Volume 4 Issue 2, February 2023

Overall survival for children with rare, relapsed, metastatic and/or refractory cancers has remained unacceptably low over the past four decades. A new precision oncology study introduces an integrative germline and somatic sequencing approach that could breach this impasse to advance cures for children with cancer.

Developing approaches to identify patients who may benefit from specific treatments is an important area of research. A study now defines an HDAC6 score to predict the response of patients with breast cancer to the HDAC6 inhibitor ricolinostat and characterizes its anti-tumor effects with preclinical mechanistic work and a phase 1b clinical trial.

Using an unbiased algorithm based on kinase–phosphorylation site interactions that is applicable to any proteomic dataset, we identified and experimentally validated two protein kinases (PKCδ and DNA-PKcs) as the master kinases that drive two functional subtypes of glioblastoma multiforme and are potential therapeutic targets of other cancer subtypes.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each generating characteristic mutational signatures. Our systematic mutational signature analysis of single base substitutions and small insertions and deletions in pediatric cancers indicates that the contribution of signatures of homologous recombination repair defect is limited and identifies a leukemia-specific signature.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of mortality worldwide. Integrative analysis of the genome, transcriptome and proteome of PDAC tissues, also known as proteogenomic analysis, provides insight into the biology of this cancer and is a resource for therapeutic discovery.

In this review article, Christ and colleagues discuss the recent developments in antibody-based cancer therapies.

Iavarone and colleagues develop a computational approach called SPINKS to identify master kinases for functional subtypes of human glioblastoma defined using integrated multi-omics data, which show potential as subtype-specific therapeutic targets.

Shlien and colleagues report on 300 patients from the SickKids Cancer Sequencing program and identify clinically actionable variants in 56% of the patients by profiling somatic and germline data at multiple clinical time points.

Lau and colleagues show that the dietary addition of the sugar l-fucose enhances immunotherapy response in melanoma models. This is mediated via the fucosylation and cell surface enrichment of HLA-DRB1 and induction of anti-tumor immunity.

Coppé and colleagues define a resistance mechanism to combination BRAF- and EGFR-targeted therapy in BRAF^V600E colorectal cancers that could be overcome in vitro and in vivo by repurposing COX2 inhibitors.

Silva and colleagues develop a network-based HDAC6 score which could predict sensitivity to the HDAC6 inhibitor ricolinstat in preclinical models, as well as patients with HR⁺/HER2⁻ breast cancer that received ricolinstat in a phase 1b clinical trial.

Jäger and colleagues analyze single-base substitution and indel mutational signatures across 27 pediatric cancer types, revealing marked differences in mutational patterns compared with adult cancers and insights into underlying molecular mechanisms.

Baek and colleagues present a proteogenomic analysis of 196 patients with pancreatic adenocarcinoma in an Asian population, identifying subtypes with invasive and proliferative features or immunogenic features, as a resource for future studies.