Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.

Wainberg, Zev A.; Rafii, Saeed; Ramanathan, Ramesh K.; Mina, Lida A.; Byers, Lauren A.; Chugh, Rashmi; Goldman, Jonathan W.; Sachdev, Jasgit C.; Matei, Daniela; Wheler, Jennifer J.; Henshaw, Joshua; Zhang, Charlie; Gallant, Gilles; Bono, Johann S. de

doi:10.1200/jco.2014.32.15_suppl.7522

Cited by 30 publications

(23 citation statements)

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“…PARP1 protein levels are upregulated in SCLC relative to other lung cancers, and initial studies suggested that this upregulation was associated with increased sensitivity of SCLC lines to PARP inhibitors in vitro (6). These promising preclinical data in SCLC supported the inclusion of a SCLC cohort in a phase I study of the PARP inhibitor talazoparib with promising initial signals of efficacy (7). …”

Section: Introductionmentioning

confidence: 77%

PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer

Lok

Gardner

Schneeberger

et al. 2017

Clinical Cancer Research

250

243

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Purpose PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. Experimental Design Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, were analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR-Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide were determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models. Results We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status. Conclusions SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation.

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Section: Introductionmentioning

confidence: 77%

PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer

Lok

Gardner

Schneeberger

et al. 2017

Clinical Cancer Research

250

243

View full text Add to dashboard Cite

show abstract

“…There are active studies evaluating the PARP inhibitors, BMN673 and veliparib either alone or in combination with chemotherapy for the treatment of SCLC (NCT01286987, NCT01642251, NCT02289690, NCT01638546). BMN673 has shown single agent activity in sensitive relapsed SCLC patients (75). An ongoing multi-center randomized phase II study is comparing veliparib plus temozolomide to temozolomide alone in patients with relapsed SCLC (NCT01638546).…”

Section: Dna Repairmentioning

confidence: 99%

Small Cell Lung Cancer: Will Recent Progress Lead to Improved Outcomes?

Pietanza

Byers

Minna

et al. 2015

Clinical Cancer Research

Self Cite

183

175

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Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving five years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: nearly four decades after the introduction of a platinum-etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here.

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“…Proteomic analyses of SCLC cell lines and tumors led to the discovery that PARP1 is overexpressed and that PARP inhibition has activity in pre-clinical models and in a subset of SCLC patients 41, 42 , with proteomic markers of DNA repair and PI3K pathway activation predictive for response of PARP inhibition in SCLC 43 . Beyond PARP, proteomic analysis revealed other potential targets, such as EZH2 41 and Chk1 44 .…”

Section: Genome Epigenome and Proteome Studiesmentioning

confidence: 99%

“…A phase I trial combining veliparib with cisplatin and etoposide (ECOG-ACRIN E2518) 107 successfully completed and is now active as a randomized phase II trial. The newer PARP inhibitor talazoparib kills SCLC cells more efficiently than the older PARP inhibitor olaparib 43 and had single agent activity in SCLC in a recently completed Phase 1 trial 42 . High levels of PARP and other proteins involved in DNA damage repair, like FANCD2 and pCHK2, are strongly associated with the sensitivity of SCLC cells to talazoparib.…”

Section: New Sclc Targets and Drugsmentioning

confidence: 99%

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Bunn

Minna

Augustyn

et al. 2016

Journal of Thoracic Oncology

151

123

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Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.

Cited by 30 publications

References 0 publications

PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer

PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer

Small Cell Lung Cancer: Will Recent Progress Lead to Improved Outcomes?

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

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