Monoclonal Antibody Therapies Targeting Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a poor prognosis where incidence mirrors mortality. Gemcitabine and gemcitabine plus erlotinib (epidermal growth factor receptor tyrosine kinase inhibitor) are the only FDA approved therapies for unresectable or metastatic PDA and are at best palliative. Hence, considerable efforts have been initiated to identify novel targets for monoclonal antibody (Mab) therapies that may safely and effectively be combined with gemcitabine. Mabs to cell surface receptors and/or their ligands have shown efficacy in pre-clinical and clinical studies in both solid and hematological malignancies and can safely be given with chemotherapy. A number of clinical trials have evaluated the safety and efficacy of Mabs targeting the tumor and/or tumor micro-environment and in combination with chemotherapy for PDA with very little success. Here we review the rationale for Mab therapies, targeted clinical trials, rational basis for target selection, pre-clinical models and promising novel cell surface targets and/or growth factor ligands that are amenable to ongoing and future Mab therapies that hold promise and hope for patients and their families with this devastating disease.

Unilateral face swelling as first manifestation of metastatic pancreatic cancer: Case report and review of the literature

“…One might speculate that his prolonged survival could be attributed to treatment with novel drugs that were not available when the other patients were treated. Current treatment strategies are based on gemcitabine with or without erlotinib [12].…”

Translational advances and novel therapies for pancreatic ductal adenocarcinoma: hope or hype?

“…As with SMIs, mAbs to growth factor ligands and cell-surface receptors targeting PDA, alone and/or in combination with gemcitabine, are currently not approved by the US FDA and are reviewed elsewhere (Ref. 95). Here, we review novel mAbs that may be more promising and are being evaluated alone and/or in combination with gemcitabine.…”

Design and Activity of a Murine and Humanized Anti-CEACAM6 Single-Chain Variable Fragment in the Treatment of Pancreatic Cancer

“…Most patients present with unresectable and/or metastatic PDA, with a median overall survival of 12 and 6 months respectively (2). Therefore, the molecular basis of PDA is being intensely investigated in the hope of identifying disease mechanisms and associated therapeutic targets (3, 4). Genetic lesions linked to PDA have identified germline mutations in KRAS , CDKN2A (also known as INK4a or ARF ), BRCA2 , MLH1 , STK11 (also known as LKB1 ), TP53 and SMAD4 (also known as DPC4 ) (5) and a progression model similar to colon cancer has been postulated with the identification of a precursor lesion, pancreatic intra-epithelial neoplasia (PanIN) (6–8).…”

“…A hallmark in PDA is the presence of a ‘desmoplastic reaction’ (DR) due to proliferation of fibrotic tissue with an altered extracellular matrix (ECM) conducive to tumor growth and metastasis. Novel therapies targeting the DR are required (3, 4) and CEACAM6 is one such target, expressed only in higher vertebrates (dogs, monkeys) and humans (11). …”