The final output from the largest-ever cancer genomic study reveals new possibilities for immune-based and other novel cancer therapeutics, and provides a push for clinicians to obtain and utilize comprehensive genomic information to enroll their patients into specialized "basket" or "umbrella" clinical trials. Results from The Cancer Genome Atlas (TCGA) Network are highlighted in 27 studies published this week in Cell, Cancer Cell, Cell Reports, and Immunity.
The TCGA Network, which over the past decade has involved several hundred researchers from the USA and abroad, painstakingly analyzed the DNA, RNA and protein from 33 tumor types from more than 10,000 patients. Prior to study accrual the tumors were classically identified by their anatomic site of origin, such as breast, kidney, lung, etc. Utilizing 4 to 6 different state-of-the-art technology platforms to assay all the tumor samples, researchers found that, based on their cellular and genetic makeup and independent of their anatomic site of origin, all 33 types could be re-classified into 28 different molecular types or "clusters," and that nearly two-thirds of these clusters were considered heterogeneous as they contained up to 25 different histological tumor types that traditionally, would all be treated differently. These molecular analyses and clustering results, now also linked to multiple clinical outcome endpoints, are available to clinicians and researchers worldwide.
"This comprehensive body of final TCGA Pan-cancer Atlas analyses will provide a new foundation for future cancer research efforts and clinical trials. It will also incentivize clinical oncologists to get newly diagnosed and recurrent tumors genomically characterized and encourage them to help their patients become enrolled in specialized precision medicine basket clinical trials evaluating promising new targeted therapies against molecularly similar tumors, despite different histologies and anatomic sites of origin," said Christopher Benz, MD, Professor of Cancer and Developmental Therapeutics at the Buck Institute for Research on Aging and a clinical oncologist at the University of California, San Francisco. "Patients will have the best shot at successful treatment if their tumors can first be classified according to their genomic and molecular makeup." Benz has been involved in the TCGA since its inception in 2005 and is a senior co-author on several of the papers being published in Cell.
New data boosts the promise of immunotherapies
Benz says the new TCGA data hold particular promise for expanding treatments designed to enlist the immune system to beat cancer, including approved immunotherapies now showing extremely promising results against a limited number of classical cancer types. Remarkably, the study shows that one of the most diverse of the observed 28 molecular clusters was composed of 25 different classical tumor types and exhibited very strong features linked to activation of the patient's immune response. "This finding supports the growing notion that specific immunotherapies approved by the FDA for one cancer type would likely benefit patients with various other cancer types, if these other types could be molecularly identified," Benz said. "These latest Pan-Cancer Atlas results will likely be of great interest to pharmaceutical companies scrambling to develop new cancer therapies based on immune function or interested in re-purposing some of their already approved agents based on this new molecular classification."
Repurposing drugs used for other diseases
Drugs approved for other diseases could also be effective against some of the newly classified cancer types. "A couple of our newly defined cancer clusters also show activation of a molecular pathway (JAK/Stat) that's commonly upregulated in rheumatoid arthritis," said Christina Yau, PhD, a senior scientist in the Benz lab and new UCSF faculty member, who provided bioinformatics expertise for much of TCGA's work over the past decade. "This may provide the molecular rationale to explore repurposing of drugs used to treat that non-malignant chronic disease, as a novel treatment strategy."
Even though TCGA is done - the database won't be added to or changed - this same kind of comprehensive and collaborative multi-platform genomic analysis continues nationwide under new NCI sponsorship. As with their TCGA efforts, Benz and Yau continue to team up with University of California Santa Cruz investigators (Josh Stuart, PI, and colleagues) as part of their bioinformatic analysis center for the newly constituted Genomic Data Analysis Network. Among other challenges, it is tasked with determining clinically measurable biomarkers that would make it easier and more cost effective to identify a priori those same tumor molecular subsets identified by the TCGA network's multi-platform analysis. Benz attributes the innovative and highly effective bioinformatic algorithms developed by their University of California Santa Cruz partners for much of the shared success of their TCGA Buck-UCSC GDAC over the past decade.
"It's time to re-write the textbooks on cancer, and it's time to break down the silos in clinical oncology that make it difficult for patients to take advantage of this paradigm shift in cancer classification," said Benz. "This body of TCGA work is crucial for the success of our nation's "Cancer Moonshot" initiative, and all of us who have been involved in the TCGA are excited to make it available to the worldwide community of cancer researchers."
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Citation: Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer https://doi.org/10.1016/j.cell.2018.03.022
Citation: An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics https://doi.org/10.1016/j.cell.2018.02.052
About The Cancer Genome Atlas (TCGA) Research Network
These studies were was performed as part of the TCGA's Buck Institute-UCSC Genome Data Analysis Center (GDAC), co-led by the Buck's Christopher Benz and UC Santa Cruz investigators Josh Stuart and David Haussler. The TCGA Research Network includes over 150 researchers at many different institutions across the country. A full list of TCGA consortia participants are provided in the publications. All TCGA-generated data are freely available at the TCGA Data Portal, http://tcga-data.nci.nih.gov/tcga, and the CGHub, https://cghub.ucsc.edu. The TCGA Research Network is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health (NIH). Additional details about TCGA, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics and a media library of images can be found at http://cancergenome.nih.gov.
About the Buck Institute for Research on Aging
At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. Our goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, we are globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer's, Parkinson's, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Our success will ultimately change healthcare. Learn more at https://buckinstitute.org
Journal
Cell