Browsing by Author "Rassool, Feyruz V."

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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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    How Epigenetic Therapy Beats Adverse Genetics in Monosomy Karyotype AML
    (AACR, 2021-02) O'Hagan, Heather M.; Rassool, Feyruz V.; Nephew, Kenneth P.; Radiation Oncology, School of Medicine
    The study by Greve and colleagues, in this issue of Cancer Research, provides new molecular insights into the intriguing clinical activity of DNA hypomethylating agents (HMA) in patients with acute myeloid leukemia (AML) with monosomal karyotypes. Patients with AML with adverse monosomal karyotypes are known to benefit from HMAs, but not cytarabine, a cytidine analog without HMA activity, but the specific molecular mechanisms remain poorly understood. The authors investigated the mechanistic effects of HMAs on gene reactivation in AML in the context of the most common monosomal karyotypes, genetic deletion of chromosome 7q and 5q. They identified genes with tumor-suppressive properties, an endogenous retrovirus cooperatively repressed by DNA hypermethylation, and increased genetic losses on hemizygous chromosomal regions versus normal biallelic regions in AML cell models. Treatment with HMAs preferentially induced expression of these hemizygous genes to levels similar to those of genes in a biallelic state. In addition to CpG hypomethylation, decitabine treatment resulted in histone acetylation and an open chromatin configuration specifically at hemizygous loci. By using primary blood blasts isolated from patients with AML receiving decitabine and AML patient-derived xenograft models established from patients with either monosomal karyotypes or normal cytogenetics, Greve and colleagues both validated their findings in primary patient samples and demonstrated superior antileukemic activity of decitabine compared with chemotherapy with cytarabine. These mechanistic insights into how epigenetic therapy beats adverse genetics in monosomy karyotype AML will open new therapeutic opportunities for a difficult-to-treat patient group.
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    ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer
    (bioRxiv, 2024-10-21) Stojanovic, Lora; Abbotts, Rachel; Tripathi, Kaushlendra; Coon, Collin M.; Rajendran, Saranya; Farid, Elnaz Abbasi; Hostetter, Galen; Guarnieri, Joseph W.; Wallace, Douglas C.; Liu, Sheng; Wan, Jun; Calendo, Gennaro; Marker, Rebecca; Gohari, Zahra; Inayatullah, Mohammed M. A.; Tiwari, Vijay K.; Kader, Tanjina; Santagata, Sandro; Drapkin, Ronny; Kommoss, Stefan; Pfisterer, Jacobus; Konecny, Gottfried E.; Coopergard, Ryan; Issa, Jean-Pierre; Winterhoff, Boris J. N.; Topper, Michael J.; Sandusky, George E.; Miller, Kathy D.; Baylin, Stephen B.; Nephew, Kenneth P.; Rassool, Feyruz V.; Medical and Molecular Genetics, School of Medicine
    DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.