Applying small molecule signal transducer and activator of transcription-3 (STAT3) protein inhibitors as pancreatic cancer therapeutics

Carolyn C. Arpin, Stephen Mac, Yanlin Jiang, Huiwen Cheng, Michelle Grimard, Brent D G Page, Malgorzata Kamocka, Sina Haftchenary, Han Su, Daniel P. Ball, David A. Rosa, Ping Shan Lai, Rodolfo F. Gómez-Biagi, Ahmed M. Ali, Rahul Rana, Helmut Hanenberg, Kagan Kerman, Kyle C. McElyea, George Sandusky, Patrick T. GunningMelissa Fishel

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Constitutively activated STAT3 protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.

Original languageEnglish (US)
Pages (from-to)794-805
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number5
DOIs
StatePublished - May 1 2016

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STAT Transcription Factors
STAT3 Transcription Factor
Pancreatic Neoplasms
Neoplasms
Coculture Techniques
Therapeutics
Tumor Microenvironment
Surface Plasmon Resonance
Growth
Heterografts
Confocal Microscopy
Transcriptional Activation
Cell Survival
Cell Death
Phosphotransferases
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Applying small molecule signal transducer and activator of transcription-3 (STAT3) protein inhibitors as pancreatic cancer therapeutics. / Arpin, Carolyn C.; Mac, Stephen; Jiang, Yanlin; Cheng, Huiwen; Grimard, Michelle; Page, Brent D G; Kamocka, Malgorzata; Haftchenary, Sina; Su, Han; Ball, Daniel P.; Rosa, David A.; Lai, Ping Shan; Gómez-Biagi, Rodolfo F.; Ali, Ahmed M.; Rana, Rahul; Hanenberg, Helmut; Kerman, Kagan; McElyea, Kyle C.; Sandusky, George; Gunning, Patrick T.; Fishel, Melissa.

In: Molecular Cancer Therapeutics, Vol. 15, No. 5, 01.05.2016, p. 794-805.

Research output: Contribution to journalArticle

Arpin, CC, Mac, S, Jiang, Y, Cheng, H, Grimard, M, Page, BDG, Kamocka, M, Haftchenary, S, Su, H, Ball, DP, Rosa, DA, Lai, PS, Gómez-Biagi, RF, Ali, AM, Rana, R, Hanenberg, H, Kerman, K, McElyea, KC, Sandusky, G, Gunning, PT & Fishel, M 2016, 'Applying small molecule signal transducer and activator of transcription-3 (STAT3) protein inhibitors as pancreatic cancer therapeutics', Molecular Cancer Therapeutics, vol. 15, no. 5, pp. 794-805. https://doi.org/10.1158/1535-7163.MCT-15-0003
Arpin, Carolyn C. ; Mac, Stephen ; Jiang, Yanlin ; Cheng, Huiwen ; Grimard, Michelle ; Page, Brent D G ; Kamocka, Malgorzata ; Haftchenary, Sina ; Su, Han ; Ball, Daniel P. ; Rosa, David A. ; Lai, Ping Shan ; Gómez-Biagi, Rodolfo F. ; Ali, Ahmed M. ; Rana, Rahul ; Hanenberg, Helmut ; Kerman, Kagan ; McElyea, Kyle C. ; Sandusky, George ; Gunning, Patrick T. ; Fishel, Melissa. / Applying small molecule signal transducer and activator of transcription-3 (STAT3) protein inhibitors as pancreatic cancer therapeutics. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 5. pp. 794-805.
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AU - Page, Brent D G

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