Abstract 694: Evaluation of a synergistic drug combination with 177Lu-rhPSMA-10.1 for prostate cancer: Results of an in vitro screen and in vivo proof of concept study
Authors: Foxton Caroline , Cornelissen Bart , O'Neill Edward , Waldron Bradley , Pretzmann Freja , Grønlund Rikke Veggerby , Hallund Mathias Wikke , Stevens Daniel J. 
Published: March 2024

Purpose: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has been shown to extend survival in men with advanced prostate cancer (PCa). Novel radiohybrid (rh) PSMA-targeted 177Lu-rhPSMA-10.1 has shown promising preclinical efficacy and advantageous radiation dosimetry in humans. We conducted an in vitro screen to identify known anticancer drugs with potential for synergistic interaction with 177Lu-rhPSMA-10.1. Here we present key screening data and a subsequent in vivo efficacy analysis of the lead novel drug combination in PSMA-expressing 22Rv1 PCa xenografts.

Methods: Over 150 FDA-approved anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells using the test drug alone, at a range of concentrations &lt;20 µM to determine the IC50, and results compared to incubations of the drug + 15 MBq/mL 177Lu-rhPSMA-10.1 after 10 d. A focused screen of 5 lead candidates was then conducted to determine the impact of 177Lu-rhPSMA-10.1 (0-25 MBq/mL) on the drug IC50. A synergy score was determined using the zero interaction potency (ZIP) reference model and the multi-dimensional synergy of combinations (MuSyc) platform.

Subsequently, to evaluate the efficacy of the lead combination, 177Lu-rhPSMA-10.1 (single 30 MBq iv dose) and Cobimetinib (0.25 mg orally per day for 21 d) alone and in combination were administered to 22Rv1 tumor-bearing NMRI nude mice (n = 8 per group plus untreated controls). Tumor volume was measured 2x week for 69 d. Two-way ANOVA and Tukey’s multiple comparisons test (data analyzed until n = 3 remained per group) and Kaplan-Meier Log-rank survival analyses were performed.

Results: The in vitro screen identified MEK inhibitor Cobimetinib as a lead candidate for synergistic combination with 177Lu-rhPSMA-10.1 across a wide concentration range, with a ZIP synergy score of 13.25% (95% CI ± 2.17) and promising results on MuSyc analysis. The 177Lu-rhPSMA-10.1 + Cobimetinib combination significantly suppressed tumor growth in vivo vs untreated controls (from day 13-30; p&lt;0.01) and 177Lu-rhPSMA-10.1 alone (from day 17-30; p&lt;0.001). The median survival in the combination group (49 d) was significantly longer vs the untreated group (23 d; p=0.001) and the group treated with 177Lu-rhPSMA-10.1 alone (36 d; p=0.002).

Conclusions: Through an extensive in vitro screen, we identified Cobimetinib to have potential for a synergistic anti-tumor effect in combination with 177Lu-rhPSMA-10.1. This may be due to inhibition of the MEK-MAPK pathway by Cobimetinib during DNA damage response, resulting in radiosensitization of cancer cells to 177Lu-labeled RLT agents such as 177Lu-rhPSMA-10.1. This novel combination showed an enhanced therapeutic efficacy vs the single agents in 22Rv1 xenografts and the lack of overlapping monotherapy toxicity reported in the clinic supports clinical investigation in men with PCa.

Citation Format: Caroline Foxton, Bart Cornelissen, Edward O'Neill, Bradley Waldron, Freja Pretzmann, Rikke Veggerby Grønlund, Mathias Wikke Hallund, Daniel J. Stevens. Evaluation of a synergistic drug combination with 177Lu-rhPSMA-10.1 for prostate cancer: Results of an in vitro screen and in vivo proof of concept study [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 694.