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T.J. Brown



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    P2.03 - Poster Session 2 - Technology and Novel Development (ID 151)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.03-006 - Determining Read Origin of Next-Generation Sequencing Datasets from Lung Cancer Xenografts (ID 2647)

      09:30 - 09:30  |  Author(s): T.J. Brown

      • Abstract

      Background
      Next-generation sequencing (NGS) studies in cancer are often limited by the amount, quality and purity of tissue samples obtained from patients. In this situation, primary xenografts have proven useful in providing preclinical models. Although xenograft lines are maintained in immunodeficient mice, we and others have shown that they retain important characteristics that are irreversibly lost in cell culture. Since the stromal component of xenograft tumors is derived from the host, the presence of mouse DNA and RNA has the potential to limit the use of these models for next-generation sequencing (NGS) analysis.

      Methods
      We prospectively addressed this question in an established primary xenograft model of small cell lung cancer (SCLC), a malignancy that is almost always diagnosed using small biopsies or needle aspiration cytology. We first developed an in-silico strategy that separates human and mouse reads with at least 97% accuracy. We then compared NGS data from a series of primary xenograft models with clonally derived, stroma-free cell lines, and with published datasets derived from the same models.

      Results
      Starting with the NCI-H209 cell line as a reference sample, we show that low coverage whole genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. NGS analysis of exon-capture DNA revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene signatures, whereas mouse- transcript profiles correlated with published datasets from human cancer stroma.

      Conclusion
      Primary xenograft models may therefore be a useful NGS platform for cancers where tissue samples are limiting.

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    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.13-006 - A Phase IIa study of HA-Irinotecan, a CD44-targeted formulation of hyaluronic acid and irinotecan, in the treatment of extensive stage small cell lung cancer and its effect on cancer stem-like cells. (ID 2761)

      09:30 - 09:30  |  Author(s): T.J. Brown

      • Abstract

      Background
      Preclinical studies in small cell lung cancer cell lines and xenograft models have shown that Hyaluronic acid (HA) can be effectively used to deliver Irinotecan (IR) and selectively decrease CD44 expressing (stem cell-like) tumour cells and prolong duration of response. This “proof of principle” study aims to replicate these findings in the clinical setting and obtain data on safety and response rates.

      Methods
      Extensive Small Cell Lung Cancer (ESCLC) patients with measurable disease (suitable for biopsy), PS 0-2, medically fit and able to give informed consent were screened for this study. A safety cohort (n=5) were treated with HA-IR (150mg/m[2]) and Carboplatin(C) at 5 AUC, q3 weekly with subsequent patients stratified as 1[st] or 2[nd] line. All 2[nd] line patients received open label HA-IR+C while 1[st] line patients were randomized to receive either HA-IR+C or equivalent dosing regimen of IR+C. Sequential tumour biopsies were obtained at baseline and after 1 or 2 cycles. Tumour response was measured by CT/PET scan at baseline, after 1 cycle and every 2 cycles subsequently. A final biopsy at disease progression was planned. Blood samples for circulating tumour cells (CTCs) were obtained at baseline, and at every cycle.

      Results
      Patients N=16, Age: median= 60; Range 39-78. Three 2nd line patients were not evaluated due to rapid early disease progression after Cycle 1. Overall toxicity profile of HA-IR+C was similar to IR+C with grade III/IV diarrhoea and neutropenia seen in 15% and 20% respectively. One patient (7%) had grade III anaemia, while no grade III/IV nausea or vomiting was observed. No biopsy related complications were observed. Of 13 patients evaluated for tumour response, the overall response rate was 60% with 1 (7%) complete and 7 (53%) partial responses. Three patients (24%) achieved stable disease while 2 patients (16%) progressed during the treatment. To date median progression-free survival is 5.9 months (7.6 months in first line and 3.1 months in the second line cohort). Preliminary CTCs data shows close correlation between the number of CTCs and tumour response and relapse. Patients with CD44+ tumours appear to have obtained most durable response. Analysis of sequential biopsies is underway and will be presented.

      Conclusion
      HA-IR+C appears to be an active option for ESCLC. This regimen is designed to target CD44[+ve] subpopulation within the tumour.