Abstract 7039: Synergistic antitumor activity of the combined PARP1 inhibition and alkylating DNA damage in malignant rhabdoid tumors

Abstract Background: Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4) - a pivotal component of the SWI/SNF chromatin remodeling complex - is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. Methods: We evaluated the antitumor activity of the PARP1 inhibitor talazoparib (TLZ) in combination with the DNA alkylating agent temozolomide (TMZ) across six MRT xenograft models in CB-17 scid mice. The dosing schedule for this combination followed a previously reported protocol (iScience 2021; 25(2):103725). Time-to-event was defined as 4-fold increase in tumor xenograft volume from the treatment initiation date. Event-free survival (EFS) between treated and control groups was analyzed using Kaplan-Meier method. Objective response categories including partial (PR), complete (CR), and maintained complete responses (MCR), were determined based on previously established criteria (Ped Blood Cancer 2007;49:928). To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG-TLZ), which has been reported to reduce systemic toxicity through slow drug release. Results: Remarkably, our findings indicate that five out of six MRT xenografts exhibited objective response to PEG-TLZ+TMZ therapy. Notably, SMARCB1 loss was found to confer a protective effect, correlating with elevated expression of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, MGMT emerged as a potential biomarker predictive of in vivo MRT response to PEG-TLZ+TMZ treatment. In addition, our analysis revealed alterations in signaling pathways associated with the observed antitumor activity. Conclusions: This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response. Citation Format: Elena Mironova, Sebastian Molinas, Vanessa Del Pozo, Abhik Bandyopadhyay, Zhao Lai, Dias Kurmashev, Eric L. Schneider, Daniel V. Santi, Yidong Chen, Raushan Kurmasheva. Synergistic antitumor activity of the combined PARP1 inhibition and alkylating DNA damage in malignant rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7039.