The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum-and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.
Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Although most patients respond to frontline therapy, virtually all patients relapse with chemoresistant disease. This study addresses the hypothesis that carboplatin or tamoxifen + FTY720, a sphingosine analogue, will minimize or circumvent drug-resistance in ovarian cancer cells and tumor models. In vitro data demonstrate that FTY720 sensitized two drug-resistant (A2780. cp20, HeyA8. MDR) and two high-grade serous ovarian cancer cell lines (COV362, CAOV3) to carboplatin, a standard of care for patients with ovarian cancer, and to the selective estrogen receptor modulator tamoxifen. FTY720 + tamoxifen was synergistic in vitro, and combinations of FTY720 + carboplatin or + tamoxifen were more effective than each single agent in a patient-derived xenograft model of ovarian carcinoma. FTY720 + tamoxifen arrested tumor growth. FTY720 + carboplatin induced tumor regressions, with tumor volumes reduced by ∼86% compared to initial tumor volumes. Anti-tumor efficacy was concomitant with increases in intracellular proapoptotic lipid ceramide. The data suggest that FTY720 + tamoxifen or carboplatin may be effective in treating ovarian tumors.
Despite satisfactory initial responses to frontline therapies that combine surgical debulking with platinum based chemotherapy, virtually all women with advanced ovarian cancer relapse with drug resistant disease. There is a critical need to identify alternative, effective therapies. Previously, we used patient derived xenograft (PDX) models of ovarian cancer in mice to identify the sphingosine1 phosphate (S1P) pathway as one of the pathways most affected by two agents frequently used to treat ovarian cancer, carboplatin and paclitaxel. The S1P pathway contributes to multiple biological processes recognized as essential for tumor development, and aberrations in sphingolipid metabolism have been directly correlated with advanced disease and with resistance to chemotherapy and radiation. Further, recent studies indicate that tamoxifen may counteract drug resistance mechanisms through modulation of sphingolipid metabolism, specifically through inhibition of the ceramide converting enyzmes acid ceramidase and glucosylceramide synthase. Therefore, we evaluated the efficacy of modulating S1P metabolism using the sphingosine analog FTY720 and tamoxifen as an approach to inhibit the proliferation of drug-resistant ovarian tumor cells. We used alamarBlue cell proliferation assays to compare the anti-proliferative effect of FTY720 and tamoxifen with the effect of each drug as a single agent. FTY720 + tamoxifen synergistically decreased the cell viability of 3/3 ovarian cancer cell lines: estrogen receptor alpha (ERα) positive SKOV3.TR (taxane resistant), ERα negative A280.cp20 (platinum resistant) and HeyA8.MDR (taxane-platinum resistant). The combination also increased levels of apoptosis as reflected by Annexin V staining and cleaved caspase 3 levels. Further, administration of 5mg/kg i.p. FTY720 + 20mg/kg p.o. tamoxifen daily for 21 days to PDX-bearing mice demonstrated that FTY720 + tamoxifen suppressed tumor growth by ~60% compared to vehicle controls. Notably, immunohistochemical staining of tumors harvested from treated mice showed that the combination decreased expression of the proliferation marker Ki-67 and increased expression of apoptosis indicators ceramide and cleaved caspase 3 to a greater degree than in tumors exposed to either drug alone. We conclude that FTY720 + tamoxifen merit further investigation as potentially effective agents for the treatment of drug-resistant ovarian cancer. Citation Format: Kelly Marie Kreitzburg, Charles N. Landen, Tracy Gamblin, Rebecca Arend, Ronald Alvarez, Karina Yoon. Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4115. doi:10.1158/1538-7445.AM2017-4115
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