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Effect of PAWI-2 on pancreatic cancer stem cell tumors

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Abstract

Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5 million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Develo** efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ3 cells. PAWI-2 represents a safe, new approach to combat PC.

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References

  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921. https://doi.org/10.1158/0008-5472.CAN-14-0155

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21387

    Article  PubMed  Google Scholar 

  3. Li D, **e K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet. 363(9414):1049–1057. https://doi.org/10.1016/S0140-6736(04)15841-8

  4. Ansari D, Tingstedt B, Andersson B, Holmquist F, Sturesson C, Williamsson C et al (2016) Pancreatic cancer: yesterday, today and tomorrow. Future Oncol 12(16):1929–1946. https://doi.org/10.2217/fon-2016-0010

    Article  CAS  PubMed  Google Scholar 

  5. National Cancer Institute at the National Institutes of Health (2020) Drugs Approved for Pancreatic Cancer. https://www.cancer.gov/about-cancer/treatment/drugs/pancreatic

  6. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413. https://doi.org/10.1200/jco.1997.15.6.2403

    Article  CAS  PubMed  Google Scholar 

  7. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. https://doi.org/10.1056/NEJMoa1011923

    Article  CAS  PubMed  Google Scholar 

  8. ** J, Teng C, Li T (2018) Combination therapy versus gemcitabine monotherapy in the treatment of elderly pancreatic cancer: a meta-analysis of randomized controlled trials. Drug Des Devel Ther 12:475–480. https://doi.org/10.2147/DDDT.S156766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966. https://doi.org/10.1200/JCO.2006.07.9525

    Article  CAS  PubMed  Google Scholar 

  10. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C et al (2008) Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomized phase II study. Lancet 371(9630):2101–2108. https://doi.org/10.1016/S0140-6736(08)60661-3

    Article  CAS  PubMed  Google Scholar 

  11. Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ et al (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 28(22):3605–3610. https://doi.org/10.1200/JCO.2009.25.7550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14:275–291. https://doi.org/10.1016/j.stem.2014.02.006

    Article  CAS  PubMed  Google Scholar 

  13. Nassar D, Blanpain C (2016) Cancer Stem cells: Basic concepts and therapeutic implications. Annu Rev Pathol 11:47–76. https://doi.org/10.1146/annurev-pathol-012615-044438

    Article  CAS  PubMed  Google Scholar 

  14. Dean M, Fojo T, Bates S (2005) Tumor stem cells and drug resistance. Nat Rev Cancer 5:275–284. https://doi.org/10.1038/nrc1590

    Article  CAS  PubMed  Google Scholar 

  15. Hermann PC et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323. https://doi.org/10.1016/j.stem.2007.06.002

    Article  CAS  PubMed  Google Scholar 

  16. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  17. Meacham CE, Morrison SJ (2013) Tumor heterogeneity and cancer cell plasticity. Nature 501:328–337. https://doi.org/10.1038/nature12624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bivona TG et al (2011) FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471:523–526. https://doi.org/10.1038/nature09870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Seguin L et al (2014) An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457–468. https://doi.org/10.1038/ncb2953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Desgrosellier JS et al (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15:1163–1169. https://doi.org/10.1038/nm.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Seguin L et al (2017) Galectin-3, a Druggable vulnerability for KRAS-Addicted cancers. Cancer Discov 7:1464–1479. https://doi.org/10.1158/2159-8290.CD-17-0539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22. https://doi.org/10.1038/nrc2748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Adhikari AS, Agarwal N, Iwakuma T (2011) Metastatic potential of tumor-initiating cells in solid tumors. Front Biosci 16:1927–1938

    Article  CAS  Google Scholar 

  24. Miller PG et al (2013) In vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell 24:45–58. https://doi.org/10.1016/j.ccr.2013.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vaillant F et al (2008) The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammarytumorigenesis. Cancer Res 68:7711–7717. https://doi.org/10.1158/0008-5472.CAN-08-1949

    Article  CAS  PubMed  Google Scholar 

  26. Cheng J, Cashman JR (2020) Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator wnt Inhibitor-2 (PAWI-2) and protein biomarker expression. Investig New Drugs. https://doi.org/10.1007/s10637-020-00998-z

    Article  Google Scholar 

  27. Cashman JR, Mercola M, Schade D, Tsuda M (2013) Compounds for inhibition of cancer cell proliferation. Google Patents. 2013:US 13/748,70

  28. Okolotowicz KJ, Dwyer M, Ryan D, Cheng J, Cashman EA, Moore S et al (2018) Novel tertiary sulfonamides as potent anti-cancer agents. Bioorg Med Chem 26(15):4441–4451. https://doi.org/10.1016/j.bmc.2018.07.042

    Article  CAS  PubMed  Google Scholar 

  29. Cheng J, Dwyer M, Okolotowicz KJ, Mercola M, Cashman JR (2018) A novel inhibitor targets both wnt Signaling and ATM/p53 in Colorectal Cancer. Cancer Res 78(17):5072–5083. https://doi.org/10.1158/0008-5472.CAN-17-2642

    Article  CAS  PubMed  Google Scholar 

  30. Cheng J, Okolotowicz KJ, Ryan D, Mose E, Lowy AM, Cashman JR (2019) Inhibition of invasive pancreatic cancer: restoring cell apoptosis by activating mitochondrial p53. Am J Cancer Res 9(2):390–405

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheng J, Moore S, Gomez-Galeno J, Lee DH, Okolotowicz KJ, Cashman JR (2019) A Novel Small Molecule inhibits Tumor Growth and synergizes effects of Enzalutamide on prostate Cancer. J Pharmacol Exp Ther 371(3):703–712. https://doi.org/10.1124/jpet.119.261040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng J, Cashman JR (2020) PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRAS dependent pancreatic cancer stem cells. Sci Rep 10:9162–9173. https://doi.org/10.1038/s41598-020-65804-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheng J, Cashman JR (2020) PAWI-2: a novel inhibitor for eradication of Cancer. Med Chem Res 29:1147–1159. https://doi.org/10.1007/s00044-020-02575-8

    Article  CAS  Google Scholar 

  34. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-∆∆CT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  35. Tseng WW, Winer D, Kenkel JA, Choi O, Shain AH, Pollack JR, French R, Lowy AM, Engleman EG (2010) Development of an orthotopic model of invasive pancreatic cancer in an immunocompetent murine host. Clin Cancer Res 16:3684–3695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lillie LE, Temple NJ, Florence LZ (1996) Reference values for young normal Sprague-Dawley rats: weight gain, hematology and clinical chemistry. Hum Exp Toxicol 15:612–616

    Article  CAS  PubMed  Google Scholar 

  37. Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA, Mulvihill SJ (2010) Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39:425–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu J, Wang J, Hu Y, Qian J, Xu B, Chen H, Zou W, Fang JY (2014) Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity. Cell Death Dis 5:e1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Burris H, Storniolo AM (1997) Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 33(Suppl 1):S18–22

    Article  CAS  PubMed  Google Scholar 

  41. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, Tuveson DA (2012) Nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2:260–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. David Cheresh of University of California, San Diego and The Scripps Research Institute for FGβ3 cells. We thank Drs. Ashutosh Tiwari and Deepak Rohila for help with the orthotopic xenograft surgeries. The contents of this publication are solely the responsibility of the author and do not necessarily represent the official view of The Conrad Prebys Foundation.

Funding

This work was supported by a grant award from The Conrad Prebys Foundation (Grant Number-44; J. R. Cashman) and by funds from the Human BioMolecular Research Institute. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of The Conrad Prebys Foundation.

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  1. Human BioMolecular Research Institute, San Diego, 5310 Eastgate Mall, San Diego, CA, 92121, USA

    John R. Cashman & Emily A. Cashman

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  1. John R. Cashman
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Contributions

J.R.C. conceived the study conception and design. Material preparation was done by E.A.C. and J.R.C. conducted data collection and analysis. Both authors contributed to the study. The first draft of the manuscript was written by J.R.C and both authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to John R. Cashman.

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Animal work was approved by the appropriate institutional committee. Animal work was conducted in accordance with the Guide for Care and Use of Laboratory Animals as adopted by the NIH. Formal approval was obtained from the IACUC of HBRI. The animal work did not require ethics approval.

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Not applicable. No human subjects were used.

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Not applicable. No human subjects were used.

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The authors do not have any competing interests.

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Cashman, J.R., Cashman, E.A. Effect of PAWI-2 on pancreatic cancer stem cell tumors. Invest New Drugs (2024). https://doi.org/10.1007/s10637-024-01447-x

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