Pilot Phase II Trial of 13-cis-Retinoic Acid and Interferon-α Combination Therapy for Advanced Pancreatic Adenocarcinoma

Moore, Dennis F.; Pazdur, Richard; Sugarman, Steve; Jones, D. D.; Lippman, Scott M.; Bready, Beth; Abbruzzese, James L.

doi:10.1097/00000421-199512000-00013

Cited by 21 publications

(11 citation statements)

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“…ATRA could dramatically inhibit tumor growth and metastatic spread in a dose‐independent manner by inducing PIN1 degradation and blocking multiple signaling pathways. In practice, ATRA has been used to treat APL for decades but with less efficiency against solid tumors, including PDAC, for which the reason is partly the underlying molecular determinants. Retinoic acid receptors (RAR) are as a major substrate of ATRA.…”

Section: Discussionmentioning

confidence: 99%

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Chen

Wen

et al. 2019

Cancer Science

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The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease‐free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer‐driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal‐epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer‐driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Chen

Wen

et al. 2019

Cancer Science

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“…The systemic effects in patients with pancreatic cancer have not been clearly elucidated. In fact, numerous phase II trials have been conducted that utilize IFN therapy in combination with other agents, such as 5‐FU and leucovorin, to treat patients with metastatic or locally advanced pancreatic cancer 10–17. However, the results from these early trials were not encouraging.…”

Section: Discussionmentioning

confidence: 99%

Interferon receptor alpha/beta is associated with improved survival after adjuvant therapy in resected pancreatic cancer

Saidi

ReMine

Jacobs

2007

HPB

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“…In fact, in some instances, retinoids can induce an increase in PDAC cell migration, through upregulation of intracellular oncogenic pathways (7). Nonetheless, based on the weight of preclinical evidence, two pilot phase II clinical trials have been conducted using the related retinoid, 13-cis RA, in patients with advanced PDAC, but the results were disappointing (8, 9). …”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Retinoic Acid Sensitivity in Pancreatic Cancer

Gupta

Pramanik

Mukherjee

et al. 2012

Clinical Cancer Research

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Purpose To identify a predictive molecular ‘signature’ for sensitivity to retinoic acid in pancreatic cancer. Experimental Design Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks. Results Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition, and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5highCRABP2null cells could be circumvented by ectopic expression of CRABP2. Alternatively, re-expression of endogenous CRABP2 could be enabled in FABP5highCRABP2null PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13/63, ~20%) which are negative for FABP5 expression and might be candidates for ATRA therapy. Conclusions The widely used agent ATRA deserves a “second look” in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin modifying agent in order to re-express endogenous CRABP2.

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Pilot Phase II Trial of 13-cis-Retinoic Acid and Interferon-α Combination Therapy for Advanced Pancreatic Adenocarcinoma

Cited by 21 publications

References 0 publications

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Interferon receptor alpha/beta is associated with improved survival after adjuvant therapy in resected pancreatic cancer

Molecular Determinants of Retinoic Acid Sensitivity in Pancreatic Cancer

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