Response to Immune Checkpoint Blockade is Influenced by HLA-I Genotype [Research Watch]

Maximal HLA-I loci heterozygosity is linked to improved survival after immune checkpoint blockade.

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YY1 Facilitates Enhancer-Promoter Contacts to Promote Gene Expression [Research Watch]

YY1 preferentially occupies active enhancers and promoters and forms dimers to promote DNA looping.

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KAT2A Is a {alpha}-KGDH-Dependent Histone Succinyltransferase [Research Watch]

Succinylation of histone H3K27 induces changes in gene expression that promote glioblastoma growth.

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CAR T-cell Therapy Impresses in Multiple Myeloma [News in Brief]

Phase I trial detects responses in 81% of patients with relapsed or refractory disease.

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The Alcohol-Abuse Drug Disulfiram Targets NPL4 to Exert Antitumor Effects [Research Watch]

Disulfiram reduced cancer mortality in patients who continued disulfiram for alcohol dependency.

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Accelerating discovery of functional mutant alleles in cancer [Research Briefs]

Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in cancer patients. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.

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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study [Research Articles]

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors.

SIGNIFICANCE: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 1–12. ©2017 AACR.

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