Oncology Central

Cancer-causing mutation target of clinical trials after three decades

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Researchers at the University of Colorado Denver (CO, USA) and elsewhere are matching drugs to a long overlooked oncogene termed TRK, as discussed in a recent article published in Cancer Discovery.

The use of high-throughput, next-generation sequencing techniques in multiple tumor types has identified NTRK1, NTRK2 and NTRK3 gene rearrangements that encode novel oncogenic fusions in many different tumor types. These recent developments have led researchers to revisit the TRK family of genes, which was first identified in 1982. This means that targeted treatment options can be offered for cancers that harbor these abnormalities.

“We didn’t initially discover the gene. But now technology lets us find the gene in actual patient samples and drugs are available to target these gene rearrangements, making it possible to treat TRK cancers in clinical trials in ways we only dreamed of 32 years ago,” commented Robert C Doebele, investigator at the University of Colorado Cancer Center.

The TRK family of genes are involved in the developing nervous system and are essential for the growth and survival of new neurons in the womb. Following birth, these genes are no longer needed and so become dormant. However, when improperly fused with other nearby genes, the TRK family of genes can cause cells to grow and become immortal, which can lead to cancer in adult tissues.

“What we’re finding is that while TRK fusions may not be the major cause in any single, major cancer, it’s the cause of small percentages of many cancer types,” Doebele continued. Recent research suggests that NTRK fusions are present in 3.3% of lung cancers, 1.5% of colorectal cancer, 12.3% of thyroid cancers and approximately 2% of glioblastomas and 7.1% of pediatric gliomas.

Ten years ago, TRK fusions and other similar gene rearrangements were undruggable. However, since then, tyrosine kinase inhibitors have been developed to target these types of genetic abnormalities. Examples of investigational anticancer agents that target TRK fusions are RXDX-101, TSR-011, LOXO-101 and PLX-7486.

“A lot of doctors in academia or community hospitals are ordering next-generation sequencing panels for their patients. If it turns out that patients’ tumors have TRK alterations, I want their doctors to know that there are treatment options available via clinical trials,” Doebele concluded.

Source: Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 5(1), 25-34 (2015); University of Colorado Denver press release via EurekaAlert

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