Browsing by Subject "carboplatin"

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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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    Using VBIM technique to identify novel carboplatin resistance gene in ovarian cancer
    (Office of the Vice Chancellor for Research, 2015-04-17) Wei, Han; She, Yun; Sandusky, George; Lu, Tao
    Ovarian cancer (OC) is the most lethal gynecology cancer in the world. Although carboplatin is one of the major drugs used to treat OC, resistance to carboplatin remains a major barrier to successful treatment. To date, the mechanisms of carboplatin resistance are still poorly understood. The purpose of this study is to use the novel validation-based insertional mutagenesis (VBIM) technique to identify carboplatin resistance gene in A2780 OC cells. A2780 cells were infected with VBIM virus to cause the overexpression of drug resistance genes, then were further selected under carboplatin treatment. Targeted gene was then identified by using VBIM specific primers. In a preliminary screen, we identified the novel carboplatin resistance gene 1 (NCR1). Overexpression of NCR1 increased carboplatin resistance in A2780 OC cells, while knocking it down with shRNA had the opposite effect. In an attempt to investigate the molecular mechanism that underlying NCR1-mediated carboplatin resistance, we found that NCR1 is a potential NF- B activator. In summary, we conclude that using a novel VBIM technique, we discovered a previously unknown carboplatin resistance gene NCR1, which may mediate drug resistance via NF-B signaling pathway. This study is of extreme importance by identifying a potential novel therapeutic target NCR1 in carboplatin resistance. Development of small chemical inhibitors targeting NCR1 could ultimately lead to novel therapeutic approach for ovarian cancer treatment.