Abstract P6-20-11: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models
Authors: SS Pairawan, E Yuca, K Evans, A Annis, N Narasimhan, D Sutton, LA Carvajal, J-G Ren, S Santiago, V Guerlavais, A Akcakanat, C Tapia, EE Illeana Dumbrava, M Aivado, F Meric-Bernstam
Journal: Cancer Research (2019)

Abstract Background: MDMX and MDM2 are endogenous inhibitors of the p53 tumor suppressor protein. MDMX levels are frequently elevated in luminal breast cancer, which generally expresses wild-type p53. ALRN-6924, an α-helical stapled peptide, is the first and only dual inhibitor of MDMX and MDM2 currently in clinical trials for solid tumors and hematological malignancies. We sought to determine the antitumor efficacy of the combination of ALRN-6924 with taxanes in models of human breast cancer. Methods: Sulforhodamine B colorimetric assay was used to assess the cytotoxicity of the combination of ALRN-6924 with taxanes in vitro. Athymic nude mice were implanted with MCF-7 tumors and treated for four weeks with ALRN-6924 alone and in combination with paclitaxel in cremaphor (Taxol®, study #1) or a nanoparticle-albumin-bound (nab) formulation (Abraxane®, study #2). In study #1, ALRN-6924 (5, 10 mg/kg) was dosed twice weekly and paclitaxel (10, 15 mg/kg) was dosed weekly, with paclitaxel administered 6 h prior to ALRN-6924. In study #2, ALRN-6924 alone (5 mg/kg) was dosed twice weekly while nab-paclitaxel (15 mg/kg) was administered weekly in combination at -24h, -6h, 0h, +6h, or +24h relative to ALRN-6924 administration. Results: ALRN-6924 was found to have synergistic activity with paclitaxel in both MCF-7 and ZR-75-1 cell lines in vitro (Combination index: 0.874 and 0.323 respectively). In in vivo study #1, the combination of ALRN-6924 and paclitaxel significantly inhibited MCF-7 tumor growth compared to either agent alone (p&amp;lt;0.005). Paclitaxel 15 mg/kg + ALRN-6924 5 mg/kg resulted in the greatest tumor inhibition with average tumor size decreased by 13% at four weeks versus the starting size. In study #2, the combination of nab-paclitaxel with ALRN-6924 administered -6h to +24h relative to nab-paclitaxel resulted in improved efficacy over either single agent and a significant increase in the number of tumor regressions (up to 6/10 with 3 consecutive measurements &amp;lt;50% of starting volume) compared to nab-paclitaxel alone (1/10, p&amp;lt;0.005). When ALRN-6924 was administered 24h prior to nab-paclitaxel, there was a marked decrease in efficacy and no tumor regressions were observed. In both studies, drug treatments were well tolerated with no significant weight loss in mice. Conclusion: The significant increase in efficacy observed with ALRN-6924 in combination with paclitaxel supports further evaluation in patients with breast cancer. Citation Format: Pairawan SS, Yuca E, Evans K, Annis A, Narasimhan N, Sutton D, Carvajal LA, Ren J-G, Santiago S, Guerlavais V, Akcakanat A, Tapia C, Illeana Dumbrava EE, Aivado M, Meric-Bernstam F. The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-11.