Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

Catenacci, Daniel V.T.; Junttila, Melissa R.; Karrison, Theodore; Bahary, Nathan; Horiba, M. Naomi; Nattam, Sreenivasa; Marsh, Robert de Wilton; Wallace, James A.; Kozloff, Mark; Rajdev, Lakshmi; Cohen, Deirdre Jill; Wade, James L.; Sleckman, Bethany G.; Lenz, Heinz Josef; Stiff, Patrick; Kumar, Pankaj; Xu, Peng; Henderson, Les; Takebe, Naoko; Salgia, Ravi; Wang, Xi; Stadler, Walter M.; Sauvage, Frédéric J. de; Kindler, Hedy L.

doi:10.1200/jco.2015.62.8719

Cited by 475 publications

(343 citation statements)

References 52 publications

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“…Despite the strong biologic data supporting Hh inhibition in PDAC, two recent studies failed to demonstrate any additional benefit of SMO inhibitors (saridegib and vismodegib) in unselected patients with metastatic PDAC compared with placebo (26,27). Furthermore, in the KPC model of pancreatic cancer, deletion of Shh induced stroma depletion and resulted in an undifferentiated aggressive tumor phenotype suggesting a protective role of Shh and the desmoplastic reaction (28).…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Maréchal

Bachet

Calomme

et al. 2015

Clinical Cancer Research

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Purpose: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. Experimental Design: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. Results: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). Conclusions: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC. Clin Cancer Res; 21(5); 1215–24. ©2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Maréchal

Bachet

Calomme

et al. 2015

Clinical Cancer Research

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“…Interim data analysis indicated that median OS for the saridegib plus gemcitabine arm was less than 6 mo whereas the median OS for the placebo plus gemcitabine arm was greater than 6 mo, resulting in termination of the clinical trial (23). In another randomized, placebo-controlled phase 2 study, the FDA-approved Smo antagonist vismodegib plus gemcitabine was compared with placebo plus gemcitabine in patients with previously untreated metastatic PDA (24). At the time of interim analysis, the OS was 6.3 versus 5.4 mo for vismodegib versus the placebo arm, with an unimpressive hazard ratio of 0.97.…”

Section: Significancementioning

confidence: 99%

Stromal response to Hedgehog signaling restrains pancreatic cancer progression

Lee

Perera

Wang

et al. 2014

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

451

382

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Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.tumor stroma | cancer therapy | Sonic hedgehog | hedgehog agonist | cerulein P ancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer-related death in the United States and is the most lethal of common human malignancies, with a 5-y survival rate of ∼7% (1, 2). The most effective chemotherapy regimens for metastatic or locally advanced inoperable disease are largely palliative and are capable of extending overall survival by only several months (3, 4). Even localized disease, treatable with surgery followed by adjuvant chemotherapy, has a dismal 5-y survival rate of 24% (1). Among gastrointestinal malignancies, PDA is unique in that it is predominantly driven by oncogenic Kras activity. In addition, PDA pathogenesis is marked by a striking desmoplastic reaction to invading tumor cells. This desmoplasia includes a dense extracellular matrix with abundant stromal fibroblasts and influences the cellular biology of the tumor as well as its response to chemotherapeutic agents.Hedgehog (Hh) signaling has been thought to play a role in PDA desmoplasia and tumor progression but is notable during embryonic development of the pancreas for its absence in the region of embryonic endoderm from which the pancreas forms (5-7). This absence of activity is required for normal specification of early pancreatic progenitor fate, and pharmacologic or antibody treatments that inhibit Hh ...

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“…The authors and other researchers have demonstrated that inhibition of the Hh signaling pathway reduces or suppresses growth of PDA and that SHH primarily acts on the stromal compartment of the tumor [16,17,18,19]. However, despite being demonstrated to have significant anti-tumor functions in pre-clinical animal models, in clinical trials, the Hh inhibitor vismodegib in PDA was not found to improve the response of an unselected cohort [20]. The discrepancy between the expectations that were based on the pre-clinical model and the results of the clinical trial calls for a revision of our theoretical views on the signaling pathways at different stages of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Gli2 protein expression level is a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms

Sugiyama¹,

Sasajima

Mizukami³

et al. 2016

pjp

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The hedgehog pathway is known to promote proliferation of pancreatic ductal adenocarcinoma (PDA) and has been shown to restrain tumor progression. To understand how hedgehog causes these effects, we sought to carefully examine protein expression of hedgehog signaling components during different tumor stages. Genetically engineered mice, Pdx1-Cre;LSL-Kras G12D and Pdx1-Cre;LSLKras G12D;p53 lox/+ , were utilized to model distinct phases of tumorigenesis, pancreatic intraepithelial neoplasm (PanIN) and PDA. Human pancreatic specimens of intraductal papillary mucinous neoplasm (IPMN) and PDA were also employed. PanIN and IPMN lesions highly express Sonic Hedgehog, at a level that is slightly higher than that observed in PDA. GLI2 protein is also expressed in both PanIN/ IPMN and PDA. Although there was no difference in the nuclear staining, the cytoplasmic GLI2 level in PDA was modest in comparison to that in PanIN/IPMN. Hedgehog interacting protein was strongly expressed in the precursors, whereas the level in PDA was significantly attenuated. There were no differences in expression of Patched1 at early and late stages. Finally, a strong correlation between Sonic Hedgehog and GLI2 staining was found in both human and murine pancreatic tumors. The results indicate that the GLI2 protein level could serve as a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms.

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Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

Cited by 475 publications

References 52 publications

Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Sonic Hedgehog and Gli1 Expression Predict Outcome in Resected Pancreatic Adenocarcinoma

Stromal response to Hedgehog signaling restrains pancreatic cancer progression

Gli2 protein expression level is a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms

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