Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

Hodgkinson, Cassandra L.; Morrow, Christopher J.; Li, Yaoyong; Metcalf, Robert; Rothwell, Dominic G.; Trapani, Francesca; Polański, Radosław; Burt, Deborah J.; Simpson, Kathryn; Morris, Karen; Pepper, Stuart D; Nonaka, Daisuke; Greystoke, Alastair; Kelly, Paul A.; Bola, Becky M.; Krebs, Matthew; Antonello, Jenny; Ayub, Mahmood; Faulkner, Suzanne; Priest, Lynsey; Carter, Louise; Tate, Catriona; Miller, Crispin; Blackhall, Fiona; Brady, Ged; Dive, Caroline

doi:10.1038/nm.3600

Cited by 628 publications

(606 citation statements)

References 48 publications

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“…30) were disaggregated (gentleMACS dissociator/human tumor kit; Miltenyi Biotec) immediately after sacrifice of the mouse host when tumors reached 400 mm 3 . Red blood cells were lysed (RBC lysis buffer; G-Biosciences), remaining cells were filtered (through 70 mm pores), and cell viability was checked (trypan blue exclusion).…”

Section: Methodsmentioning

confidence: 99%

“…To expand our results to a model that more accurately effects patients tumors, we assessed efficacy of GDC-0941 and Navitoclax in a SCLC CDX2 derived from circulating tumor cells (CTC) enriched prior to the donor patient's chemotherapy (30). This is a high hurdle for drug development as SCLC cells that derived the model had already invaded tissue, were disseminating, and were tumorigenic in the mouse.…”

Section: Effect Of Combined Pi3k Inhibition and Bh3 Mimetic In Vivomentioning

confidence: 99%

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Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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Section: Methodsmentioning

confidence: 99%

Section: Effect Of Combined Pi3k Inhibition and Bh3 Mimetic In Vivomentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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“…One solution to this challenge is to develop xenografts from circulating tumor cells (CTC), so-called CTC-derived xenografts (CDX), recently developed for small cell lung cancer (SCLC; ref. 23 ) but not yet for melanoma.…”

Section: Introductionmentioning

confidence: 99%

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

et al. 2016

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Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell–derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. Significance: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. Cancer Discov; 6(3); 286–99. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 217

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“…They provide an excellent tool with which to investigate the dynamics of oncogenesis, tumor heterogeneity, evolution, and responses to therapy (1)(2)(3)(4)(5)(6)(7)(8). This has led to considerable interest in combining them with next-generation sequencing (NGS).…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

Khandelwal

Girotti

Smowton

et al. 2017

Molecular Cancer Research

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Patient-derived xenograft (PDX) and circulating tumor cellderived explant (CDX) models are powerful methods for the study of human disease. In cancer research, these methods have been applied to multiple questions, including the study of metastatic progression, genetic evolution, and therapeutic drug responses. As PDX and CDX models can recapitulate the highly heterogeneous characteristics of a patient tumor, as well as their response to chemotherapy, there is considerable interest in combining them with next-generation sequencing to monitor the genomic, transcriptional, and epigenetic changes that accompany oncogenesis. When used for this purpose, their reliability is highly dependent on being able to accurately distinguish between sequencing reads that originate from the host, and those that arise from the xenograft itself. Here, we demonstrate that failure to correctly identify contaminating host reads when analyzing DNAand RNA-sequencing (DNA-Seq and RNA-Seq) data from PDX and CDX models is a major confounding factor that can lead to incorrect mutation calls and a failure to identify canonical mutation signatures associated with tumorigenicity. In addition, a highly sensitive algorithm and open source software tool for identifying and removing contaminating host sequences is described. Importantly, when applied to PDX and CDX models of melanoma, these data demonstrate its utility as a sensitive and selective tool for the correction of PDX-and CDX-derived wholeexome and RNA-Seq data.

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Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

Cited by 628 publications

References 48 publications

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

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