Abstract 4390: Heat shock protein (HSP) Grp94-targeted combinatorial immunotherapy for pancreatic cancer
Authors: Wang Yangyang , Favoino Elvira , Yu Ling , Ferrone Cristina R. , Ferrone Soldano , Wang Xinhui 
Published: August 2012

Pancreatic cancer is among the deadliest of cancers as it is rarely curable and the 5-year survival rate of patients with any stage of the disease is approximately 6%. This dismal clinical picture is reflective of the poor response of this disease to chemo- and radio- therapy, as well as to surgery as conventionally used. The unmet clinical needs for patients with pancreatic cancer highlight the urgency to develop effective novel therapies for this disease. To address this need, we have developed a combinatorial immunotherapy which eliminates differentiated pancreatic adenocarcinoma cells and pancreatic cancer initiating cells (CICs). According to the cancer stem cell theory, CICs are responsible for disease recurrence and metastases. Therefore, they have to be eradicated in order to “cure” a malignant disease. The tumor antigen we have selected as a target is the HSP glucose-regulated protein of 94 kDa (Grp94), a member of the HSP90 family, since it plays an important role in the biology of malignant cells. Furthermore, we have recently developed a human monoclonal antibody (mAb), named mAb W9, which has a unique specificity. It recognizes an extracellular epitope of Grp94, which is expressed on many types of malignant cells, including differentiated pancreatic adenocarcinoma cells and pancreatic CICs. mAb W9 inhibited in vitro growth of the human pancreatic cancer cell lines PANC2.03 and PANC3.27 by ∼40%. The antiproliferative activity was increased to 90% when mAb W9 was combined with cyclopamine and 5-FU, both of which inhibit the hedgehog signaling pathway that is aberrantly activated in pancreatic adenocarcinoma, particularly in pancreatic CIC. The antitumor activity of mAb W9 reflected a decreased level of RAS, C-Raf, phosphorylated (p)-MEK, p-ERK, and p-AKT. mAb W9 had also an effect on pancreatic CICs, identified as cells with high aldehyde dehydrogenase expression. These cells are referred to as ALDHbright cells. Treatment of the human pancreatic cancer cell line MIA PaCa-2 in vitro with mAb W9, cyclopamine and 5-FU inhibited the growth of ALDHbright cells by ∼90%. In contrast, the inhibition was only 50% when cells were treated with mAb W9 or cyclopamine individually, 20% when they were treated with 5-FU and 70% when they were treated with mAb W9 in combination with cyclopamine or 5-FU. Apoptosis was induced in 70% of pancreatic cancer cells PANC1 by mAb W9 in combination with cyclopamine and 5-FU, but in less than 35% by the agents individually and by the combinations of any two of the agents. Our in vitro findings strongly suggest that targeting cell surface Grp94 with mAb W9 in combination with cyclopamine and 5-FU may represent an effective strategy to eliminate differentiated pancreatic cancer cells and pancreatic CICs.

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 4390. doi:1538-7445.AM2012-4390