Abstract PR03: Synthetic peptides suppress M2 macrophages and synergize with chemotherapy in prostate and breast cancer models

Abstract

Abstract Multiple lines of evidence suggest that macrophages, in particular M2-polarized tumor associated macrophages (TAMs), promote tumor aggressiveness and chemoresistance. Thus, limiting the pro-tumorigenic activity of TAMs may hold great therapeutic promise. To assess this potential, we synthesized artificial peptides (10-12mers) with a striapathic arrangement of hydrophobic and hydrophilic amino acids, designed to specifically target TAMs within the tumor microenvironment. These peptides, including drug candidate RP-182, are basic in design and bind to human albumin prior to binding to their eventual target, which enhances peptide half-life to around 2 hours. In vitro experiments demonstrated that exposure to 50uM peptide significantly reduced M2 macrophage viability and increased apoptosis after 48 hours of exposure, but had no effect on M1 macrophages. Interestingly, we did not observe a significant effect of RP-182 in vitro on various cancer cell lines, including MDA-MB-231, C42B or cells isolated from KPC960 mice. To determine whether RP-182 had in vivo efficacy we used multiple animal models, beginning with inflammatory indications where macrophage activity is also implicated, and progressing to solid organ cancer models: (1) In bleomycin animal models of lung and skin fibrosis, mice developed very high levels of inflammatory markers including IL6, which remained at control levels in mice treated with 10 mg/kg RP-182 qD subcu. At increased pulmonary bleomycin levels, all control animals died while 65% of treated animals survived. (2) In xenograft models of triple negative breast cancer (MDA-MB-231) mice treated with peptide (10 mg/kg qD subcu) demonstrated 37% reduction in MD-MB-231 tumor growth; gemcitabine @ 40 mg/kg q4D demonstrated 70% reduction; however, peptide plus gemcitabine completely blocked tumor growth. (3) In a xenograft model of castration resistant prostate cancer (CRPC) (C42B) mice treated with 2.5 mg/kg Docetaxel q7D demonstrated 45% reduction in tumor growth relative to control; mice treated with 10 mg/kg RP-182 qD demonstrated 52% reduction in tumor growth; but Docetaxel plus RP-182 reduced tumor growth 65%. (4) In the KPC960 model of pancreatic cancer, RP-182 treatment caused a 30% reduction in tumor growth and reduced the expression of a number of inflammatory genes in the tumors. (5) Finally, in the KRAS/p53 transgenic model of pancreatic cancer, treatment with peptide for one week reduced tumor growth, and was associated with 5.8 fold reduction in PDL1 and a 5.5 fold reduction in PDL2 expression in tumors. Toxicity testing on animals given much higher doses of RP-182 showed no changes in histology, blood counts, body or tissue weight. These results suggest that these novel designed peptides suppress macrophages in the tumors, enhancing the tumor response to chemotherapy and downregulating certain checkpoint proteins. This abstract is also presented as Poster B23. Citation Format: Henry Lopez, George R. Martin, Jesse M. Jaynes, Clayton Yates. Synthetic peptides suppress M2 macrophages and synergize with chemotherapy in prostate and breast cancer models. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR03.