Abstract 1454: Expanding the therapeutic application of PARP inhibitor: AI evaluation of real-word clinico-genomic data from spontaneous canine tumors
Authors: Lucas Rodrigues, Kevin Wu, Garrett Harvey, Gerald Post, Abigail Hull, Aubrey Miller, Lindsay Lambert, Christina Lopes, James Zou
Journal: Cancer Research (2024)

Abstract The widespread application of Poly-ADP ribose polymerase (PARP) inhibitors in anti-cancer therapy is constantly increasing their role as a treatment strategy across various neoplasms, the majority of which are linked with BRCA deficiency. While the most significant advantages are observed in cancers with BRCA1/2 mutations, it is evident that the benefits extend beyond this specific group. Preclinical evidence encourages the exploration of PARP inhibitors in neoplasms demonstrating BRCAness or homologous recombination deficiency (HRD), both as monotherapy and in combination with chemotherapy. This study employs spontaneous canine tumors as a complementary model for cancer research, aiming to seamlessly bridge the transition from preclinical investigations to clinical application. Leveraging the FidoCure® Precision Medicine Platform, we identified biomarkers associated with prognosis and treatment prediction, specifically with the PARP inhibitor olaparib, facilitating a smoother translation from laboratory findings to practical clinical use. Analyzing real-world clinico-genomic data from 1278 dogs with cancer revealed intriguing insights of specific targeted treatments developed for humans showing a positive prognosis when applied to canine tumors with specific genomic alterations. Notably, olaparib exhibited efficacy in TP53 and BRCA1-mutated cases (OS HR 0.34, P &amp;lt; 0.001; HR 0.39, P = 0.004), while rapamycin (mTOR inhibitor) demonstrated promising outcomes in TP53 and RB1-mutated canine tumors (OS HR 0.73, P = 0.028; HR 0.32, P = 0.024). Further stratification by tumor types unveiled noteworthy correlations. TP53 mutant osteosarcomas exhibited improved prognosis with olaparib treatment (OS HR 0.11, P &amp;lt; 0.001), and soft tissue sarcomas with TP53 mutations demonstrated favorable responses to rapamycin and olaparib therapy (OS HR 0.11, P = 0.012; HR 0.07, P = 0.011). These findings underscore the potential of leveraging canine tumor models and clinico-genomic analyses to inform targeted treatment strategies, offering valuable insights for advancing precision medicine in both veterinary and human oncology. Further investigation into the association between TP53 mutation and olaparib response is warranted. The intriguing aspect lies in the role TP53 mutation has been linked in previous studies to heightened chromosomal instability and elevated HRD scores. Utilizing real-world evidence and data tools within the FidoCure dataset, we have effectively pinpointed correlations between gene mutations and survival, particularly in relation to responses to targeted therapy treatment. Canine models, mirroring human diseases with intact immune systems and comparable tumor genomic profiles, as verified by the FidoCure database, expedite clinical studies of novel treatments that face significant scalability challenges. Citation Format: Lucas Rodrigues, Kevin Wu, Garrett Harvey, Gerald Post, Abigail Hull, Aubrey Miller, Lindsay Lambert, Christina Lopes, James Zou. Expanding the therapeutic application of PARP inhibitor: AI evaluation of real-word clinico-genomic data from spontaneous canine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1454.