Chantal Carrez

Abstract 2338: Aflibercept (VEGF Trap) impairs tumor growth and perfusion, and restrains metastasis invasion in orthotopic models

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Aflibercept (VEGF Trap), a potent angiogenesis inhibitor that binds to all isoforms of circulating VEGF as well as to placental growth factor, is currently in Phase 3 clinical trials in combination with chemotherapy for several cancer indications. The VELOUR Phase 3 trial in oxaliplatin pre-treated metastatic colorectal cancer showed that aflibercept in combination with FOLFIRI significantly improved overall survival, progression-free survival and response rate (in comparison with FOLFIRI plus placebo), with some increases in adverse events. The aim of the current study was to explore the effect of aflibercept on tumor vessel function and determine the impact of a prolonged treatment regimen on the development of metastases in orthotopic preclinical models. For the functional evaluation of tumor perfusion by contrast enhanced ultrasound imaging (CE-US), SCID mice underwent renal subcapsular implantation of the human renal SK-NEP-1 Ewing sarcoma. The pattern of vascularization in these rapidly growing tumors was found to be heterogeneous: tumor areas in the proximal kidney remained highly perfused, while avascular areas appeared in the distal kidney region which is likely a consequence of spontaneous necrosis in large tumors. Aflibercept administered bi-weekly at 40mg/kg for two weeks showed a statistically significant effect on tumor growth (5% T/C). Aflibercept efficiently down-regulated tumor perfusion inducing a reduction of tumor blood volume immediately after the first injection, followed by subsequent stabilization and rebound two weeks after the end of treatment. The MDA-MB-231-D3H2LN-luc breast tumor model spontaneously induces lymph node metastasis when orthotopically implanted into the inguinal mammary fat pads of SCID mice. Aflibercept (at 25 mg/kg) or vehicle were administered bi-weekly for five weeks in mice pair-matched by bioluminescent photon emission rates into aflibercept treatment and control groups. This continuous aflibercept treatment induced antitumor activity on the primary tumors with 19% T/C based on bioluminescent signal at the end of treatment. Aflibercept also controlled metastatic dissemination to the axillary regions with a median 21-day delay for lymph node invasion in treated mice. Conclusion: In an orthotopic Ewing sarcoma model in mice, repeated administrations of aflibercept reduced tumor perfusion and stabilized tumor growth. In an orthotopic mammary carcinoma model, prolonged treatment with aflibercept inhibited tumor growth and delayed spontaneous lymph node metastasis. These outcomes are consistent with the mechanism of action postulated for aflibercept which, upon prolonged treatment is expected to reduce the density of tumor vasculature and the leakiness of tumor vessels, thereby controlling tumor growth and metastatic dissemination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2338. doi:1538-7445.AM2012-2338

Abstract LB-295: Combination of PI3K (SAR245408 and SAR245409) and MEK (MSC1936369B) inhibitors induce tumor apoptosis in vivo: fluorescence molecular tomography study in a human colon carcinoma xenograft model

The Merck-Serono MEK1/2 allosteric inhibitor MSC1936369B (formerly known as AS703026) was combined with the sanofi-aventis pan-PI3K inhibitor SAR245408 (also known as XL147) or the pan-PI3K/mTOR inhibitor SAR24540 (also know as XL765) in mice bearing colon carcinoma HCT116 xenograft tumors. These tumors harbor both KRAS (G13D) and PIK3CA (H1047R) mutations. Apoptosis induction was monitored non-invasively in vivo using fluorescence molecular tomography (FMT) after injection of fluorescent Annexin-V. Ex vivo apoptosis was assessed on tumor lysates using assays for cleaved caspase-3 and cleaved PARP detection. Suboptimal doses of SAR245408, SAR245409, and MSC1936369B were administered orally on a daily schedule as single agents or in combination. Single agent treatments showed marginal or no activity on HCT116 tumor growth inhibition. In contrast, robust enhanced anti-tumor activity was observed with the combination treatments, resulting in sustained tumor stasis and regression for both SAR245408/MSC1936369B (p in vivo by FMT was induced for the SAR245408/MSC1936369B combination, with p=0.005 and p In conclusion, the combination between the MEK1/2 inhibitor MSC1936369B with the pan-PI3K inhibitor SAR245408 or the pan-PI3K/mTOR SAR245409 resulted in significantly enhanced anti-tumor activity in a KRAS/PIK3CA mutated tumor xenograft model, with synergistic induction of tumor apoptosis as demonstrated ex vivo for both combinations and in vivo using longitudinal FMT imaging for the SAR245408/MSC1936369B combination. 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 LB-295. doi:10.1158/1538-7445.AM2011-LB-295