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Background MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Methods Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. Results ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. Conclusion The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

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 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 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.