Inhibition of STAT3 in pancreatic ductal adenocarcinoma and immunotherapeutic implications


Presenter/Authors

Rafal Zielinski, Izabela Fokt, Stanislaw Skora, Edward Felix, Krzysztof Grela, Jayakumar Arumugam, Radj Venugopal, Midan Ai, Genevieve Hartley, Michael Curran, Waldemar Priebe. UT MD Anderson Cancer Center, Houston, TX; Carolina BioOncology Institute, Houston, TX.

Disclosures
R. Zielinski: None. I. Fokt: None. S. Skora: None. E. Felix: None. K. Grela: ; Moleculin Biotech, Inc. J. Arumugam: None. R. Venugopal: None. M. Ai: None. G. Hartley: None. M. Curran: None. W. Priebe: ; Moleculin Biotech, Inc.



Abstract

Introduction: Signal Transducer and Activators of Transcription 3 (STAT3) plays a pivotal role in carcinogenesis, chemo- and radio-sensitivity, metastasis and immune evasion in multiple malignances including Pancreatic Ductal Adenocarcinoma (PDAC). Our drug discovery program focused on modulators of transcriptional activity led us to identify small molecules that potently inhibits tyrosine 705 phosphorylated STAT3 (p-STAT3). Compound WP1066, currently being evaluated in a Phase I clinical trial (NCT01904123) as orally administered agent and its novel, analog WP1732 suitable for IV administration, were selected as promising, potent p-STAT3 inhibitors with drug-like properties for further development as lead compounds. The purpose of these study is to perform a preclinical evaluation of WP1066 and WP1732 aiming at their future application for treatment of PDAC.



Materials and Methods: 
The chemical synthesis of WP1066 and WP1732 and their characterization was performed at UT MD Anderson Cancer Center. In vitro efficacy of both inhibitors was assessed using proliferation and apoptosis induction assays in a panel of patient-derived and commercially-available PDAC cell lines. Inhibition of p-STAT3 was investigated using western blot (WB) and immunofluorescence. Acute and multiple dose toxicity of WP1732 was tested in CD-1 mice. Pharmacokinetic parameters of WP1732 after intravenous administration was evaluated in naïve CD-1 mice using Mass Spectrometry LC/MS/MS or rats by liquid scintillation counting (LSC) using radio-labeled agent. Efficacy of both agents alone or in combination with immune checkpoints inhibitors was tested in PDAC tumor models.



Results:
Both WP1066 and WP1732 were shown to induce apoptosis and inhibit p-STAT3 and its nuclear localization in all tested PDAC cell lines. Observed IC50 values ranged from 0.5 to 2 μM. WP1732 was well tolerated by mice (LD50 85 mg/kg given IV). Pharmacokinetic and biodistribution studies indicate high plasma levels of the drug and significant accumulation of WP1732 in the pancreas of mice and rats after a single bolus injection of the drug. Importantly, both agents show in vivo efficacy in preliminary experiments when tested alone or in combination with T cell immune checkpoint inhibitors.



Conclusion:
WP1066 and WP1732 are inhibitors of p-STAT3 with demonstrated in vitro and in vivo activity against PDAC tumor models. Our preliminary data warrant the further pre-clinical and clinical evaluation of these oncology agents alone and in combination with immunotherapy as a promising new therapeutics for pancreatic cancer.

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Huang, R., D. Faratian, A. H. Sims, D. Wilson, J. S. Thomas, D. J. Harrison and S. P. Langdon (2014). “Increased STAT1 signaling in endocrine-resistant breast cancer.” PloS ONE 9(4): e94226/11.

Huang, Y., X. Zhou, A. Liu, S. Li, X. Wang and L. Zhang (2014). “Signal transducer and activator of transcription-3 inhibitor WP1066 affects human tongue squamous cell carcinoma proliferation and apoptosis in vitro and in vivo.” Chinese Journal of Stomatology 49(5): 308-313.

Judd, L. M., T. R. Menheniott, H. Ling, C. B. Jackson, M. Howlett, A. Kalantzis, W. Priebe and A. S. Giraud (2014). “Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo.” PLoS ONE 9(5): e95993.

Kong, L.-Y., J. Wei, A. S. Haider, B. D. Liebelt, X. Ling, C. A. Conrad, G. N. Fuller, N. B. Levine, W. Priebe and R. Sawaya (2014). “Therapeutic targets in subependymoma.” Journal of Neuroimmunology 277(1): 168-175.

Mielecki, M., M. Milner-Krawczyk, K. Grzelak, D. Mielecki, K. A Krzysko, B. Lesyng and W. Priebe (2014). “Analogs of Cinnamic Acid Benzyl Amide As Nonclassical Inhibitors of Activated JAK2 Kinase.” Current Cancer Drug Targets 14(7): 638-651.

Tang, Y., Z. Sun, W. Wu, J. Xing, Y. He, D. Xin and P. Han (2014). “Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro.” Genetics and Molecular Research: GMR 14(1): 2450-2460.

Vangala, J. R., S. Dudem, N. Jain and S. V. Kalivendi (2014). “Regulation of PSMB5 Protein and β Subunits of Mammalian Proteasome by Constitutively Activated Signal Transducer and Activator of Transcription 3 (STAT3): potential role in bortezomib-mediated anticancer therapy.” Journal of Biological Chemistry 289(18): 12612-12622.

Xue, Z.-j., L. Shen, Z.-y. Wang, S.-y. Hui, Y.-g. Huang and C. Ma (2014). “STAT3 inhibitor WP1066 as a novel therapeutic agent for bCCI neuropathic pain rats.” Brain Research 1583: 79-88.

Yuan, F., X. Fu, H. Shi, G. Chen, P. Dong and W. Zhang (2014). “Induction of Murine Macrophage M2 Polarization by Cigarette Smoke Extract via the JAK2/STAT3 Pathway.” PLoS ONE 9(9): e107063

Zheng, L., M. Zhang, J. Xue, Y. Li, Y. Nan, M. Li, J. Wang and X. Du (2014). “Effect of Angiotensin II on STAT3 mediated atrial structural remodeling.” European Review for Medical and Pharmacological Sciences 18(16): 2365-2377.

Zheng, Q., L. Han, Y. Dong, J. Tian, W. Huang, Z. Liu, X. Jia, T. Jiang, J. Zhang and X. Li (2014). “JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma.” Neuro-Oncology 16(9): 1229-1243.

Zhou, X., Y. Ren, A. Liu, L. Han, K. Zhang, S. Li, P. Li, P. Li, C. Kang and X. Wang (2014). “STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo.” Oncology Reports 31(5): 2173-2180.

Zhou, X., Y. Ren, A. Liu, R. Jin, Q. Jiang, Y. Huang, L. Kong, X. Wang and Zhang (2014). “WP1066 Sensitizes Oral Squamous Cell Carcinoma Cells to Cisplatin by Targeting STAT3/miR-21 axis”. Scientific Reports 4: 7461

Ashizawa, T., H. Miyata, et al. (2013). “Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma.” International Journal of Oncology 43(1): 219-227.

Gan, A. M., E. D. Butoi, et al. (2013). “Inflammatory effects of resistin on human smooth muscle cells: Up-regulation of fractalkine and its receptor, CX3CR1 expression by TLR4 and Gi-protein pathways.” Cell and Tissue Research 351(1): 161-174.

Ho, Y., S. W. Tsao, et al. (2013). “STAT3 as a therapeutic target for Epstein-Barr virus (EBV) – associated nasopharyngeal carcinoma.” Cancer Letters 330(2): 141-149.

Hu, Y., H. Chen, et al. (2013). “Deficiency of Erbin induces resistance of cervical cancer cells to anoikis in a STAT3-dependent manner.” Oncogenesis 2 (e53): 1-12.

Khurana, S. S., T. E. Riehl, et al. (2013). “The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation.” Journal of Biological Chemistry 288(22): 16085-16097.

Liu, F., J. Cao, et al. (2013). “Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas.” Journal of Investigative Dermatology 133(8): 2041-2049.

Slater, L. H., E. C. Hett, et al. (2013). “Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death.” ACS Chem Biol 8(4): 812-822.

Song, B., H. Jin, et al. (2013). “Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways.” Regulatory Peptides 185: 44-51.

Stechishin, O. D., H. A. Luchman, et al. (2013). “On-target JAK2/STAT3 inhibition slows disease progression in orthotopic xenografts of human glioblastoma brain tumor stem cells.” Neuro-Oncology 15(2): 198-207.

Cai, B., J. Li, et al. (2012). “microRNA‐124 Regulates Cardiomyocyte Differentiation of Bone Marrow‐Derived Mesenchymal Stem Cells Via Targeting STAT3 Signaling.” Stem Cells 30(8): 1746-1755.

Daniel, J. M., J. Dutzmann, et al. (2012). “Inhibition of STAT3 signaling prevents vascular smooth muscle cell proliferation and neointima formation.” Basic Research in Cardiology 107(3): 261.

Hatiboglu, M. A., L. Y. Kong, et al. (2012). “The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models.” International Journal of Cancer 131(1): 8-17.

Higuchi, S., M. Ii, et al. (2012). “Delta-opioid receptor activation promotes mesenchymal stem cell survival via PKC/STAT3 signaling pathway.” Circulation Journal 76(1): 204-212.

Jung, M., J. Rho, et al. (2012). “Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells.” Oncogene 32(2): 209-221.

Liang, J., W. Huang, et al. (2012). “Suicide Gene Reveals the Myocardial Neovascularization Role of Mesenchymal Stem Cells Overexpressing CXCR4 (MSCCXCR4).” PloS ONE 7(9): e46158.

Liu, J.-W., Y.-C. Hsu, et al. (2012). “Leukemia Inhibitory Factor-Induced Stat3 Signaling Suppresses Fibroblast Growth Factor 1-Induced Erk1/2 Activation to Inhibit the Downstream Differentiation in Mouse Embryonic Stem Cells.” Stem Cells and Development 22(8): 1190-1197.

Loh, K. C., W. I. Leong, et al. (2012). “Sphingosine-1-phosphate enhances satellite cell activation in dystrophic muscles through a S1PR2/STAT3 signaling pathway.” PloS ONE 7(5): doi:10.1371/journal.pone.0037218.

Qu, X., G. Zhuang, et al. (2012). “Induction of Bv8 Expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: Key role of Stat3 signaling.” Journal of Biological Chemistry 287(23): 19574-19584.

Roller, D. G., M. Axelrod, et al. (2012). “Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.” Molecular Cancer Therapeutics 11(11): 2505-2515.

Shang, Y., X. Yang, et al. (2012). “Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways.” Amino Acids 42(5): 1879-1887.

Verweij, M. M., V. Sabato, et al. (2012). “STAT5 in Human Basophils: IL-3 Is Required for Its FceRI-Mediated Phosphorylation.” Cytometry Part B (Clinical Cytometry) 82B(2): 101-106.

Chiu, H. C., D. L. Chou, et al. (2011). “Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells.” Biochemical Pharmacology 81(11): 1263-1270.

Demyanets, S., C. Kaun, et al. (2011). “Oncostatin M-enhanced vascular endothelial growth factor expression in human vascular smooth muscle cells involves PI3K-, p38 MAPK-, Erk1/2- and STAT1/STAT3-dependent pathways and is attenuated by interferon-γ.” Basic Research in Cardiology 106(2): 217-231.

Li, Y., H. Zhang, et al. (2011). “Transactivated EGFR mediates alpha(1)-AR-induced STAT3 activation and cardiac hypertrophy.” Am J Physiol Heart Circ Physiol 301(5): H1941-1951.

Okumura, M., T. Iwakiri, et al. (2011). “Hepatocyte growth factor suppresses the anticancer effect of irinotecan by decreasing the level of active metabolite in HepG2 cells.” Biochemical Pharmacology 82(11): 1720-1730.

Peng, Z., A. Pal, et al. (2011). “Tyrphostin-like compounds with ubiquitin modulatory activity as possible therapeutic agents for multiple myeloma.” Bioorganic & Medicinal Chemistry 19(23): 7194-7204.

Wang, Y., L. Chen, et al. (2011). “Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and beta-catenin signaling pathways.” Oncol Rep 26(5): 1173-1180.

Wei, C. C., S. Ball, et al. (2011). “Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells.” International Journal of Oncology 38(1): 279-285.

Wei, J., A. Wu, et al. (2011). “Hypoxia potentiates glioma-mediated immunosuppression.” PloS ONE 6(1).

Bill, M. A., J. R. Fuchs, et al. (2010). “The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity.” Molecular Cancer 9: 165.

Horiguchi, A., T. Asano, et al. (2010). “STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma.” British Journal of Cancer 102(11): 1592-1599.

Humphries, W., J. Wei, et al. (2010). “The Role of Tregs in Glioma-Mediated Immunosuppression: Potential Target for Intervention.” Neurosurgery Clinics of North America 21(1): 125-137.

Kong, L. Y., A. S. Wu, et al. (2010). “Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immunotherapeutic responses.” Clinical Cancer Research 16(23): 5722-5733.

Lin, L., B. Hutzen, et al. (2010). “A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells.” Neoplasia (New York, NY) 12(1): 39.

Manea, S.-A., A. Manea, et al. (2010). “Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells.” Cell and Tissue Research 340(1): 71-79.

Shabbir, A., D. Zisa, et al. (2010). “Activation of host tissue trophic factors through JAK-STAT3 signaling: A mechanism of mesenchymal stem cell-mediated cardiac repair.” American Journal of Physiology – Heart and Circulatory Physiology 299(5): H1428-H1438.

Wei, J., J. Barr, et al. (2010). “Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway.” Molecular Cancer Therapeutics 9(1): 67-78.

Heimberger, A. B., L. Y. Kong, et al. (2009). “The role of tregs in human glioma patients and their inhibition with a novel STAT-3 inhibitor.” Clinical Neurosurgery 56: 98-106.

Kong, L. Y., J. Wei, et al. (2009). “A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells.” Cancer Immunol Immunother 58(7): 1023-1032.

Kupferman, M. E., A. Jayakumar, et al. (2009). “Therapeutic suppression of constitutive and inducible JAK\STAT activation in head and neck squamous cell carcinoma.” Journal of Experimental Therapeutics and Oncology 8(2): 117-127.

McGaffin, K. R., B. Zou, et al. (2009). “Leptin attenuates cardiac apoptosis after chronic ischaemic injury.” Cardiovascular Research 83(2): 313-324.

Vogiatzi, P., M. Cassone, et al. (2009). “Targeted therapy for advanced prostate cancer: Looking through new lenses.” Drug News and Perspectives 22(10): 593-601.

Kong, L. Y., M. K. Abou-Ghazal, et al. (2008). “A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells.” Clinical Cancer Research 14(18): 5759-5768.

Verstovsek, S., T. Manshouri, et al. (2008). “WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation.” Clinical Cancer Research 14(3): 788-796.

Wilks, A. F. (2008). “The JAK kinases: Not just another kinase drug discovery target.” Seminars in Cell and Developmental Biology 19(4): 319-328.

Ferrajoli, A., S. Faderl, et al. (2007). “WP1066 disrupts janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells.” Cancer Research 67(23): 11291-11299.

Hussain, S. F., L. Y. Kong, et al. (2007). “A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients.” Cancer Research 67(20): 9630-9636.

Iwamaru, A., S. Szymanski, et al. (2007). “A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo.” Oncogene 26(17): 2435-2444.

Tabe, Y., L. Jin, et al. (2007). “Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells.” Cancer Research 67(2): 684-694.

Yokoyama, T., Y. Kondo, et al. (2007). “Roles of mTOR and STAT3 in autophagy induced by telomere 3′ overhang-specific DNA oligonucleotides.” Autophagy 3(5): 496-498.

WP1122 Bibliography

Felix, E., I. Fokt, J. Arumugam, M. Krasinski, M. Tai Khuong, R. Zielinski, S. Skora, V. Radjendirane and W. Priebe (2018). “EXTH-07. DESIGN AND EVALUATION OF WP1122, AN INHIBITOR OF GLYCOLYSIS WITH INCREASED CNS UPTAKE.” Neuro-Oncology 20(suppl_6): vi86-vi86.

Shao, B., C.-W. Li, S.-O. Lim, L. Sun, Y.-J. Lai, J. Hou, C. Liu, C.-W. Chang, Y. Qiu and J.-M. J. A. j. o. c. r. Hsu (2018). “Deglycosylation of PD-L1 by 2-deoxyglucose reverses PARP inhibitor-induced immunosuppression in triple-negative breast cancer.”  8(9): 1837.

Conrad, C. “WP1122: Novel Therapy for CNS Malignancies”, National Brain Tumor Society

https://braintumor.org/assets/docs/advanced-research/integrated-initiatives/art/anti-glycolysis-charles-conrad-overview-presentation-mdacc.pdf