"The study of how indolent and treatable low grade gliomas can evolve into clinically intractable GBM has captured the interest of my lab. This is because elucidating the molecular genetic basis of such a directed evolutionary process occurring in patients requires the use of all the multidisciplinary tools at our disposal."
- Dr. Barry Taylor
- Memorial Sloan Kettering Cancer Center
- Assistant Member, Human Oncology and Pathogenesis Program
- Assistant Attending, Department of Epidemiology and Biostatistics
- Associate Director, Marie-Josee and Henry R. Kravis Center for Molecular Oncology
About DSA-Funded Research
Death from cancer is commonly associated with tumor recurrence and metastasis. Among the most urgent questions is how a low-grade tumor may progress to a more aggressive state, either naturally or as the result of therapy, portending significantly worse outcomes. This is particularly ominous in low-grade gliomas, which have a favorable prognosis, but often recur after surgery and can progress to more advanced and less clinically tractable disease. Our long-term goal is to understand how gliomas evolve over time at the molecular level to devise new therapeutic strategies to intervene in this process, thereby improving the precision of recurrent glioma treatment. Toward these ends, we have begun to study pairs of newly diagnosed and recurrent tumors from the same patient collected over many years. We have found that these tumors follow diverse evolutionary trajectories, often displaying radical genetic differences between diagnosis and relapse. We have also discovered that chemotherapy itself can induce a catastrophic burden of new mutations, paradoxically increasing the aggressiveness of disease. In this proposal, we dissect how gliomas progress and identify those therapy-induced genetic changes that potentiate more malignant disease, but may too be subsequent targets of therapy. Using a state-of-the-art approach, we will define the distinct evolutionary routes gliomas follow and how they impact clinical outcome. Ultimately, we aim to bridge the gap between our ability to detect mutations in tumors and the accurate interpretation of their impact on the evolution of disease and then apply that knowledge to personalize the care of individual glioma patients.
"Barry is one of those exceptional individuals who, unfortunately, comes along very rarely. He brings an impeccable pedigree in computational biology to an extremely mature understanding of cancer biology and clinical management, together with exceptional collaborative skills."
Charles L. Sawyers, M.D.
Memorial Sloan-Kettering Cancer Center
"Barry is one of the most outstanding young scientists I have encountered, easily in the top 1%. He is extremely bright, creative and innovative and, in a field in which there is often more hype than substance, his mode of thinking and his work are substantive and represent real breakthroughs."
Neal Rosen, M.D., Ph.D.
Memorial Sloan-Kettering Cancer Center
- Joseph Costello, University of California, San Francisco
- Ingo Mellinghoff, Memorial Sloan Kettering Cancer Center
- Johnson BE, Mazor T, Hong C, Barnes M, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Aihara K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungal AJ, Jones SJM, Hirst M, Marra MA, Mukasa A, Saito N, Aburatani H, Berger MS, Chang SM, Taylor BS, Costello JF**. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science, 2014; 343(6167): 189-93
- Van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmstrom A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers MLM, Saito N, Aburatan H; Berger MS, Söderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 2015; 129(4): 597-607
- Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower grade gliomas. N. Eng. J. Med. 2015; 372(26): 2481-98
- Mazor T, Pankov A, Johnson BE, Hong C, Bell RJA, Smirnov IV, Reis GF, Phillips JJ, Barnes M, Bollen AW, Taylor BS, Molinaro AM, Olshen AB, Song JS, Berger MS, Chang SM, Costello JF. Cell cycle signature and tumor phylogeny are encoded in the evolutionary dynamics of DNA methylation. Cancer Cell, 2015; 38(3): 307-17
- Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, Gao JJ, Socci ND, Solit DB, Olshen AB, Schultz N, Taylor BS. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nature Biotechnol, 2016; 34(2): 155-63
- Rosenthal R, McGranahan N, Herrero J, Taylor BS, Swanton C*. DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Research, 2016; 17: 31. PMC4762164