Aflibercept Exerts Antivascular Effects and Enhances Levels of Anthracycline ChemotherapyIn vivoin Human Acute Myeloid Leukemia Models

Abstract

We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients. Mol Cancer Ther; 9(10);

Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models

“…Twenty days after leukemia inoculation when all animals had clear evidence of systemic AML disease by BLI, mice were treated with single doses of vehicle (PBS), cytarabine, doxorubicin, or the VEGF inhibitor aflibercept (VEGF Trap, Regeneron/Sanofi Aventis; ref. 31). Animals were sacrificed 3 days later for marrow immunohistochemistry and flow cytometry.…”

“…Six-to 8-week-old female severe combined immunodeficient (SCID) mice (RPCI, Department of Laboratory Animal Research, Buffalo, NY) were sublethally irradiated (200 rad) followed by tail vein (1 Â 10 7 cells) injection of human HEL and HL60 cells stably transfected with a pGL4 luciferase reporter vector (Promega) as described previously (31). Mice were evaluated weekly for evidence of leukemia engraftment and overall leukemia disease progression by serial bioluminescent …”

“…daily for 3 days, doxorubicin 35 mg/kg i.p. single dose, or aflibercept (VEGF Trap) 5 mg/kg single injection (31). Three days later, mice were injected i.p.…”

Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours

“…Aflibercept has broad affinity for all ligands that bind to these receptors, including isoforms of VEGF-A, VEGF-B, and placental growth factors (Holash et al , 2002; Verheul et al , 2007). In preclinical models, aflibercept demonstrated antitumour effects and antiangiogenic activity as a single agent and enhanced activity in combination with chemotherapy, including cisplatin, taxanes, and gemcitabine (Holash et al , 2002; Byrne et al , 2003; Huang et al , 2003; Fukasawa and Korc, 2004; Verheul et al , 2007; Leujeune et al , 2008; Lal et al , 2010; Lassoued et al , 2011). …”

Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

“…The preliminary in vivo studies of Lal et al showed that aflibercept slowed disease progression in two systemic human AML mouse xenograft models. Combining aflibercept with doxorubicin enhanced antileukemia effects, decreased microvessels, and induced perivascular apoptosis [46]. …”