CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer
Autor: | Kristopher K. Frese, Christian Pilarsky, Todd W. Seeley, Albrecht Neesse, Tashinga E. Bapiro, Mark D. Sternlicht, Suzanne M. Spong, David A. Tuveson, Duncan I. Jodrell, Tomoaki Nakagawa |
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Rok vydání: | 2013 |
Předmět: |
Antineoplastic Agents
Apoptosis X-Linked Inhibitor of Apoptosis Protein Antibodies Monoclonal Humanized Deoxycytidine 03 medical and health sciences Mice 0302 clinical medicine Pancreatic cancer Medicine Animals 030304 developmental biology 0303 health sciences Tumor microenvironment Multidisciplinary business.industry Liver Neoplasms Connective Tissue Growth Factor Antibodies Monoclonal Cytidine deaminase medicine.disease Survival Analysis Gemcitabine 3. Good health Desmoplasia CTGF Pancreatic Neoplasms Cell killing 030220 oncology & carcinogenesis Immunology Cancer research Neoplastic cell medicine.symptom business medicine.drug Carcinoma Pancreatic Ductal |
Zdroj: | Proceedings of the National Academy of Sciences; Vol 110 Proceedings of the National Academy of Sciences |
ISSN: | 1091-6490 |
Popis: | Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit the access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA tumor microenvironment promote concomitant chemotherapy delivery and increased antineoplastic response in murine models of PDA. Prior studies could not determine whether chemotherapy delivery or microenvironment modulation per se were the dominant features in treatment response, and such information could guide the optimal translation of these preclinical findings to patients. To distinguish between these possibilities, we used a chemical inhibitor of cytidine deaminase to stabilize and thereby artificially elevate gemcitabine levels in murine PDA tumors without disrupting the tumor microenvironment. Additionally, we used the FG-3019 monoclonal antibody (mAb) that is directed against the pleiotropic matricellular signaling protein connective tissue growth factor (CTGF/CCN2). Inhibition of cytidine deaminase raised the levels of activated gemcitabine within PDA tumors without stimulating neoplastic cell killing or decreasing the growth of tumors, whereas FG-3019 increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. The response to FG-3019 correlated with the decreased expression of a previously described promoter of PDA chemotherapy resistance, the X-linked inhibitor of apoptosis protein. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models, and by extension in PDA patients. |
Databáze: | OpenAIRE |
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