The genomic cancer strategy shift

Jim Kozubek in Nautilus:

Cancer-a-191A few years ago, James Watson, one of the co-discovers of the double helix structure of DNA, wrote a manifesto on cancer. He attacked the pursuit of cancer drugs based on next-generation personal genome sequencing, which seeks to unravel the genetic mutations that enable cancer. “The now much-touted genome-based personal cancer therapies,” he wrote, “may turn out to be much less important tools for future medicine than the newspapers of today lead us to hope.” Although next-generation sequencing is now affordable, and even allows us to read the genetic code of a single cancer cell, incident rates of new cases of cancer are still on the rise; and while the cancer death-rate is slightly down, most of the gains have been made in blood and immune cell cancers, like leukemia and lymphoma, not the solid-state tumors deep in our organs, which are harder to detect and treat. The use of personal genetic profiles to rethink cancer was no giant leap for mankind, and the press, Watson pointed out, began to report the hyperbole. We’re gaining “comprehensive views of how most cancers arise and function at the genetic and biochemical level,” he noted. But the vast set of tricks that cancer cells can use to escape cellular controls on their growth and migration means that the “curing” of cancers now unfortunately seems “an even more daunting objective” than it was in 1971, when Richard Nixon initiated the “war on cancer.”

Simply learning how to stop cells from becoming cancerous doesn’t seem to be a promising way to fight cancer, since hundreds of human genes are serious “drivers” that may alter multiple pathways—any chain of events that cells can readjust to alter energy use or production, or to grow and divide abnormally. Other molecules bind to DNA or to the proteins that holster it, resulting in cell types as diverse as bone, liver, or neuron—miraculous changes that can happen without ever altering the permanent code of a cell. (Each tissue or cell—no matter the type—has a unique epigenetic code that determines what genes are expressed and what type of cell it becomes.) When cells become cancerous, they may reverse these shapeshifting tricks, undergoing so-called “epithelial-to-mesenchymal cell transitions.” This turns dedicated cells—that is, cells working as a specific type—into free-floating cells. Their flexible shapes and ability to generate high amounts of the molecular fuel, ATP, allow them to achieve “anchorage independence.” They break from neighboring cells, becoming “motile,” or free to move elsewhere—to the brain, liver, or lungs, perhaps. Mutations to genes in some key pathways related to energy use or cell division can also enable cells to undergo unchecked growth or proliferation.

More here.