Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma

Cook, Natalie; Frese, Kristopher K.; Bapiro, Tashinga E.; Jacobetz, Michael A.; Gopinathan, Aarthi; Miller, Jodi; Rao, Sudhir; Demuth, Tim; Howat, William J.; Jodrell, Duncan I.; Tuveson, David A.

doi:10.1084/jem.20111923

Cited by 85 publications

(69 citation statements)

References 36 publications

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“…These results and our prior work (17) suggest that disrupting the stromal barrier to increase drug delivery is not required to increase antitumor responses in murine PDA models. Rather, increased drug delivery may be most relevant when various intratumoral survival cues are concomitantly disrupted.…”

Section: Discussionsupporting

confidence: 71%

“…However, the aforementioned studies could not address whether the disruption of stromally derived factors also sensitized cancer cells to gemcitabine. Indeed, we also recently published that γ-secretase inhibition synergized with gemcitabine in the same mouse PDA model by cotargeting tumor endothelial cells and neoplastic cells, without increasing chemotherapy delivery (17). Therefore, we asked whether increasing chemotherapy concentrations alone is sufficient to elicit improved response rates, or rather that ECM modulation/degradation sensitizes tumors to the antineoplastic properties of chemotherapy.…”

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confidence: 99%

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CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Neeße

Frese

Bapiro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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218

173

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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.

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Neeße

Frese

Bapiro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

218

173

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“…Although pharmacological inhibition of CDA raised the levels of activated intratumoural gemcitabine to a comparable level to PEGPH20 or SHH inhibition, the apoptotic rate in neoplastic cells and overall tumour growth was surprisingly unaffected 93. These data and prior work from our group suggest that disrupting the stromal barrier to increase drug delivery is not the only factor that increases antitumour responses 40. Rather, increased drug delivery may be most effective when various intratumoural survival cues are concomitantly targeted.…”

Section: Stromal Depletion In Pda: Therapeutic and Biological Implicamentioning

confidence: 58%

Stromal biology and therapy in pancreatic cancer: a changing paradigm

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Algül

Tuveson

et al. 2015

Gut

472

386

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Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.

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“…Therefore it is interesting to speculate whether introduction of combinatorial therapeutic regimens might be able to delay or to even completely abolish this development of resistance in the future, as has already been suggested for other targeted approaches in the recent past [98][99][100][101].…”

Section: Expert Opinionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of sunitinib for the treatment of advanced pancreatic neuroendocrine tumors

Feldmann

Brossart

2013

Expert Opinion on Drug Metabolism & Toxicology

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Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma

Abstract: Blocking Notch signaling in pancreatic cancer promotes hypoxia and cell death.

Cited by 85 publications

References 36 publications

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Stromal biology and therapy in pancreatic cancer: a changing paradigm

Pharmacokinetics and pharmacodynamics of sunitinib for the treatment of advanced pancreatic neuroendocrine tumors

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