Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses

Owonikoko, Taofeek K.; Niu, Huifeng; Nackaerts, Kristiaan; Csőszi, Tibor; Ostoros, Gyula; Mark, Z.; Baik, Christina S.; Joy, Anil A.; Chouaïd, C.; Jaime, Jesús Corral; Kolek, Vı́tězslav; Majem, Margarita; Roubec, Jaromı́r; Santos, Edgardo S.; Chiang, Anne C.; Speranza, G.; Belani, Chandra P.; Chiappori, Alberto; Patel, Manish R.; Czebe, Krisztina; Byers, Lauren A.; Bahamón, Brittany; Liu, Cong; Sheldon-Waniga, Emily; Kong, Eric; Williams, Miguel; Badola, Sunita; Shin, Hyunjin; Bedford, Lisa M; Ecsedy, Jeffrey; Bryant, Matthew; Jones, Siân; Simmons, John K.; Leonard, E. Jane; Ullmann, Claudio Dansky; Spigel, David R.; investigators, C study

doi:10.1016/j.jtho.2019.10.013

Cited by 113 publications

(100 citation statements)

References 38 publications

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“…Conversely, patients who were c-Myc negative had a shorter PFS with the combination (3.32 vs. 5.16 months; HR, 11.8) [10]. In our patient, the presence of JAZF1-MYCL1 fusion without additional genomic alterations may have made it particularly sensitive to AKI, though this is speculative.…”

Section: Discussionmentioning

confidence: 63%

“…Genomic studies of SCLC have identified several alterations, such as genes in MYC and mTOR pathways, which are potentially druggable [5][6][7][8]. Clinical trials targeting mTOR and MYC pathways have been disappointing [9,10]. These trials included patients without consideration of the tumor molecular profile, which may in part explain the lack of promising results.…”

Section: Introductionmentioning

confidence: 99%

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Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

Kolla

Racila

Patel

2020

Case Reports in Oncological Medicine

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Small-cell lung carcinoma (SCLC) is one of the most aggressive solid tumors, and the prognosis has not improved significantly in 25 years. Despite a recent understanding of the genomic aberrations seen in SCLC, these insights have not led to any breakthroughs in treatment. We present a patient with SCLC harboring a novel MYCL1 fusion protein who experienced a prolonged disease course due to the use of Aurora A kinase inhibitor and subsequently nivolumab. MYC family genes are master regulators of several cellular pathways including proliferation, differentiation, and apoptosis and recently have been shown to be involved in tumor immune evasion. Large studies have shown that a significant proportion of patients with SCLC have amplification or overexpression of MYC family genes. Preclinical data have exposed vulnerability of MYC-driven tumors to Aurora kinase inhibitors, bromodomain and extraterminal domain inhibitors, and recently to immune checkpoint blockers. Further studies using these agents with selective enrolling of patients with MYC-altered tumors are warranted to exploit these vulnerabilities.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

Kolla

Racila

Patel

2020

Case Reports in Oncological Medicine

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“…Alisertib, also known as MLN8237, is a selective small molecule inhibitor of Aurora A kinase that has shown modest antitumor activity in a number of clinical settings [7]. The Aurora kinases are a highly conserved family of serine/threonine protein kinases that localize to centrosomes and the proximal mitotic spindle to ensure accurate mitosis [8].…”

Section: Trial Informationmentioning

confidence: 99%

“…Although the biomarker analysis was ultimately underpowered owing to early termination of the study and few MYC copy number gains detected, there were no signals to support MYC status as a predictive biomarker in this context. This is in contrast to small cell lung cancer, where MYC status predicted improved clinical outcomes, although in that case detectable MYC expression by immunohistochemistry (rather than MYC copy number gain) was used as cutoff [7].…”

Section: Trial Informationmentioning

confidence: 99%

A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

et al. 2020

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• Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. • In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.

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“…Targeting of histone-lysine N-methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was found to maintain the sensitivity of SCLC xenografts to chemotherapy by preventing schlafen family member 11 (SLFN11) silenc ing [12]. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs encouraged an anti-DLL3-antibody-drug conjugate for preclinical and clinical activity [13].…”

Section: Introductionmentioning

confidence: 99%

Abnormal genome-wide DNA methylation induced by cisplatin may contribute to the chemo-resistance of human small cell lung cancer

Ji¹,

Yu²,

Wu³

et al. 2019

Preprint

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Background: So far, the platinum-based chemotherapy (e.g. cisplatin-etoposide doublet) is still the backbone for SCLC management due to its high respond rate both in LS-SCLC and ES-SCLC. However, cisplatin treatment often results in the development of chemo-resistance, leading to therapeutic failure and becoming the main obstacle to improve the therapeutic efficacy. Currently, little has been known about the genome-wide abnormal methylation of SCLC induced by cisplatin, which might provide prospective layouts to discover the potential genes and the signal pathways related with chemo-resistance of SCLC. Results: A total of 58,401 sites was identified to be differentially methylated (|Δβ| ≧ 0.20) in H446/DDP cells compared with that of H446 cells, of which 25,991 genes were found to be hypomethylated and 32,410 genes were shown to be hypermethylated. KEGG enrichment displayed that the differentially hypomethylated genes were mainly gathered in MAPK signaling pathway, ECM-receptor interaction, and Focal adhesion, while the differentially hypermethylated genes were clustered in Neuroactive ligand-receptor interaction, Type I diabetes mellitus, Focal adhesion, Allograft rejection, ECM-receptor interaction, CAMs, Graft-versus-host disease, Intestinal immune network for IgA production, ARVC, and Viral myocarditis (KEGG enrichment, qvalue < 0.05). Among the 152 genes which were selected as the MDR-related candidate genes for qRT-PCR to testify whether the abnormal methylation regulated the expression of related genes at the mRNA level, 69 hypomethylated genes were revealed to be significantly increased and the other 54 hypermethylated genes evidently decreased in H446/DDP cells compared with that of H446 cells. Moreover, the upregulated genes with the hypomethylated sites were found to be mainly clustered in Pathways in cancer, MAPK signaling pathway, Cytokine-cytokine receptor interaction, and Cell adhesion molecules (CAMs), while the downregulated genes with the hypermethylated sites were mainly clustered in MAPK signaling pathway, Pathways in cancer, Melanoma, Osteoclast differentiation, and Prostate cancer. Conclusions: Cisplatin could induce a large-scale abnormal methylation in the whole genome of SCLC. Pathways in cancer, MAPK signaling pathway, Cytokine-cytokine receptor interaction, and Cell adhesion molecules (CAMs) were most likely to be affected by cisplatin via. methylation to contribute to the development of chemo-resistance and other malignant biological behavior of SCLC cells.

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Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses

Cited by 113 publications

References 38 publications

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

Abnormal genome-wide DNA methylation induced by cisplatin may contribute to the chemo-resistance of human small cell lung cancer

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