Cancer is Quantum

Andrea Califano began his career as a physicist. But that’s not why he’s now calling cancer a quantum disease.

“We’re really just following the data,” says Califano, the Clyde '56 and Helen Wu Professor of Chemical Biology at Columbia University Vagelos College of Physicians and Surgeons and head of Biohub, New York. “What we’ve seen over and over again is that each type of cancer has a limited number of cellular states. Just as electrons are restricted to a limited number of quantized energy states in an atom, cancer cells can only occupy one of these stable states or be in rapid transit between them. More critically, these states are conserved across virtually all patients with a specific type of cancer.”

The newest findings from the Califano lab—published recently in two papers in Nature Genetics—add critical evidence in support of the concept, which has enormous potential to transform and simplify the treatment of almost all cancers.

“If cancer is quantum, the good news is that we may not need personalized medicine,” Califano says. “A combination of therapies targeting the handful of distinct, detectable states may be all that is needed, and those combinations should be effective for virtually every patient.”

A sea change for personalized medicine

Cancer today is still treated with drugs and radiation that have been used for decades to kill rapidly growing cells by causing massive and irreparable damage to the cells’ DNA.

More recently, researchers have shifted to developing targeted drugs that counteract specific mutations found in cancer. Herceptin is a prime example and was designed to inhibit mutated HER2 proteins that cause cancer cells to grow uncontrollably.

These targeted drugs form the foundation of personalized medicine, the idea that cancer treatment can be tailored each patient’s specific array of mutations, which vary widely from patient to patient.

But Califano believes this approach can only address the tip of the iceberg.

“Going after mutations in cancer genes—so called oncogenes—is a very powerful concept,” Califano says. “Yet, most often, it only buys patients some extra time. The reality is that cancer is much more complex, because the potential number of mutational patterns in about 2000 oncogenes is larger than the number of atoms in the universe.”

Building an “equation of cancer”

With his background in physics and mathematics, Califano has taken an alternate approach.

“I was trained a physicist, and what physicists like to do is figure out how things work,” Califano says “Cancer is like a box with a complex set of levers and pulleys and gears that work together. Can we fully reconstruct these mechanisms to make sense of what we observe?”

To model how that box works, the lab captures data from living cancer cells to build what’s essentially an equation of cancer.

With this “equation,” Califano’s lab identifies critical proteins that maintain the cancer cell. “These are the generals that control the state of the cell,” he says.  “If you shut down these proteins—we call them cancer’s master regulators—the cell can’t sustain its malignant state anymore.”

Fortunately—and perhaps surprisingly—previous research from the lab has shown that the number of master regulator combinations, and therefore, the number of possible states a cancer cell can adopt seems to be limited. Califano’s analysis of more than 10,000 samples in more than 20 distinct cancer cohorts identified a mere 112 unique states. Based on more recent master regulator analyses of individual cancer cells, only one cancer was found to have a single state, and none so far with more than seven.

Identifying treatments for cancer’s quantum states

But finding the right treatment to eliminate these states isn’t as easy as identifying the dominant cellular state within in a tumor.

In a new paper published Aug. 26 in Nature Genetics, Pasquale Laise, Mikko Turunen, and Alvaro Curiel Garcia, researchers in Califano’s lab, examined hundreds of thousand cancer of pancreatic cancer cells, one-by-one, and found that every tumor contains cells representing the same six distinct states. “What really differed among patients wasn’t their cancer cells’ states but rather the fraction of cells in one state versus another, which seems to be key effect of mutations,” Califano says.

“The good news is that, because the same states are found in every patient, if you find a few drugs that, together, target all the states, that combination could be potentially curative. The bad news is that in pancreatic cancer each state can spontaneously change into any of the other states, suggesting that we may never be able to treat these tumors with a single drug.”

The situation may be more promising in diffuse midline glioma, a rare but devastating pediatric brain cancer. Using clinical-grade algorithms developed to identify existing drugs that target specific cancer states (OncoTreat and OncoTarget), Ester Calvo Fernandez, a graduate student in the lab, identified three drugs—avapritinib, ruxolitinib, and larotrectinib—that can be combined to target all seven possible states of this universally fatal disease.

In a paper published April 22 in Nature Genetics, Calvo Fernandez confirmed in laboratory studies that, individually, these drugs effectively target the predicted cancer cell states and all but one of the two-drug combinations targeting complementary states dramatically outperformed the associated monotherapies. The hope is to test the full triple-drug therapy in a clinical trial.

 “That’s the ultimate goal. A lot of our work sound theoretical,” Califano says. “But everything we predict gets tested in the lab and, when possible, in the clinics. We’ve already shown that these analyses can predict therapies for patients who had failed multiple lines of therapy.

“Hopefully, the identification of drugs targeting hyperconserved, quantized cancer states will help many more.”