GEN Exclusives

More »

Feature Articles

More »
Feb 1, 2014 (Vol. 34, No. 3)

Cancer Genomics Enters a New Era

  • The Genome Institute’s cases are research studies supported by discretionary funds or grants. If something clinically relevant is found, findings are verified in a CLIA pathology lab with all the appropriate metrics to fit with the current pathology paradigm.

    The institute includes RNA expression in their analyses. On average, about 40% of genes that are found to be mutated by sequencing DNA are not expressed in the RNA. RNA sequencing, although complex, has allowed, in some cases, identification of overexpressed genes for which therapeutics exist and patients have been successfully treated.

    “We are still discovering what cancer is,” reflected Dr. Mardis. “We have done a ton of discovery about genes that are mutated, but the follow-on functional data to demonstrate activating mutations that drive cancer, and [to show] what the interactions are between the different pathways, is largely untouched.”

    “Soon we will make or break the argument for doing genomic studies across cancer patients. The basic question is whether sequencing, at some level, provides information that is helpful for guiding patient care and results in better outcomes,” concluded Dr. Mardis.

  • Shutting Down Networks

    Click Image To Enlarge +
    The multiscale approach taken by Mt. Sinai’s Icahn Institute integrates many different dimensions of data to depict the molecular states at play in an individual. It may be possible to see how variations in these states lead to phenotypic changes related to disease or other traits of interest.

    A multifaceted cancer research program recently launched at Mount Sinai embraces the complexity and uniqueness of each tumor. This program seeks to understand each tumor’s entire mutational landscape, weaving DNA, RNA, CNV (copy number variant), and other information together to generate probabilistic causal networks in the hopes of identifying the perturbations that drive cancer.

    “Treating single genes, or mutations, as the target is valuable but not sustainable. To increase therapeutic success and lower drug resistance, you have to start looking at networks as the target,” commented Joel Dudley, Ph.D., assistant professor of genetics and genomic sciences and director of biomedical informatics at Mount Sinai’s Icahn School of Medicine.

    “Our network-modeling approach will let us build a predictive network for various tumor types. Projecting the individual patient’s information onto these networks will help identify the network where each particular tumor seems to be most active, and help determine how to target that network by downregulating or shutting it down.”

    This approach may appear to be somewhat counterintuitive if one is accustomed to the current approach, which focuses on mutations and is highly targeted. All the connections and pathways that exist in biology are not fully understood, and the data-driven networks could end up looking very different what may have been imagined on the basis of common beliefs.

    Various approaches are under evaluation, including second-generation, real-time, observational sequencing technology, which not only provides the sequence and long reads, but also measures kinetics. Different kinetics allows observation of epigenetic marks, and longer reads are critical for looking at structural variations, duplications, fusions, etc.

    “We also look for novel epitopes. Finding an epitope that you can target on a novel gene fusion will allow vaccine design, and an immunotherapy-based therapeutic approach within an amenable timeframe,” observed Dr. Dudley. “We want to add years or more to people’s lives on average, and are taking a high-complexity, more-ambitious route because we think the payoff will be better in the long run.”

    “This is a research project with translation. As we define the process, we are also operationalizing it, so when our clinical trials are completed, and we start to get evidence that this is the way to go, we can just flip the switch and start treating patients. That will be the best reward,” concluded Dr. Dudley.

  • Putting Discovery to Use

    Decades of cancer research have provided a wealth of information about cancer drivers, or oncogenes, and accessory cancer genes, and it is time to progress past the discovery phase. This is the motivation for the approach used by a leading research team at the Karmanos Cancer Institute to focus cytogenomic analyses, an approach that relies heavily on integrating knowledge-based evidence. One of the team’s goals is to rapidly turn around translatable insights for presently understudied cancer types such brain metastases arising from lung and breast cancers.

    “There have been great attempts to integrate and curate the information from molecular cancer research. We apply this information in a comprehensive way to results of our genomic laboratory analyses to allow us to quickly interpret results from small sets of tumors, or individual primary cancer and matched metastases, to gain meaningful insights and appreciate molecular underpinnings of the tumors,” explained Aliccia Bollig-Fischer, Ph.D., assistant professor of oncology at Wayne State University and associate director of the Genomics Core at the Karmanos Cancer Institute.

    “We know a lot about the biological process of metastases but little about the genomic landscape or mutation architecture of brain metastases. We collect specimens and data, analyze the tumors, and gain additional information as to the true frequencies of any individual cancer gene mutation in our patient population. We want to understand what potentially actionable oncogenes are important in the cancer subsets that we are looking at. The discovery of new oncogenes is not our emphasis.”

    The very early results of this research concurs with ideas put forth already in the literature. Increased diversity of mutated oncogenes and co-oncogene expression appears to be a feature of the brain tumors arising from metastases of lung and breast cancers. Metastatic tumors arising in the brain have increased gains in amplified oncogenes compared to the primary, or original, tumors.

    To improve patient treatments sooner, clinical genomic researchers at the Karmanos Cancer Institute also integrate information on existing targeted therapies and clinical trials, not necessarily limited to brain tumors, into their knowledge base to project which insights may clinically translate more rapidly.



Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Children and Antipsychotic Drugs

Do you think children and adolescents with behavioral problems are overmedicated?