Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer.
M. Catherine Pietanza,Saiama N. Waqar,Lee M. Krug,Afshin Dowlati,Christine L. Hann,Alberto Chiappori,Taofeek K. Owonikoko,Kaitlin M. Woo,Robert J. Cardnell,Junya Fujimoto,Lihong Long,Lixia Diao,Jing Wang,Yevgeniva Bensman,Brenda Hurtado,Patricia M. de Groot,Erik P. Sulman,Ignacio I. Wistuba,Alice P. Chen,Martin Fleisher,John V. Heymach,Mark G. Kris,Charles M. Rudin,Lauren Averett Byers +23 more
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TLDR
SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.Abstract:
Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.read more
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State-of-the-art strategies for targeting the DNA damage response in cancer
TL;DR: The authors review the progress made to date with PARP inhibitors, describe the expanding landscape of novel anticancer therapies targeting the DNA damage response and potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.
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Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Triparna Sen,B. Leticia Rodriguez,Limo Chen,Carminia Maria Della Corte,Naoto Morikawa,Junya Fujimoto,Sandra Cristea,Thuyen Nguyen,Lixia Diao,Lerong Li,Youhong Fan,Yongbin Yang,Jing Wang,Bonnie S. Glisson,Ignacio I. Wistuba,Julien Sage,John V. Heymach,Don L. Gibbons,Lauren Averett Byers +18 more
TL;DR: This study shows that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1 and supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.
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PARP and PARG inhibitors in cancer treatment.
TL;DR: Clinical performance of four PARP inhibitors used in cancer therapy are highlighted and the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy are discussed.
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Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities
C. Allison Stewart,Elizabeth M. Park,Lixia Diao,Sarah M. Groves,Simon Heeke,Barzin Y. Nabet,Junya Fujimoto,Luisa M. Solis,Wei Lu,Yuanxin Xi,Robert J. Cardnell,Qi Wang,Giulia Fabbri,Kasey R. Cargill,Natalie I. Vokes,Kavya Ramkumar,Bingnan Zhang,Carminia Maria Della Corte,Paul Robson,Stephen G. Swisher,Jack A. Roth,Bonnie S. Glisson,David S. Shames,Ignacio I. Wistuba,Jing Wang,Vito Quaranta,John D. Minna,John V. Heymach,Lauren Averett Byers +28 more
TL;DR: In this paper, the authors used tumor expression data and non-negative matrix factorization to identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature.
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Chemoresistance in Pancreatic Cancer.
TL;DR: New perspectives for enhancing the efficacy of gemcitabine are outlined after reviewing the related factors of gem citabine metabolism, mechanism of action, and chemoresistance.
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