Abstract A010: PARP1 selective inhibition sensitize triple-negative breast cancers to photon and alpha-particle therapy regardless of homologous recombination proficiency status
Authors: Marinello Poliana C. , Freitas Reis Marco Tulio , Da Silva Brito Walison Augusto , Wu Amy , Rubinstein Alexandre , Wasley Mark D. , Manandhar Mandira , Bright Scott J. , Rai Yogesh , Hosseini Ghahfarokhi Seyed Mojtaba , Segal Ronen , Domankevich Vered , Sawakuchi Gabriel O. 
Published: January 2025

Abstract
The association of Poly (ADP-ribose) polymerase (PARP) inhibitors with radiotherapy (RT) increase RT-induced DNA damage and radiosensitize tumors regardless deficiency in DNA repair pathways. Although PARP1 is the main protein responsible for PARP-mediated DNA repair, all first-generation PARP inhibitors act on both PARP1 and PARP2, which the latter is associated with hematological toxicity. The RT ability to induce DNA damage can be influenced by the radiation linear energy transfer (LET). High-LET radiation, such as alpha particles (LET: 60-200 keV/μm), induces more complex DNA damage than does low-LET radiation (photon, LET: 0.2 keV/μm). Thus, high-LET radiation combined with selective PARP1 inhibitors may be a promising strategy to radiosensitize tumors. The purpose of this study was to investigate if the selective PARP1 inhibition could radiosensitize BRCA1 mutant and wild-type triple-negative breast cancers (TNBC) to photons and alpha particles. The radiosensitization effect in vitro was assessed using TNBC cells: MDA-MB-436 (BRCA1 mutated), and its isogenic pair with BRCA1 recovered, MDA-MB-436 BRCA1, and 4T1. The IC50 of the PARP1 selective inhibitor (AZD5305) was determined across all cell lines by the clonogenic assay, and concentrations of AZD5305 that did not affect the colony formation ability without radiation were chosen for the radiopotentiation evaluation (clonogenic assay). Mice were inoculated with 4T1 cells in the hind leg. Diffusing Alpha-emitter Radiation Therapy (Alpha DaRT) was used to deliver alpha particles intratumorally, by the implantation of 224Ra-loaded sources. AZD5305 (1 mg/kg) was daily administered by oral gavage for 6 consecutive days, starting 24 h before Alpha DaRT implantation. Tumor growth delay and survival were assessed. AZD5305 significantly radiosensitized all the evaluated cell lines in vitro. AZD5305 alone (mice implanted with inert seeds) did not affect the tumor growth in mice (p=0.12) in comparison with inert+vehicle. Alpha DaRT delayed tumor growth in comparison with mice treated with inert+vehicle (p=0.03), but the Alpha DaRT+AZD5305 reduced tumor growth in comparison with Alpha DaRT+vehicle (p=0.05). Alpha DaRT promoted a non-significant (p=0.09) increase in survival when compared with inert+vehicle, but Alpha DaRT+AZD5305 increased survival in comparison with inert+vehicle (p=0.002), and Alpha DaRT+vehicle (p=0.06). Our findings demonstrate that AZD5305 significantly radiosensitizes TNBC to photons and alpha particles, regardless of the homologous recombination proficiency status. These results are novel because there no studies investigating selective PARP1 inhibition in combination with photons and alpha particles. Our work is relevant because the combination of AZD5305 with Alpha DaRT offers a promising strategy to minimize the adverse effects of PARP inhibition. AZD5305 presents less off-target effects than non-selective PARP inhibitors, while Alpha DaRT delivers alpha particles directly into the tumor, limiting radiosensitization of normal tissue.
Citation Format: Poliana C. Marinello, Marco Tulio Freitas Reis, Walison Augusto Da Silva Brito, Amy Wu, Alexandre Rubinstein, Mark D. Wasley, Mandira Manandhar, Scott J. Bright, Yogesh Rai, Seyed Mojtaba Hosseini Ghahfarokhi, Ronen Segal, Vered Domankevich, Gabriel O. Sawakuchi. PARP1 selective inhibition sensitize triple-negative breast cancers to photon and alpha-particle therapy regardless of homologous recombination proficiency status. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A010.