the orthotopically implanted 4T1 model, the combination of camonsertib (30 mg/kg, 3 days on; 4 days off) with RT (20Gy x 1) significantly delayed tumor growth in Atm-/- tumors compared to WT (p < 0.001; n=10 mice per group). Overall survival (OS) also improved in mice with Atm-/- tumors (20% alive at 150 days) vs. WT (0% alive; p < 0.001; log-rank test). Similar results were observed using other RT dose-fractionations (4Gy x 5 daily, 6Gy x 3, 8Gy x 2) with camonsertib. In the flank-implanted CT26 model, Atm-/- tumors had markedly improved response to combination therapy with 7/8 mice achieving a complete response (CR) compared to only 1/8 WT tumors (p<0.001). OS was also significantly improved with 87% of mice with CT26 Atm-/- tumors cured compared to 0% of CT26 WT tumors (p < 0.001). To evaluate the genotype-specificity for synergy from combination therapy, we performed similar experiments in a 4T1 Brca1-/- model, a key mediator of homologous recombination, and observed an absence of synergy, consistent with our hypothesis. Analysis of the microenvironment of 4T1 Atm-/- treated with combination therapy by flow cytometry did not reveal significant increases in CD4 or CD8 T-cells compared to vehicle nor increases in activated CD8 T-cells (Ki67+, PD1+, or GzmB+) suggesting the therapeutic benefit was primarily mediated by cell intrinsic effects. Similarly, re-challenge experiments in cured mice did not identify strong evidence of immunologic memory, again suggesting a modest immunologic role for efficacy of combination therapy in this setting. Based on these results, we initiated a Phase I/II study of camonsertib with RT (4Gy x 5) in patients with metastatic cancer that require palliative RT and have mutations in ATM (pathogenic or variant of unknown significance). The first two patients with pathogenic ATM mutant tumors enrolled in the Phase I portion of the study have demonstrated metabolic CR to combination therapy on PET scan. Overall, our findings suggest that genotype-directed concurrent radio-sensitization could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments. Further research to test this hypothesis is ongoing.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM del breast cancer predicted - sensitive Radiotherapy + RP-3500 Preclinical Actionable In a preclinical study, RP-3500 and radiotherapy synergistically inhibited growth of an ATM knockout mouse breast cancer cell line in culture, delayed tumor growth (p<0.001), and improved survival (20% vs 0% alive at 150 days) in a mouse syngeneic model (Cancer Res (2024) 84 (1_Supplement): A002). detail...
ATM inact mut Advanced Solid Tumor predicted - sensitive Radiotherapy + RP-3500 Case Reports/Case Series Actionable In a Phase I trial, the addition of RP-3500 to radiotherapy treatment resulted in metabolic complete responses in two patients with advanced solid tumors harboring ATM inactivating mutations (Cancer Res (2024) 84 (1_Supplement): A002, NCT05566574). detail...
ATM del colon cancer predicted - sensitive Radiotherapy + RP-3500 Preclinical Actionable In a preclinical study, RP-3500 and radiotherapy synergistically inhibited growth of an ATM knockout mouse colon cancer cell line in culture and improved survival in a mouse syngeneic model, with complete responses achieved in 7 out of 8 ATM knockout mice compared to 1 out of 8 ATM wild-type mice (Cancer Res (2024) 84 (1_Supplement): A002). detail...