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AACR: The Search for Novel Therapeutic Targets

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At a mini-symposium on the genetic approaches to finding novel therapeutic targets for cancer, moderator Peter Lichter of the German Cancer Research Center said there has been success getting drugs into the clinic using genetic approaches. No matter where researchers start or where they end up, they usually follow a common strategy, Lichter said — genome-wide sequencing to indentify and prioritize candidate genes, and then functional studies of those candidates both in vitro and in vivo, with the goal of developing preclinical models for drug testing.

Huriye Cin of the German Cancer Research Center presented her research into two novel BRAF fusion genes in pilocytic astrocytoma, the most common type of brain tumor in children. While many patients are treated with surgical resection, this is not possible in about 20 percent of cases, leading to a need for therapeutics, Cin said. She and her team identified duplications of 7q34 in a fusion of BRAF and KIAA1549, a mutation found in 70 percent of pilocytic astrocytoma cases. They also found a novel fusion between BRAF and FAM131B, resulting from a deletion of 7q34 that activated MAPK effectors and contributes to the development of the brain tumor. There are still undiscovered fusion genes in this cancer, Cin said, and all of them may make for potential therapeutic targets.

Yusuke Sato of the University of Tokyo presented his work on discovering copy number changes in renal cell carcinoma, with the goal of identifying prognostic parameters for the disease as well as discovering novel molecular targets. Sato and his team tested 216 patients with various stages of renal cell carcinoma using SNP array-based karyotyping, and found that 96 percent of the patients had at least one genetic lesion, allowing the researchers to classify the patients into several subgroups. Those with hyperploidy, Sato said, were quickly found to have advanced or metastatic disease, suggesting that hyperploidy could serve as a biomarker for poor prognosis. At least 70 percent of the cases, he added, had mutations in genes that regulate chromatin modification, indicating that it may play a role in development or progression of the disease, especially in advanced disease.

Virginia Commonwealth University's Santanu Dasgupta presented his group's work on mitochondrial mutations in lung cancer patients, particularly patients who never smoked. At least 15 percent of lung cancer patients fall into the never-smoker category, and researchers have long wondered why it is that they develop lung cancer. Dasgupta and his team sequenced the mitochondrial genome of 30 smokers and 30 never-smokers with lung cancer, and saw that 63.3 percent of the never-smokers showed mutations in their mtDNA, compared to only 26.6 percent of smokers who did. Dasgupta added that more research is needed in larger patient populations, but that these findings may yield targets for therapy.

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