Browsing by Subject "PARP"

Now showing 1 - 4 of 4
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    A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)
    (Wiley, 2022-11) Leal, Ticiana A.; Sharifi, Marina N.; Chan, Nancy; Wesolowski, Robert; Turk, Anita A.; Bruce, Justine Y.; O'Regan, Ruth M.; Eickhoff, Jens; Barroilhet, Lisa M.; Malhotra, Jyoti; Mehnert, Janice; Girda, Eugenia; Wiley, Elizabeth; Schmitz, Natalie; Andrews, Shannon; Liu, Glenn; Wisinski, Kari B.; Medicine, School of Medicine
    Background Inhibitors of poly(ADP‐ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods We conducted a phase I study of talazoparib with carboplatin AUC5‐6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21‐day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4–6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results Forty‐three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment‐related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13‐month median duration of maintenance. Conclusion We have established the recommended phase II dose of Talazoparib at 250mcg on a 3‐ or 7‐day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21‐day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.
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    Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents
    (bioRxiv, 2024-09-07) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of Medicine
    During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.
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    Olaparib Induced Moderate Killing of ATM-Deficient Mantle Cell Lymphoma Cells In Vitro and In Vivo
    (Austin Publishing Group, 2019) Kiel, P. J.; Overholser, B. R.; Feng, H.; Sinn, A.; Riley, A. A.; McCarthy, P. B.; Pollok, K.; Territo, P. R.; Srivastava, S.; Medicine, School of Medicine
    The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as and Mantle Cell Lymphoma (MCL) and is associated with defective apoptosis, especially in response to standard cytotoxic chemotherapy. ATM deficient cells exhibit impaired homologous recombination and the inability to correct double strand DNA breaks. Inhibition of poly (ADPribose) Polymerase (PARP), which is required for DNA double strand break repair, has been shown to sensitize ATM-deficient tumor cells to killing. We investigated in vitro and in vivo sensitivity to the PARP inhibitor olaparib in the ATM deficient mantle cell lymphoma cell line Granta-519. Olaparib monotherapy and in combination with cisplatin or bendamustine confirmed decreased proliferation in vitro. A Nonobese Diabetic/Severe Combined Immunodeficient (NOD/SCID) murine xenograft model with the Granta-519 cell line did not result in a significantly reduced tumor load following treatment with olaparib in vivo.
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    STAT6 and PARP Family Members in the Development of T Cell-dependent Allergic Inflammation
    (KoreaMed Synapse, 2016-08) Krishnamurthy, Purna; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
    Allergic inflammation requires the orchestration of altered gene expression in the target tissue and in the infiltrating immune cells. The transcription factor STAT6 is critical in activating cytokine gene expression and cytokine signaling both in the immune cells and in target tissue cells including airway epithelia, keratinocytes and esophageal epithelial cells. STAT6 is activated by the cytokines IL-4 and IL-13 to mediate the pathogenesis of allergic disorders such as asthma, atopic dermatitis, food allergy and eosinophilic esophagitis (EoE). In this review, we summarize the role of STAT6 in allergic diseases, its interaction with the co-factor PARP14 and the molecular mechanisms by which STAT6 and PARP14 regulate gene transcription.