An example of tumor oncotecture. Transcription factors involved in the activation of mesenchymal glioblastoma subtype are shown in purple. Together, they comprise a tightly knit tumor checkpoint, controlling 74% of the genes in the mesenchymal signature of high-grade glioma. CEBP (both β and δ subunits) and STAT3 regulate the other three transcription factors in the tumour checkpoint, synergistically regulating the state of mesenchymal GBM cells. (Image: Nature Reviews Cancer)
In a detailed Perspective article published in Nature Reviews Cancer, Department of Systems Biology chair Andrea Califano and research scientist Mariano Alvarez (DarwinHealth) summarize more than a decade of work to propose the existence of a universal, tumor independent “oncotecture” that consistently defines cancer at the molecular level. Their findings, they argue, indicate that identifying and targeting highly conserved, essential proteins called master regulators — instead of the widely diverse genetic and epigenetic alterations that initiate cancer and have been the focus of much cancer research — could offer an effective way to classify and treat disease.
As coverage of the paper in The Economist reports:
ONE of the most important medical insights of recent decades is that cancers are triggered by genetic mutations. Cashing that insight in clinically, to improve treatments, has, however, been hard. A recent study of 2,600 patients at the M.D. Anderson Cancer Centre in Houston, Texas, showed that genetic analysis permitted only 6.4% of those suffering to be paired with a drug aimed specifically at the mutation deemed responsible. The reason is that there are only a few common cancer-triggering mutations, and drugs to deal with them. Other triggering mutations are numerous, but rare—so rare that no treatment is known nor, given the economics of drug discovery, is one likely to be sought.
Facts such as these have led many cancer biologists to question how useful the gene-led approach to understanding and treating cancer actually is. And some have gone further than mere questioning. One such is Andrea Califano of Columbia University, in New York. He observes that, regardless of the triggering mutation, the pattern of gene expression—and associated protein activity—that sustains a tumour is, for a given type of cancer, almost identical from patient to patient. That insight provides the starting-point for a different approach to looking for targets for drug development. In principle, it should be simpler to interfere with the small number of proteins that direct a cancer cell’s behaviour than with the myriad ways in which that cancer can be triggered in the first place. (Read full article.)