APOBEC3 SNPs Predict APOBEC Mutagenesis and Cancer Risk [Mutations]

SNPs in APOBEC3 alter expression of APOBEC3A/APOBEC3B to affect somatic APOBEC-signature mutations.

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EZH2 and Tyrosine Kinase Inhibition in CML Stem Cells [Research Briefs]

A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.

Significance: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248–57. ©2016 AACR.

See related article by Xie et al., p. 1237.

This article is highlighted in the In This Issue feature, p. 1197

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Dual Inhibition of MDM2 and XIAP Induces Cancer Cell Apoptosis [Drug Discovery]

Blocking the MDM2 protein–XIAP mRNA interaction reduces MDM2 and XIAP levels and activates p53.

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When Drug Trials Are Halted [News in Depth]

When significant safety questions arise during a trial, the FDA has the option to place a full or partial clinical hold on treatment and new enrollment. Clinical holds are designed to protect patients from serious harm but they can also cause expensive delays for drug developers and frustrations for patients. While some problems can be resolved quickly, others can permanently derail a drug's development.

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Stereotactic Radiosurgery Keeps Brain Metastases at Bay [News in Brief]

According to two clinical trials presented at the American Society for Radiation Oncology's 2016 annual meeting, stereotactic radiosurgery following surgical removal of brain metastases decreases the risk of local recurrence and, compared with whole-brain radiotherapy, offers patients a better quality of life. As such, postoperative stereotactic radiosurgery should be considered a new standard of care for patients whose cancer has spread to the brain.

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Radiation Therapy Advances for Prostate Cancer [News in Brief]

Three studies on prostate cancer indicate, respectively, that a hypofractionated schedule of intensity-modulated radiation therapy reduces treatment time without negatively affecting quality of life; treatment with stereotactic body radiotherapy is a powerful, potentially more cost-effective option; and prostate brachytherapy, without external radiation, may be sufficient to control disease progression. The data were presented at the American Society for Radiation Oncology's 2016 annual meeting.

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PGC1{alpha} Represses Melanoma Cell Invasion and Metastasis [Melanoma]

PGC1α inhibits melanoma metastasis independent of its role in mitochondrial energetic metabolism.

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