Precision Medicine Platform Aims to Advance Cancer Gene Therapies

A team from Cleveland Clinic has developed a precision medicine platform designed to accelerate cancer gene therapies and genome-informed drug discovery.

In a study published in Nature Genetics, researchers describe the My Personal Mutanome (MPM) platform. The platform features an interactive database that offers insight into the role of somatic mutations in cancer – acquired mutations that can’t be passed to offspring – and prioritizes mutations that may be responsive to drug therapy.

“Although advances in sequencing technology have bestowed a wealth of cancer genomic data, the capabilities to bridge the translational gap between large-scale genomic studies and clinical decision making were lacking,” said Feixiong Cheng, PhD, assistant staff in the Genomic Medicine Institute, and the study’s lead author.

“MPM is a powerful tool that will aid in the identification of novel functional mutations/genes, drug targets and biomarkers for cancer, thus accelerating the progress towards cancer precision medicine.”

The team used clinical data to integrate nearly 500,000 mutations from over 10,800 tumor exomes – the protein-coding part of the genome – across 33 cancer types into the platform. The team then systematically mapped the mutations to over 94,500 protein-protein interactions (PPIs) and over 311,000 functional protein sites where proteins physically bind with one another. Researchers then incorporated patient survival and drug response data.

The platform analyzes the relationships between genetic mutations, proteins, PPIs, protein functional sites, and drugs to help users easily search for clinically actionable mutations. The MPM database includes three interactive visualization tools that offer two- and three-dimensional views of somatic mutations and their associated survival and drug responses.

According to the researchers, previous studies have linked disease pathogenesis and progression to mutations and variations that disturb the human interactome, the complex network of proteins and PPIs that impact cellular function. Mutations can disrupt the network by directly changing the normal function of a protein, known as nodetic effect, or by altering PPIs, known as edgetic effect.

Additionally, in a separate, previous study, a team of researchers found that somatic mutations were highly enriched where PPIs occurred. The group also demonstrated that PPI-perturbing mutations were significantly correlated with drug sensitivity or resistance as well as poor survival rate in cancer patients.

“The results from another study published in Nature Genetics, which was a collaboration between Cleveland Clinic and several other institutions, motivated us to develop the mutanome platform,” said Cheng.

“Our Nature Genetics findings, along with previous research, provide proof-of-concept of both nodetic and edgetic effects of somatic mutations in cancer. What we learned from that study inspired us to develop a systems biology tool that, by mapping mutations to PPI interfaces and protein functional sites and integrating survival and drug response data, identifies cancer-driving and actionable mutations to guide personalized treatment and drug discovery.”

Researchers expect that MPM will lead to a better understanding of mutations at the human interactome network level. This could lead to new insights in cancer genomics and treatments, ultimately achieving the goal of cancer precision medicine.

The team will continue to update MPM annually in order to provide researchers and physicians with the most comprehensive, complete data available. Researchers also plan to apply advanced analytics technologies to their insights to improve treatment development for other conditions.

“Our Nature Genetics study also demonstrates the nodetic and edgetic effects of mutations/variations in other diseases,” said Cheng.

“As a next step, we are developing new artificial intelligence algorithms to translate these genomic medicine findings into human genome-informed drug target identification and precision medicine drug discovery (i.e., protein-protein inhibitors) for other complex diseases, including heart disease and Alzheimer’s disease.”