Abstract Introduction: The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy, especially with a K-ras mutation is poor with median survival of less than one year. The purpose of this study was to perform whole genome sequencing (WGS) to identify therapeutically actionable somatic events in mCRC patient samples, so as to select targeted treatment strategies for individual patients. Methods: IRB approval was obtained and 3 patients have been enrolled. All had > 2 prior regimens and had known K-ras mutations (age 73, 45 and 50 years, all were male). Percutaneous needle biopsies of liver metastases were performed with whole blood collection for the extraction of constitutional DNA. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing system, which yielded coverage of greater than 30X for both the normal and tumor samples. Somatic genomic alterations (point mutations and indels, copy number alterations, translocations and rearrangements) were analyzed using our custom pipeline for paired analysis. Results: In all 3 samples sufficient DNA was extracted for sequencing. WGS and bioinformatics analysis took 3–4 weeks for completion. We found that all 3 tumor samples had KRAS mutations, while 2 samples had mutations in the APC gene and the PIK3CA gene. Other genes with therapeutic implications in single tumor samples were INPPL1, INPP4B and SMAD4. No EGFR amplifications were detected in our sample set. The concomitant mutations in MAPK (K-ras) and PI3K (PIK3CA, INPPL1, INPP4B) pathways suggest that combination therapies might be required for effective treatment of these tumors. In two instances, tumors were sent to a CLIA laboratory to allow for clinical validation of genomic events. Conclusions: WGS is feasible from DNA obtained from percutaneous biopsies in a clinical setting. Our study has revealed a series of therapeutically actionable events in mCRC and prospective clinical trials are needed to validate this approach. Funded by the Bisgrove-Scottsdale Healthcare and TGEN foundations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A183.
Supplementary Figure from Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
Supplementary Figure from Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
Supplementary Figure from Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
<p>Canine primary lung cancer cell line sensitivity to lapatinib. Four canine cell lines (three HER2WT and one HER2V659E) were treated with 14 lapatinib doses ranging from 100 μM to 5.5x10-2 nM for 72 hours with CellTiterGlo viability endpoints were measured and shown as percent survival relative to DMSO vehicle control.</p>
<p>Somatic copy number plots derived from exome sequencing of five primary canine pulmonary adenocarcinomas (cPAC) and matched constitutional DNA. Tumor copy number states determined by tCoNutT analysis of tumors and matched constitutional DNA from five cPAC cases is shown with each canine chromosome plotted on the x-axis (shown in alternating green and black) and log2 fold change shown on the y-axis.</p>
<p>Canine primary lung cancer cell line sensitivity to erlotinib. Five canine cell lines (three HER2WT and two HER2V659E) and one human cell line BT474 (HER2amp) were treated with 10 erlotinib doses ranging from 5x10-8 to 50 μM for 72 hours with CellTiterGlo viability endpoints measured and shown as percent growth inhibition relative to DMSO vehicle control.</p>
