Browsing by Author "Keer, Harold"

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    A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer
    (Wiley, 2021) Albany, Costantine; Fazal, Zeeshan; Singh, Ratnakar; Bikorimana, Emmanuel; Adra, Nabil; Hanna, Nasser H.; Einhorn, Lawrence H.; Perkins, Susan M.; Sandusky, George E.; Christensen, Brock C.; Keer, Harold; Fang, Fang; Nephew, Kenneth P.; Spinella, Michael J.; Medicine, School of Medicine
    Purpose: Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next-generation HMA guadecitabine (SGI-110) with cisplatin in recurrent, cisplatin-resistant GCT patients. Methods: Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28-day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Results: The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions: The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.
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    An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations
    (AACR, 2018-07) Pulliam, Nicholas; Fang, Fang; Ozes, Ali R.; Tang, Jessica; Adewuyi, Adeoluwa; Keer, Harold; Lyons, John; Baylin, Stephen B.; Matei, Daniela; Nakshatri, Harikrishna; Rassool, Feyruz V.; Miller, Kathy D.; Nephew, Kenneth P.; Medicine, School of Medicine
    Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed. Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP “trapping” by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models. Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.
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    Epigenetic Targeting of Adipocytes Inhibits High-Grade Serous Ovarian Cancer Cell Migration and Invasion
    (American Association for Cancer Research, 2018-08) Tang, Jessica; Pulliam, Nicholas; Özeş, Ali; Buechlein, Aaron; Ding, Ning; Keer, Harold; Rusch, Doug; O’Hagan, Heather; Stack, M. Sharon; Nephew, Kenneth P.; Medical and Molecular Genetics, School of Medicine
    Ovarian cancer (OC) cells frequently metastasize to the omentum and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion and proximal and direct co-culture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells towards adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor suppressor genes and EMT inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cells migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid α-oxidation suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may impact the tumor microenvironment to decrease cancer cell metastasis.
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    A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian CancerA Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer
    (American Association for Cancer Research, 2020-03-01) Oza, Amit M.; Matulonis, Ursula A.; Secord, Angeles Alvarez; Nemunaitis, John; Roman, Lynda D.; Blagden, Sarah P.; Banerjee, Susana; McGuire, William P.; Ghamande, Sharad; Birrer, Michael J.; Fleming, Gini F.; Markham, Merry Jennifer; Hirte, Hal W.; Provencher, Diane M.; Basu, Bristi; Kristeleit, Rebecca; Armstrong, Deborah K.; Schwartz, Benjamin; Braly, Patricia; Hall, Geoff D.; Nephew, Kenneth P.; Jueliger, Simone; Oganesian, Aram; Naim, Sue; Hao, Yong; Keer, Harold; Azab, Mohammad; Matei, Daniela; Anatomy and Cell Biology, School of Medicine
    PURPOSE: Platinum resistance in ovarian cancer (OC) is associated with epigenetic modifications. Hypomethylating agents (HMAs) have been studied as carboplatin re-sensitizing agents in OC. This randomized phase 2 trial compared guadecitabine, a second generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant OC. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 SC once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.