Abstract A4: Combretastatin A-4 Phosphate (CA4P) is effective for the treatment of functional pancreatic neuroendocrine tumors (PNETs) in a transgenic mouse model.

Abstract

Abstract Background: PNETs are rare highly vascular tumors that are increasing in incidence. Management of advanced tumors, both functional and nonfunctional, can be challenging, as systemic treatment options are limited. CA4P is a systemically delivered vascular disrupting agent that has shown clinical activity for the treatment of other advanced endocrine cancers. We evaluated the efficacy of systemic administration of CA4P for the treatment of functional insulinomas in a transgenic mouse model of PNETs. Methods: Twelve month-old mice with homozygous deletion of the Men1 gene in the pancreas and confirmation of a functional insulinoma by presence of elevated serum insulin were divided into two groups (4 mice per group). The treatment group received CA4P, 100 mg/kg, IP on Monday, Wednesday and Friday for four weeks. The control group received PBS by the same route, frequency and for the same duration. Serum insulin was measured by enzyme-linked immunosorbent assay (ELISA) pre and at intervals during treatment. After four weeks, mice were euthanized and whole pancreata were dissected, formalin-fixed with paraffin embedding, and sectioned (5 μm) on a rotating microtome. Hematoxylin and eosin staining was performed and the tumor cross-sectional area in the sections with maximal tumor diameter was determined in three sections for each mouse in a blinded fashion. Tumor size was assessed by measuring the length and width of the tumor in two dimensions and then calculating the maximum tumor area for each mouse and for each group. Statistical analysis was performed with ANOVA and Student's t-test. Results: Treatment was well tolerated in all mice without treatment related death or weight loss. At baseline, mean serum insulin was elevated, but equivalent in both groups (CA4P group 3.695 ± 0.669 µg/L, versus PBS group 3.485 ± 0.666 µg/L, p=0.672). Treatment with CA4P resulted in a significant and sustained decrease in circulating insulin, with maximum effect seen by day 17 (CA4P group 0.213 ± 0.075 µg/L, versus PBS group 4.578 ± 0.161 µg/L, p<0.0001). The reduction in insulin was accompanied by a significantly (p=0.0128) reduced tumor size in the CA4P group (1.83 ± 1.27 mm2) compared to the PBS group (9.88 ± 2.99 mm2). Conclusions: Systemic administration of CA4P is effective in treating functional insulinomas in a transgenic mouse model. Both circulating hormone and tumor size was significantly reduced without obvious toxicity. Further evaluation of the vascular disrupting agent CA4P as a therapy for patients with enteropancreatic neuroendocrine tumors is warranted. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A4. Citation Format: Ziqiang Yuan, Nikolas Zaphiros, Asha Adem, Norvilia Etienne, Jai Balkissoon, Dai Chaplin, Steven K. Libutti. Combretastatin A-4 Phosphate (CA4P) is effective for the treatment of functional pancreatic neuroendocrine tumors (PNETs) in a transgenic mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A4.