P2.06-028 A Phase 2 Study of Prexasertib in Patients with Extensive Stage Small Cell Lung Cancer

Byers, Lauren A.; Golden, Lisa; Zhang, Wei; Lin, Aimee Bence; Förster, Martin

doi:10.1016/j.jtho.2016.11.1521

Cited by 3 publications

(3 citation statements)

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“…Prexasertib is presently being investigated in several combinations in multiple tumor types, including SCLC. 56 In conclusion, Chk1 is a promising therapeutic target for the treatment of p53-mutant SCLC. Combination of Chk1 inhibitor with DNA damaging agents such as cisplatin can unleash a much stronger antitumor activity, and has the potential to overcome cisplatin resistance.…”

Section: Discussionmentioning

confidence: 95%

Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Hsu

Zhao

Zhu

et al. 2019

Journal of Thoracic Oncology

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Introduction: Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response.Methods: We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatinsensitive and -resistant preclinical models.Results: Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC.Conclusions: Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.

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Section: Discussionmentioning

confidence: 95%

Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Hsu

Zhao

Zhu

et al. 2019

Journal of Thoracic Oncology

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“…3 ). Among the 10 patients in whom radiographic relapse was identified, three did not receive further systemic therapy; three received nivolumab plus ipilimumab with best responses of stable disease in one patient and progression of disease at first evaluation in two patients; two patients with platinum-sensitive disease received platinum rechallenge and both initially responded; one patient enrolled on a clinical trial of a CHK1 inhibitor (LY2606368; NCT02735980) 23 and responded; and one patient received paclitaxel and progressed at first disease evaluation. Only patients who clinically responded to second-line systemic therapy experienced bloodstream clearance of their ctDNA (three of seven, 43%).…”

Section: Resultsmentioning

confidence: 99%

Blood-Based Surveillance Monitoring of Circulating Tumor DNA From Patients With SCLC Detects Disease Relapse and Predicts Death in Patients With Limited-Stage Disease

Iams

Kopparapu

Yan

et al. 2020

JTO Clinical and Research Reports

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Introduction: Most patients (70%) with limited-stage SCLC (LS-SCLC) who are treated with curative-intent therapy suffer disease relapse and cancer-related death. We evaluated circulating tumor DNA (ctDNA) as a predictor of disease relapse and death after definitive therapy in patients with LS-SCLC. Methods: In our previous work, we developed a plasmabased ctDNA assay to sequence 14 genes (TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN) that are frequently mutated in SCLC. In this work, we evaluated 177 plasma samples from 23 patients with LS-SCLC who completed definitive chemoradiation (n ¼ 21) or surgical resection (n ¼ 2) and had an end-of-treatment blood collection (median 4 d, range 0-40 d from treatment completion) plus monthly surveillance blood sampling. Median overall survival (OS) and progression-free survival (PFS) were compared using a Wilcoxon test. Results: The median OS among patients in whom we ever detected ctDNA after definitive treatment (n ¼ 15) was 18.2 months compared with a median OS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (n ¼ 8; p ¼ 0.081). The median PFS among patients in whom we ever detected ctDNA after definitive treatment was 9.1 months compared with a median PFS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (p < 0.001). Conclusions: Detection of ctDNA in patients with LS-SCLC after curative-intent therapy predicts disease relapse and death. Prospective trials using ctDNA as an integral biomarker for therapeutic selection should be considered in SCLC.

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“…Their efficacy was particularly enhanced in the context of MYC amplification or protein overexpression [45]. Prexasertib is being investigated in an ongoing phase 2 trial in patients with ES-SCLC [64].…”

Section: Dna Damage Response Targetingmentioning

confidence: 99%

Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer

Lum

Alamgeer

2019

Cancers

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Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient derived xenografts (PDXs) have made encouraging inroads. Whole genome sequencing (WGS) data reveals a high mutational burden and a number of genetic alterations but low frequency of targetable mutations. Despite several failures, considerable therapeutic opportunities have recently emerged. Potentially promising therapies include those targeting DNA damage repair, stem cell/renewal and drug resistant mechanisms. Modest success has also been achieved with immune checkpoint inhibitors while therapeutic exploration of various other components of the immune system is underway. However, the complex heterogeneities reflect the need for accurate bio-markers to translate novel discoveries into clinical benefit. Additionally, the molecular mechanisms that differentiate chemo-sensitive from chemo-refractory disease remain unknown. Obtaining reliable tumour samples by utilising novel techniques such as endobronchial ultrasound guided needle aspiration or adopting to liquid biopsies are becoming popular. This review will focus on recent technological and therapeutic advancements to surmount this recalcitrant disease.

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P2.06-028 A Phase 2 Study of Prexasertib in Patients with Extensive Stage Small Cell Lung Cancer

Cited by 3 publications

References 0 publications

Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death

Blood-Based Surveillance Monitoring of Circulating Tumor DNA From Patients With SCLC Detects Disease Relapse and Predicts Death in Patients With Limited-Stage Disease

Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer

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