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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
References
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Journal ArticleDOI
Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.
Andrea Ardizzoni,Heine H. Hansen,Per Dombernowsky,Teresa Gamucci,Shoshana Kaplan,Pieter E. Postmus,Giuseppe Giaccone,Brigitte Schaefer,Jantien Wanders,Jaap Verweij +9 more
TL;DR: In this paper, the authors assessed activity and toxicity of topotecan in previously treated small-cell lung cancer (SCLC) patients with measurable SCLC, progressive after one first-line regimen.
Journal ArticleDOI
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Lauren Averett Byers,Jing Wang,Monique B. Nilsson,Junya Fujimoto,Pierre Saintigny,John S. Yordy,Uma Giri,Michael Peyton,You Hong Fan,Lixia Diao,Fatemeh Masrorpour,Li Shen,Wenbin Liu,Boris Duchemann,Praveen K. Tumula,Vikas Bhardwaj,James W. Welsh,Stephanie Weber,Bonnie S. Glisson,Neda Kalhor,Ignacio I. Wistuba,Luc Girard,Scott M. Lippman,Gordon B. Mills,Kevin R. Coombes,John N. Weinstein,John D. Minna,John V. Heymach +27 more
TL;DR: SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.
Journal ArticleDOI
Clinical Relevance of MGMT in the Treatment of Cancer
TL;DR: The DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AGT), encoded by the gene MGMT, repairs alkylation at this site and is responsible for protecting both tumor and normal cells from these agents as mentioned in this paper.
Journal ArticleDOI
Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis
Eric E. Gardner,Eric E. Gardner,Benjamin H. Lok,Valentina E. Schneeberger,Patrice Desmeules,Linde A. Miles,Paige K. Arnold,Andy Ni,Inna Khodos,Elisa de Stanchina,Thuyen Nguyen,Julien Sage,John Campbell,Scott Ribich,Natasha Rekhtman,Afshin Dowlati,Pierre P. Massion,Charles M. Rudin,Charles M. Rudin,John T. Poirier +19 more
TL;DR: Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.
Journal ArticleDOI
Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer.
Manel Esteller,James G. Herman +1 more
TL;DR: MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy, and underscores the importance of MGMT in basic and translational cancer research.
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