P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau’s syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth in vivo, (3) determine the effect of P2RY12 across different digestive-tract cancers in vitro, and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau’s syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.

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142. Non-Coding XIST RNA Is Decreased in Pancreatic Cancer, and Retroviral Gene Delivery of XIST RNA Gene Inhibits Pancreatic Cancer Growth In Vitro and In Vivo

Journal of Surgical Research ◽

10.1016/j.jss.2007.12.161 ◽

2008 ◽

Vol 144 (2) ◽

pp. 239

Author(s):

Changyi J. Chen ◽

Hao Wang ◽

Min Li ◽

Uddalak Bharadwaj ◽

Hong Mu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Gene Delivery ◽

Cancer Growth ◽

Xist Rna

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A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-09-1145 ◽

2010 ◽

Vol 9 (5) ◽

pp. 1136-1146 ◽

Cited By ~ 95

Author(s):

Kuzhuvelil B. Harikumar ◽

Ajaikumar B. Kunnumakkara ◽

Nobuo Ochi ◽

Zhimin Tong ◽

Amit Deorukhkar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Protein Kinase ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Cancer Growth ◽

Protein Kinase D ◽

Molecule Inhibitor

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Proteomic Analysis of Cell Lines and Primary Tumors in Pancreatic Cancer Identifies Proteins Expressed Only In Vitro and Only In Vivo

Pancreas ◽

10.1097/mpa.0000000000001633 ◽

2020 ◽

Vol 49 (8) ◽

pp. 1109-1116

Author(s):

Orla Coleman ◽

Michael Henry ◽

Fiona O'Neill ◽

Sandra Roche ◽

Niall Swan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Proteomic Analysis ◽

Primary Tumors

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166 N-MYC Downstream Regulated Gene-1 Expression Correlates with Reduced Pancreatic Cancer Growth In Vitro and In Vivo

Gastroenterology ◽

10.1016/s0016-5085(09)60149-9 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-33

Author(s):

Eliane Angst ◽

Melvie Kim ◽

Jenny L. Park ◽

Beat Gloor ◽

Howard A. Reber ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Growth

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TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727

Cancers ◽

10.3390/cancers10080254 ◽

2018 ◽

Vol 10 (8) ◽

pp. 254 ◽

Cited By ~ 5

Author(s):

Vincent Drubay ◽

Nicolas Skrypek ◽

Lucie Cordiez ◽

Romain Vasseur ◽

Céline Schulz ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Locally Advanced ◽

Western World ◽

Pancreatic Cancer Cells ◽

Stat3 Phosphorylation ◽

The Impact

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.

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Correction: A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-10-0536 ◽

2010 ◽

Vol 9 (7) ◽

pp. 2153-2153

Keyword(s):

Pancreatic Cancer ◽

Protein Kinase ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Cancer Growth ◽

Protein Kinase D ◽

Molecule Inhibitor

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PCL20-116: Can Antisense Oligonucleotides Targeted to K-Ras Gene Inhibit the Tumor Growth, Invasiveness and Expression of MMP-2 and MMP-9 In Vitro and In Vivo in Hamster Experimental Pancreatic Cancer Model?

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2019.7514 ◽

2020 ◽

Vol 18 (3.5) ◽

pp. PCL20-116

Author(s):

Cintia Yoko Morioka ◽

Marcel Cerqueira Cesar Machado ◽

Jose Pinhata Otoch ◽

Luma Princess Schneider ◽

Edgard Mesquita Rodrigues Lima ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Antisense Oligonucleotides ◽

Cancer Model ◽

Ras Gene ◽

Experimental Pancreatic Cancer

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Effect of KRAS and P-STAT3 inhibition by SBT-100 on gemcitabine and pancreatic cancer growth in vivo.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15727 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15727-e15727

Author(s):

Sunanda Singh ◽

Genoveva Murillo ◽

Avani Singh ◽

Samara Singh ◽

Meenakshi S Parihar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Targeted Therapy ◽

Western Blot ◽

Cancer Cells ◽

Mtt Assay ◽

Blot Analysis ◽

Cancer Growth ◽

Pancreatic Cancers ◽

Pancreatic Cancer Cells

e15727 Background: Over 90% of pancreatic cancers have KRAS mutations and hyper-expression of P-STAT3 oncoproteins, which if specifically targeted may help treatment of pancreatic cancers. Singh Biotechnology’s proprietary technology engineered SBT-100, a single domain antibody that is bispecific for KRAS & STAT3, which can cross the cell membranes and bind to these intracellular oncoproteins. Combining this targeted therapy with an established chemotherapy, such as gemcitabine, may improve patient’s response to treatment. Methods: Human pancreatic cancer cells (PANC-1 and BX-PC3) were used. Biacore assay demonstrates SBT-100 binding to KRAS, KRAS (G12D), and STAT3. Immunoprecipitation (IP) and western blot analysis confirmed binding to STAT3 by SBT-100. Pancreatic cancer cells were treated at varying doses of SBT-100 ranging from 0µg/ml to 200µg/ml ± gemcitabine, and after 72 hours growth inhibition was determined by a MTT assay. PANC-1 tumors were grown in athymic nude mice, divided into four groups and staged to a range of 100-150mm3 before treatment. Groups were: vehicle only, SBT-100, gemcitabine, and SBT-100 & gemcitabine. Animals received treatments for 14 days, then monitored for 7 days. Results: Biacore study shows SBT-100 binds KRAS with an affinity of 10-9M, KRAS (G12D) with 10-8M, and STAT3 with 10-8M. IP and western blot analysis demonstrates that SBT-100 binds P-STAT3. MTT assay demonstrates SBT-100 inhibits the growth of PANC-1 and BX-PC3 (p < 0.001). In PANC1 cells a combination of SBT-100 & gemcitabine demonstrates synergism in inhibiting growth of PANC-1, even at 1/8th the gemcitabine IC50 concentration. PANC-1 xenograft study demonstrates that combination therapy of SBT-100 & gemcitabine is superior to either SBT-100 or gemcitabine alone. Compared to the vehicle group, SBT-100 & gemcitabine is far superior (p < 0.001) and gives statistically significant suppression of pancreatic cancer growth in vivo. Conclusions: Targeted therapy for KRAS and P-STAT3 expressing tumors with SBT-100 & gemcitabine is synergistic for the treatment of pancreatic cancer. This study suggests that synergism maybe achieved with lower doses of gemcitabine, thereby reducing toxicity in patients.

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