Ushering in the next generation of precision trials for pediatric cancer

Science

Cancer treatment decisions are increasingly based on the genomic profile of the patient's tumor, a strategy called "precision oncology." Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors. The landscape of genomic alterations in cancers that arise in children, adolescents, and young adults is slowly becoming clearer as a result of dedicated pediatric cancer genome-sequencing projects conducted over the past decade. Of particular note are two recent studies that produced a comprehensive picture of the genomic features that characterize many of the more common pediatric cancers (1, 2). Two major themes have emerged.


Tissue-specificity in cancer: The rule, not the exception

Science

We are in the midst of a renaissance in cancer genetics. Over the past several decades, candidate-based targeted sequencing efforts provided a steady stream of information on the genetic drivers for certain cancer types. However, with recent technological advances in DNA sequencing, this stream has become a torrent of unbiased genetic information revealing the frequencies and patterns of point mutations and copy number variations (CNVs) across the entire spectrum of cancers. One of the most important observations from this work is that genetic alterations in bona fide cancer drivers (those genes that, when mutated, promote tumorigenesis) show a remarkable spectrum of tissue specificity: Alterations in certain driver genes appear only in cancers derived from one or a few tissue types (1). Here, we discuss the concept of tissue specificity of genetic alterations in cancer and provide general hypotheses to help explain this biological phenomenon.


How Precision Medicine Could Be A Lifesaver For Kids With Brain Cancer

Forbes - Tech

A team of Dana-Farber scientists has released new research with an important message about precision medicine: Sequencing the genes of brain tumors in kids could point to treatments that target their genetic abnormalities and therefore have the best chance of being effective. At least one of those drugs is already on the market, Novartis' Tafinlar (dabrafenib), approved by the FDA to treat other types of cancer but still readily available to pediatric oncologists who may want to try it in their patients. New research out of Harvard shows how genomic screening of brain tumors in children could help tailor treatments and lead to better outcomes. The study, led by the Harvard-affiliated Dana-Farber/Boston Children's Cancer and Blood Disorders Center, involved sequencing the genes of 200 tumor samples from children with brain cancer. The researchers found that 56% of the tumors had genetic abnormalities that could influence how the disease was diagnosed or treated by drugs already on the market or in clinical trials.


How Precision Medicine Could Be A Lifesaver For Kids With Brain Cancer

Forbes - Tech

A team of Harvard scientists has released new research with an important message about precision medicine: Sequencing the genes of brain tumors in kids could point to treatments that target their genetic abnormalities and therefore have the best chance of being effective. At least one of those drugs is already on the market, Novartis' Tafinlar (dabrafenib), approved by the FDA to treat other types of cancer but still readily available to pediatric oncologists who may want to try it in their patients. New research out of Harvard shows how genomic screening of brain tumors in children could help tailor treatments and lead to better outcomes. The study, led by the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, involved sequencing the genes of 200 tumor samples from children with brain cancer. The researchers found that 56% of the tumors had genetic abnormalities that can be directly addressed by drugs already on the market or in clinical trials.


Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy

Science

Clinical trial data can provide a wealth of information about how drugs work. Yet such information often belongs to pharmaceutical companies and is rarely accessible to the scientific community at large. Cristescu et al. provide exploratory analysis of a cancer genomics dataset, collected from four separate clinical trials of Merck's PD-1 immunotherapy drug, pembrolizumab. This informative public resource examines more than 300 patient samples representing 22 different tumor types. Two widely used signatures that currently predict immunotherapy response are tumor mutational burden and a "hot" T cell–inflamed microenvironment. The study analyzed these two proposed biomarkers in combination to see what predictive clinical utility they may hold. Immunotherapy targeting the programmed cell death protein–1 (PD-1) axis elicits durable antitumor responses in multiple cancer types. However, clinical responses vary, and biomarkers predictive of response may help to identify patients who will derive the greatest therapeutic benefit. Clinically validated biomarkers predictive of response to the anti–PD-1 monoclonal antibody pembrolizumab include PD-1 ligand 1 (PD-L1) expression in specific cancers and high microsatellite instability (MSI-H) regardless of tumor type. Tumor mutational burden (TMB) and T cell–inflamed gene expression profile (GEP) are emerging predictive biomarkers for pembrolizumab. Both PD-L1 and GEP are inflammatory biomarkers indicative of a T cell–inflamed tumor microenvironment (TME), whereas TMB and MSI-H are indirect measures of tumor antigenicity generated by somatic tumor mutations.