Search

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

Byline: Barbara A. Woynarowska (1,2), Arlene L. Higdon (1,2), Ruben M. Munoz (1,2), Perry Bushong (1), Stephen J. Waters (1,2) Keywords: Irofulven; HMAF; prostate specific antigen Abstract: Irofulven (hydroxymethylacylfulvene,HMAF, MGI 114) is a novel agent withalkylating activity and a potent inducer ofapoptosis. It is currently undergoing PhaseII clinical trials for several tumor types,including hormone-refractory prostatecancer. Reduction of serumprostate-specific antigen (PSA) levels hasbeen proposed as a generally usefulendpoint for evaluating the antitumorefficacy of treatments for prostate cancer.However, the utility of PSA as a marker oftumor cell burden could be compromised, ifdrugs directly affected PSA secretionand/or expression. In these studies, weevaluated the effects of irofulven on PSAprotein and mRNA levels during the courseof treatment of prostate tumor cells in vitro. Therate of PSA secretion(normalized per equal cell number) bycontrol and drug treated cells was similar,as determined by a solid phase, two-siteimmunoradiometric assay. Consistent withthe lack of effect of irofulven on PSAprotein level, the drug does not appear toaffect the expression of PSA mRNA (on a percell basis) as assessed by RT-PCR. Thus,changes in PSA secretion and expressionappear to reflect irofulven-induced cellgrowth inhibition rather than reflecting adirect effect of the drug on PSA. Theseresults suggest that PSA should be areasonable marker of tumor burden inirofulven-treated prostate cancerpatients. Author Affiliation: (1) Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, TX (2) MGI Pharma, Inc., Bloomington, MN, U.S.A. Article History: Registration Date: 11/10/2004

A transgenic mouse tumor model was used to investigate the role of p53 in tumor response to two different platinum-based chemotherapeutic agents: (a) cisplatin and (b) oxaliplatin, a diaminocyclohexane platine recently introduced into the clinic. MMTV-v-Ha-ras transgenic mice were interbred to p53-deficient mice to generate mice that develop salivary tumors either possessing or lacking p53. Tumor-bearing mice were then treated on either a 9-day schedule to assess overall tumor growth response or on a short-term treatment schedule to assess effects on cell cycle parameters and apoptosis. Both agents induced significant apoptosis and promoted overall tumor regression, regardless of the p53 status of the tumor. This is in contrast to previous studies using this model in which treatment with paclitaxel or doxorubicin promoted tumor growth arrest but not apoptosis. These findings indicate that even in the context of an activated ras gene that potentially mediates suppression of apoptosis, both cisplatin and oxaliplatin are capable of promoting an efficient p53-independent tumor response.