Abstract P3-11-13: Synergistic inhibition of MCF-7 mammary gland tumor growth with Piqray® (alpelisib) plus SDX-7320, a novel polymer-conjugated methionine aminopeptidase 2 (MetAP2) inhibitor

Abstract

Abstract Mutations in the PI3K pathway have been observed in about 40% of ER+/Her2- breast cancer patients. Amplification as well as mutation of the catalytic p110α subunit of PI3K results in activation of this pathway within tumors, conferring a growth advantage due to increased transmission of intracellular growth signals. Recently a selective inhibitor of p110α, Piqray®(alpelisib) has been approved by the FDA (in combination with the estrogen receptor degrader/antagonist Faslodex/fulvestrant) for the treatment of ER+/Her2- breast cancers harboring mutation(s) in the p110α subunit of PI3K. Small molecule MetAP2 inhibitors have previously shown clinical anti-tumor activity. SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone. This is intended to alter biodistribution (limit CNS penetration) and improve pharmacokinetics relative to small molecule, fumagillin-derived MetAP2 inhibitors. SDX-7320 has completed a phase I trial in late-stage cancer patients (NCT02743637). The objective of this study was to evaluate the anti-tumor efficacy of Piqray®(alpelisib) in combination with SDX-7320 in a model of PI3K-mutated, ER+ breast cancer (i.e., MCF-7). Female nude mice had estrogen pellets surgically implanted and after two weeks of recovery, MCF-7 cells were injected into the fourth mammary gland. When tumors became palpable (i.e., > 50 mm3) treatment with SDX-7320 (dosed subcutaneously Q4D at 8 or 16 mg/kg) and/or Piqray®(alpelisib) (dosed PO, QD at 25 or 45 mg/kg) commenced. Combinations included SDX-7320 at 8 mg/kg plus Piqray®(alpelisib) at 25 mg/kg as well as SDX-7320 at 8 mg/kg plus Piqray®(alpelisib) at 45 mg/kg. Endpoints included tumor volume, body weight, terminal plasma glucose, insulin, leptin and adiponectin. Analysis of tumor tissue for molecular endpoints of PI3K pathway activation were also investigated (e.g., S6, Akt, 4E-BP1). Anti-tumor efficacy was assessed by calculating the %change in tumor volume from baseline for each individual animal, then comparing the average change for each group at the end of the study (day 64). One-way ANOVA with multiple comparisons was conducted to determine significance of differences in final tumor volume on day 64 relative to vehicle. Treatment with SDX-7320 at 8 or 16 mg/kg inhibited MCF-7 tumor growth -19% and -17% relative to vehicle at day 64 (NS), respectively. Piqray®(alpelisib) inhibited tumor growth in a dose-dependent manner (-30% (NS) and -82% (p<0.05) for 25 and 45 mg/kg, respectively). The combination of SDX-7320 at 8 mg/kg with Piqray®(alpelisib) at 25 mg/kg resulted in synergistic efficacy, with -105% inhibition of tumor growth relative to vehicle at day 64 (p<0.01).The combination of SDX-7320 at 8 mg/kg with Piqray®(alpelisib) at 45 mg/kg resulted in an additive effect on tumor growth relative to vehicle (-100%; p<0.01). These results show that SDX-7320 (8 mg/kg) is synergistic with Piqray®(alpelisib; 25 mg/kg) in control of orthotopic MCF-7 mammary gland tumors. A clinical trial combining SDX-7320 with Piqray®(alpelisib) plus fulvestrant is planned to start in Q1/2020 and will assess the ability of SDX-7320 to enhance the efficacy of Piqray®(alpelisib) in treating PI3K-mutated, ER+/Her2- breast cancer. Citation Format: Peter Cornelius, Benjamin Mayes, Sara Little, Andrew Slee, Adam Nir, Raphael Nir, Bradley Carver, James Shanahan. Synergistic inhibition of MCF-7 mammary gland tumor growth with Piqray® (alpelisib) plus SDX-7320, a novel polymer-conjugated methionine aminopeptidase 2 (MetAP2) inhibitor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-13.