Throughout his career, Bert Vogelstein has sought to define the genetic changes that drive human cancers. Now that most of these changes have been identified, his work is focused on using what he has learned to develop therapies and diagnostic methods to improve patients’ lives.
Vogelstein demonstrated that a tumor forms when genetic mutations cause a cell to lose its normal growth controls, and that tumors become more dangerous as additional mutations derail more growth-controlling genes. He also found that this process is accelerated by mutations that change how quickly new mutations arise.
By analyzing human tumors, Vogelstein’s team found that most colorectal cancers begin with a mutation in a gene called APC, and then went on to uncover how APC normally regulates colon cell growth. They also characterized mutations in other growth pathways that cause tumors to progress, as well as genes that are important for maintaining genetic stability in the colon.
More recently, Vogelstein’s team analyzed protein-coding genes in many types of human tumors and found that most contained 50 to 100 genetic alterations whose effects could be tied to about a dozen signaling pathways. Identifying those pathways has steered researchers toward potential new approaches to diagnosis and treatment.
In addition, Vogelstein’s group has developed blood tests to identify patients with inherited predispositions to colorectal cancer, as well as a variety of tests for the early detection of cancers. These tests are all based on a technology he and his colleague Kenneth Kinzler invented, called “digital PCR,” that can detect a single mutant gene among tens of thousands of normal copies of the same gene.
Vogelstein’s team is also developing therapies that target the unique vulnerabilities in cancer cells that result from their mutations. For example, in the past year, his team has shown that patients whose tumors contain a specific type of genetic alteration are extraordinarily sensitive to a specific form of immunotherapy. This therapy can result in pronounced regressions of tumors with this defect, even in advanced cancer patients.