Shutting Down Networks
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.