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New research shows that panobinostat, a potent multihistone deacetylase inhibitor, could have substantial therapeutic activity against diffuse intrinsic pontine glioma (DIPG), an untreatable childhood cancer. Catherine Grasso and colleagues noted that with a 5-year survival of less than 1%, DIPG is an important cause of child death by brain tumours. The researchers also noted that DIPG tumour tissue shows recurrent K27M mutations in genes that encode histone H3. To assess the efficacy of epigenetic modifying drugs on DIPG, Grasso and colleagues used 16 patient-derived cell cultures of DIPG and screened 83 drugs (including potentially useful drugs in cancer treatment and traditional chemotherapy agents) using a chemical screen, RNA deep sequencing, and integrated computational modelling. Of these 83 drugs, 14 showed activities

against three or more DIPG cultures. DIPG cell cultures were reported to have substantial sensitivity to histone deacetylase inhibitors. Panobinostat was one of the most effective drugs screened, with 12 DIPG cultures showing sensitivity to this drug. Treatment of DIPG cultures with panobinostat yielded a dose-dependent increase in H3 acetylation and H3K27 trimethylation, suggesting that panobinostat led to a partial rescue of the H3K27Minduced global hypotrimethylation phenotype. To assess the activity of a combination treatment on DIPG, the researchers treated cultures with panobinostat combined with GSK-J4 (a histone demethylase inhibitor); they showed that panobinostat yielded synergistic effects with GSK-J4. “Our findings support the emerging view that epigenetic modifying agents

represent a promising therapeutic strategy for DIPG”, commented investigator Michelle Monje (Stanford University, Stanford, CA, USA). “This study represents the collaborative efforts of scientists working together with families and foundations towards identifying a promising therapy for a lethal paediatric cancer”, she added. According to investigator Charles Keller (Children’s Cancer Therapy Development Institute, Fort Collins, CO, USA), “Panobinostat is currently being developed as a phase 1 drug for children with DIPG through the Pediatric Brain Tumor Consortium”, but added that, “panobinostat will not cure DIPG—it might extend life, but we need to find a drug combination that offers real hope of a ‘cure’”.

Mehau Kulyk/Science Photo Library

Panobinostat active against diffuse intrinsic pontine glioma

Published Online May 11, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70230-5 For Grasso and colleagues’ study see Nature Med 2015; published online May 4. DOI: 10.1038/nm.3855

Sanjeet Bagcchi

Pattern of change in telomere length: possible predictor of cancer A pattern of accelerated telomere shortening followed by stabilisation could predict the development of cancer 3–4 years before an actual diagnosis, new research suggests. Telomere shortening—a putative marker of biological age—has long been associated with having a role in cancer development, but previous studies have produced inconsistent results and been hindered by being based on measurements from telomeres that were already exposed to cancer and treatments. In this latest study, Lifang Hou (Northwestern University, Chicago, IL, USA) and colleagues investigated how blood telomeres change in time in people who develop cancer. Measurements of blood telomeres were taken during 13 years (1992–2012) from 792 men, of which 213 (27%) were diagnosed with cancer before their first blood draw, and 135 (17%) men were www.thelancet.com/oncology Vol 16 June 2015

later diagnosed with cancer including cases of prostate cancer, skin cancer, lung cancer, and leukaemia. Overall, faster shortening of telomeres was reported, as measured in pre-diagnostic blood draws in patients with an incident cancer diagnosis (β=–0·022 units per year, p

Pattern of change in telomere length: possible predictor of cancer.

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