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TCGA Lung Cancer Study IDs Potential Drug Targets in Majority of Cases

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In the most comprehensive genomic study to date of lung squamous cell carcinoma, researchers affiliated with the Cancer Genome Atlas project have identified potential drug targets in more than two-thirds of the 178 tumors sequenced, highlighting potential treatment options to a tumor type for which no targeted therapeutic strategy currently exists.

The TCGA study, published this week in Nature, indicates that lung squamous cell carcinoma "is a disease with multiple potential genomic targets for treatment," Matthew Meyerson, a project chair of the study, told Clinical Sequencing News.

"There are going to be opportunities for a wide variety of clinical trials of targeted therapies and this will be facilitated enormously by genome-based diagnosis," said Meyerson, also a professor of pathology at Harvard Medical School and founding advisor of Foundation Medicine.

The TCGA team sequenced the exomes and transcriptomes of 178 matched tumor/normal samples of lung squamous cell carcinoma, as well as the whole genomes of 19 matched tumor/normal samples. They did microRNA sequencing for 158 pairs, and evaluated copy number using array-CGH and the methylation status of all samples.

The team used the Agilent SureSelect for exome capture and all sequencing was done on the Illumina HiSeq 2000.

Exome sequencing identified a total of 48,690 non-silent mutations with a mean of 228 non-silent, and 360 total exonic mutations per tumor with a mean mutation rate of 8.1 per megabase.

Almost all of the tumors had mutations in the TP53 gene. There were also frequent alterations in the CDKN2A/RB1, NFE2L2/KEAP1/CUL3, PI3K/AKT, and SOX2/TP63/NOTCH1 pathways.

EGFR and KRAS mutations, which are common in lung adenocarcinoma, were found to be rare in squamous cell lung cancer, though mutations in the FGFR kinase family are "common," the authors reported. They also found that squamous cell tumors "share many alterations in common with head and neck squamous cell carcinomas without evidence of human papilloma virus infection, including mutations in PIK3CA, PTEN, TP53, CDKN2A, NOTCH1, and HRAS22, suggesting that the biology of these two diseases may be similar."

Druggable Targets

Mutations such as amplifications to FGFR and PI3-kinase alterations are druggable, and there are already clinical trials in place for FGFR inhibitors, as well as compounds that target genes within the PI3-kinase pathway, for other types of cancers, said Meyerson.

Whether those exact compounds end up being suitable for treating lung squamous cell carcinoma still needs to be tested, but it represents a "real opportunity," he said.

Amplifications to EGFR and ERBB2 represent other potential mutations that can be targeted. EGFR mutations were found in 7 percent of tumors. Currently, Tarceva (erlotinib), marketed by Genentech and OSI Pharmaceuticals, targets EGFR and is approved for the treatment of non-small-cell lung cancer. Additionally, Iressa (gefitinib), marketed by AstraZeneca and Teva, also acts on EGFR and is approved to treat lung cancer patients.

The team also evaluated the genomic data against available drugs approved by the US Food and Drug Administration as well as available clinical trials, and identified 114 cases, or 64 percent, with a potentially targetable gene.

Next, they looked at pathways known to be druggable, such as the PI3-kinase/AKT, receptor tyrosine kinase, and RAS pathways. Of the 178 samples, 69 percent of them had alterations in at least one of those pathways.

Additionally, eight tumors displayed inactivating mutations in the HLA-A gene, suggesting that those tumors may be responsive to immunotherapeutics such as anti-cytotoxic T-lymphocyte antigen 4 antibodies. Anti CTLA4 antibodies have already been shown to be effective in some cases of non small-cell lung cancer, and mutations to the HLA-A gene could potentially serve as a marker of sensitivity for these drugs.

"The connection between genomic alterations and immune regulatory therapy is important," Meyerson said.

Inactivating mutations to the known tumor suppressor gene CDKN2A were also found in 72 percent of cases, due to methylation, point mutations, or deletions. Currently, there are several ongoing phase I and II studies of CDK inhibitors, but no approved compound.

Lung Cancer Consortium

The patients whose samples were analyzed in the study are anonymous so will not be contacted about the results. Additionally, said Ramaswamy Govindan, also a project chair and an oncologist at Washington University School of Medicine, the samples were all from early-stage disease, so it is unknown what percentage of patients had disease recurrence and would therefore be eligible for an available clinical trial.

Rather, he said, within the context of the Squamous Lung Cancer Consortium, which is being led by Fred Hirsch at the Colorado University Cancer Center, these results will be used to screen patients with late-stage disease to identify potential clinical trials and therapeutic options.

Studies such as this TCGA study, said Govindan, will "identify targets that we can go after, but then we have to form prospective trials in selected patient populations. That's what the consortium will do."

For instance, patients could be screened for alterations to FGFR and within the PI3-kinase pathway, to be enrolled in trials for drugs that target these alterations.

Hirsch said the findings of this study were significant. "Squamous lung cancer has been a subtype of cancer where not much has happened from a therapeutic point of view," he said.

The Squamous Lung Cancer Consortium has two different goals, said Hirsch. First, a large number of tumor samples with corresponding clinical data have been collected, and one goal is to follow up on all these samples long term, to identify biomarkers that correlate with prognosis or treatment response.

The second aspect is to match patients with clinical trials.

The consortium is comprised of eight institutions: the University of Colorado, Denver; Harvard University/Brigham and Women's Hospital; Duke University; the Mayo Clinic; Princess Margaret Hospital in Toronto; the University of California, Davis; the University of Michigan; and Washington University in St. Louis.

Patient screening would be done by each institution, and the technology used would vary between the institutions.

Govindan said that researchers are already designing trials based on the findings of this paper. Additionally, he said, these 178 tumors represent part of a larger effort to sequence 1,000 lung cancer samples, including 500 squamous cell and 500 adenocarcinoma samples, the two types of non-small cell lung cancer.

He said the sequencing for these samples has already been completed, and that the analysis should be done by middle of next year.

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