Abstract 599: TMPRSS2-ERG gene fusion sensitizes VCaP human prostate tumors to the fully human anti-IGF-IR monoclonal antibody SCH 717454

A gene fusion of the androgen-regulated gene transmembrane protease, serine 2, (TMPRSS2) to the v-ets erythroblastosis virus E26 oncogene homolog (avian), ERG, of the erythroblast transformation-specific (ETS) family of transcription factors is a recently discovered genetic alteration in prostate cancer. Expression of the TMPRSS2-ERG fusion in prostate cancer patients is associated with an aggressive clinical phenotype and an early recurrence of the disease. Interestingly, in TMPRSS2-ERG positive prostate cancer cells, expression of this gene fusion is regulated by both estrogens and androgens. However, while the hormonal regulation of this fusion has been established the downstream effects of TPRSS2-ERG fusion gene have not been determined. Quantitative PCR analyses of 134 cancer cell lines, including 10 prostate cancer models, for expression of the TMPRSS2-ERG gene fusion showed that it was only present in VCaP, DuCaP, and NCI-H660 prostate cancer cells. We report here that VCaP human prostate cancer cells and tumor xenografts are sensitive to treatment with the fully human anti insulin-like growth factor-I receptor (IGF-IR) monoclonal antibody SCH 717454. After 28 days of treatment, single-agent SCH 717454 (0.5 mg, ip, 2 × week) caused complete inhibition of VCaP tumor growth. MDA PCa-2b, 22Rv1, DU-145, and LNCaP human prostate cancer tumor xenografts (negative for expression of the TMPRSS2-ERG gene fusion) did not respond to treatment with SCH 717454. Further, PTEN null NCI-H660 prostate tumors that also express the TMPRSS2-ERG gene fusion also did not respond to treatment with SCH 717454. When male SCID mice bearing established VCaP prostate cancer tumor xenografts were treated with the combination of surgical castration and SCH 717454 we observed 100% tumor regressions in all of the animals so that after 28 days of treatment there were no detectable tumors. When SCH 717454 was combined with the antiandrogen bicalutamide (50 mpk, po, bid), VCaP tumors regressed by 42%. That the combination of SCH 717454 and castration produced superior anti-tumor activity than the combination of SCH 717454 and bicalutamide provides further evidence that expression of the TMPRSS2-ERG gene fusion in VCaP prostate cancer tumors is regulated by both estrogens and androgens. TMPRSS2-ERG gene fusion expressing prostate cancer represents a new sub-classification of human prostate cancer. The precise role that the TMPRSS2-ERG fusion plays in the biology of human prostate cancer remains to be fully determined. These data indicate that PTEN wild-type VCaP prostate tumors that express the TMPRSS2-ERG gene fusion are sensitive to anti-IGF-IR treatment with SCH 717454 and that combining SCH 717454 with an androgen ablation therapy results in impressive anti-tumor activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 599. doi:10.1158/1538-7445.AM2011-599