Srivani Konduri

Antitumor effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation.

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy. The presence of both cellular and stromal fibronectin (FN) and its interaction with integrins is necessary for PDAC progression. We tested the efficacy of endothelial monocyte-activating polypeptide II (EMAP II) to inhibit PDAC progression and its ability to interfere with FN-integrin angiogenesis signaling. In heterotopic PDAC tumors EMAP II caused a significant reduction (>65%) in tumor growth, accompanied by a >50% and 44% decrease in microvessel density and proliferative activity, respectively. EMAP II therapy caused a 62% and 56% reduction in host and tumor cell FN expression. Cultured PDAC cells expressed aVb3 and a5b1 integrins. In vitro EMAP II had limited antiproliferative effects on ASPC-1, but a pronounced antiproliferative effect on endothellial cells. 3D FN matrices increased ASPC-1 cell proliferation by > 50%, and this induction was significantly blocked by a3, a5, a6 and aV integrin funtional blocking antibodies, while a1, a2 and a4 antibodies had no effect. EMAP II also inhibited 3D FN-matrix induced ASPC-1 proliferation by >43% at 20 mM. These findings suggest that EMAP II demonstrates significant antitumor activity against PDAC cells, and that this effect may be in part mediated through targeted interference with stromal FN-integrin dependent PDAC cell proliferation.

An antiendothelial combination therapy strategy to increase survival in experimental pancreatic cancer

BACKGROUND Combination treatments in addition to gemcitabine have failed to improve outcomes in pancreatic cancer. We tested gemcitabine in combination with the antiendothelial agent endothelial monocyte-activating polypeptide II (EMAP II). METHODS Human pancreatic cancer cell line murine xenografts were treated with recombinant EMAP II (80 mug/kg), gemcitabine (100 mg/kg), or a combination, and survival and local tumor outcomes were studied. RESULTS Both EMAP II and gemcitabine inhibited tumor growth, but the combination of both was always more effective. EMAP II and gemcitabine also inhibited microvessel density, with the combination being more effective. Apoptotic activity was increased by factors of 3.2-, 2.7-, and 4.2-fold in EMAP II, gemcitabine, or their combination, respectively. There was a significant extension of survival after EMAP II and gemcitabine combination therapy compared with controls in 2 different pancreatic cancer cell line models at P = .0001 and P = .006, respectively. The median EMAP II survival contribution over gemcitabine was 16 days, from 35 to 51 days (P = .017). EMAP II had no impact on gemcitabine-induced antiproliferative effects against pancreatic cancer cells in vitro. CONCLUSION The antiendothelial agent EMAP II enhanced gemcitabine-mediated tumor inhibition, pointing toward a promising strategy for improved combination treatment of pancreatic cancer.

In vivo monotherapy and combination treatment of pancreatic cancer with the antiendothelial agent EMAP-II

S: PLENARY and PARALLEL SESSIONS 5O Systemic administration of an anti-VEGF monoclonal antibody inhibits growth of human pancreatic adenocarcinoma in an orthotopic mouse model S.E. Holloway,* A. Beck, M. Davis, T. Hart, R.A. Brekken, J.B. Fleming. University of Texas Southwestern Medical