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There has been striking progress in cancer care over the past two decades. Many cancers can now be effectively managed and patient prognoses have improved markedly overall. Unfortunately however some cancers remain incurable with high patient mortality. Gliomas the most common malignant brain cancers are among the cancers that have so far resisted medical progress. The resistance is literal as at least some glioma cells are always able to evade frontline treatments leading to recurrence therapy resistance and lethality. Figuring out how to effectively target glioma for elimination is a demanding field that spans the medical spectrum from basic research to drug development to patient engagement. And at the middle of the current surge of discovery is Jackson Laboratory JAX Professor Roel Verhaak Ph.D. Improving cancer patient engagement and knowledge Verhaak began his graduate studies in medical informatics but soon pivoted to computational biology and cancer research. His background provides him with an appreciation of the value of basic research yet with an end goal always in mind improving patient care. Indeed one of Verhaaks latest projects illustrates how his scope extends beyond the lab to take on gliomas many challenges. OPTIMUM OPTimIzing engagement in discovery of molecular evolution of low grade glioma recently funded through a four-year National Cancer Center grant is not your typical laboratory research project. Low grade gliomas LGGs are rare tumors and relatively little is known about their biology or how to provide optimal patient care. While low grade may not sound all that dangerous its relative. LGG patients do in fact have good prognoses in the short term compared to those with high grade gliomas. Unfortunately however LGG is a devastating diagnosis by any other measure. LGG always progresses and is uniformly fatal with survival averaging about seven years. It also occurs in younger people than the more aggressive gliomas with most patients diagnosed in their 30s and 40s. OPTIMUM is a three-institution effort and Verhaak is a co-principal investigator with collaborators from Yale University and the University of Colorado. The project will acquire samples from 500 patients both at the time of LGG diagnosis and the time of recurrence providing invaluable data to help figure out the mechanisms of recurrence. But the key aspect of OPTIMUM is patient engagement working with participants so that they are active partners in the study with a full understanding of its progress and outcomes. The patients in turn will provide important insight into how to improve their medical care. OPTIMUM will reach underserved patient populations in regions that are often overlooked in genomics and cancer studies says Verhaak. We will empower them to understand their genomic data and what it means for their care and they will teach us how to better help them. Cancer evolution OPTIMUM will contribute significant amounts of data to another collaborative effort Verhaak has spearheaded the Glioma Longitudinal AnalySiS consortium or GLASS. Launched in 2015 GLASS brought together computational and bench researchers pathologists and clinicians to help bridge the gaps between research and the clinic. Together they are addressing a fundamental problem with glioma therapies the tumors always evolve and develop resistance to treatment. But to learn how and why they are able to do so you need to gain access to tumor tissue from multiple timepoints. That is a major challenge especially for a less common cancer type. There are therefore more than 130 contributors to GLASS from dozens of institutions around the world. We will empower them to understand their genomic data and what it means for their care and they will teach us how to better help them.By 2019 GLASS had acquired and analyzed glioma samples DNA sequencing data and clinical annotations from 222 patients. In a paper published in Nature on which Verhaak was senior author they presented findings that were on the surface a little surprising. The driver mutationsthat is the mutations in oncogenes specific genes that contribute to cancerous growthfound initially in the patient samples were also retained at recurrence. So it appeared that not much was evolving at the individual gene level. Furthermore the clonal architecture meaning the presence and numbers of different cellular populations within the tumor remained similar over time. The take-home message was that the differences between cells within the tumors develop early and they involve mechanisms that are not captured by whole genome sequencing of the glioma cells. But what are they To find out its essential to investigate the basic biology of glioma in the laboratory. Beyond genomic DNA Two major basic research programs in Verhaaks lab are investigating the inner workings of glioma cells and how they evolve. As the earlier GLASS results indicated the latest findings show the need to move beyond DNA to find what molecular processes makes glioma tumors so dangerous and impossible to eradicate. One line of research explores a process that can help cells change and adapt with no changes to their DNA sequences epigenetic reprogramming. Epigenetic marks are chemical compounds that can be bound to or removed from specific DNA sequences to help regulate gene expression. Using innovative single-cell analyses Verhaak and his lab reported in Nature Genetics that a specific epigenetic process methylation DNAme is altered in glioma cells and more DNAme disruption is associated with more aggressive tumors. When the cells are subjected to stress the DNAme disorder increases which can lead to cell state changes and important differences between individual cells. It also makes some of the cells plastic in that they can switch back and forth between specific cell states.