Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator Wnt Inhibitor-2 (PAWI-2) and protein biomarker
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PRECLINICAL STUDIES
Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator Wnt Inhibitor-2 (PAWI-2) and protein biomarker expression Jiongjia Cheng 1
&
John R. Cashman 1
Received: 13 July 2020 / Accepted: 4 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Today, pancreatic cancer (PC) is a major health problem in the United States. It remains a challenge to develop efficacious clinically useful PC therapies. New avenues, based on translational approaches and innovative validated biomarkers could be a preclinical option to evaluate PC drug candidates or drug combinations before clinical trials. Herein, we describe evaluation of combination therapies by incorporating a novel pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) with other FDAapproved cancer drugs that have been used in PC clinical trials. PAWI-2 is a potent inhibitor of drug-resistant PC cells that has been shown to selectively ameliorate human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). In the present study, we showed PAWI-2 produced therapeutic synergism with certain types of anti-cancer drugs. These drugs themselves oftentimes do not ameliorate PC cells (especially PCSCs) due to high levels of drug-resistance. PAWI-2 has the ability to rescue the potency of drugs (i.e., erlotinib, trametinib) and inhibit PC cell growth. Key molecular regulators of PAWI-2 could be used to predict synergistic/antagonistic effects between PAWI-2 and other anti-cancer drugs. Anti-cancer results showed potency could be quite accurately correlated to phosphorylation of optineurin (OPTN) in PC cells. Synergism/antagonism was also associated with inhibition of PCSC marker SOX2 that was observed in FGβ3 cells. Synergism broadens the potential use of PAWI-2 as an adjunct chemotherapy in patients with PC that have developed resistance to first-line targeted therapies or chemotherapies. Keywords Pancreatic cancer cells . Cancer stemness . Drug resistance . Drug sensitivity . Drug synergy . Cell cycle arrest . PAWI-2
Introduction Pancreatic cancer (PC) is a major health problem in the United States and is the third leading cause of cancerrelated deaths [1, 2]. PC is one of the most lethal diagnoses that oncology patients face. PC is known to be highly resistant to currently available treatments. Surgical resection with negative margins is the only potentially curative treatment for PC, but only 15%–20% of patients with PC
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00998-z) contains supplementary material, which is available to authorized users. * Jiongjia Cheng [email protected] 1
Human BioMolecular Research Institute and ChemRegen, Inc., 5310 Eastgate Mall, San Diego, CA 92121, USA
are eligible for resection at initial diagnosis [3]. The remaining PC patients usually have metastatic or locally advanced disease that generally is considered incurable [4]. Most of the drugs approved by the United States Food and Drug Administration (F
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