A new strategy for treating cancer has wiped out the disease to near completion in laboratory-based cellular cultures.
The treatment, developed by Northwestern's Vadim Backman, is unique: It’s not about discovering new drugs or treatment options, but about boosting the effectiveness of current treatments by beating cancer at its own game.
The key is controlling a complex of macromolecules, known as chromatin, which houses genetic information within cells and determines which genes get suppressed or expressed. When it comes to cancer, chromatin has the ability to regulate cancer cells’ capacity to find ways to adapt to treatment -- and become resistant to it.
As published in the journal Nature Biomedical Engineering, Backman’s solution alters the structure of chromatin, preventing cancer from evolving to withstand treatment. The technique has shown great potential at fighting cancer in cellular cultures, and is now undergoing studies in an animal model.
Changing cancer’s resilience
Perhaps no feature of cancer is more impressive than its relentless ability to survive. It can be bombarded by treatments such as chemotherapy, immunotherapy and radiation – not to mention the body’s own immune system. But while these measures might shrink or slow its proliferation, it rarely disappears.
“There is one thing that all cancers do,” says Backman, a biomedical engineering professor at Northwestern’s McCormick School of Engineering. “They have a phenomenal ability to change, to adapt, to evolve in order to evade the treacherous conditions they frequently have to face during the process of their growth or in the face of treatment.”
Chromatin is packed together at different densities throughout a cell’s nucleus. Through a combination of imaging, simulations, systems modeling and in vivo experiments, Backman’s team discovered that the way it is packed in cancer cells produces predictable changes in gene expression. The more heterogeneous and disordered, the more likely the cancer cells are to survive -- even in the face of chemotherapy. The more ordered and conservative, the more likely the cells would be killed by treatment.
“Cells with normal chromatin structures die because they can’t respond; they can’t explore their genome in search of resistance,” Backman explains. “They can’t develop resistance.”
Altering the packing density
The study leverages an imaging technique, called Partial Wave Spectroscopic (PWS) microscopy, which was developed in Backman’s lab. It allows researchers to examine chromatin in living cells in real time – and to peer inside chromatin at the 20- to 200-nanometer length scale, which is where it undergoes a transformation when cancer is formed.
Because the number of possible combinations of genes and genomic states – expressed, amplified, suppressed -- is so high, knocking out one gene most likely cannot prevent or fully treat a complex disease such as cancer. Backman’s lab instead takes a “macrogenomics” approach, altering packing densities to control the overall behavior of the system.
“If you think of genetics as hardware, then chromatin is the software,” Backman explains. “We can rewrite the software by using chromatin engineering to manipulate the genetic code.”
And that’s done by changing the electrolytes present in the cell’s nucleus – which the research team discovered by screening multiple existing drug compounds. Two that they pinpointed, Celecoxib and Digoxin, are prescribed for arthritis and heart conditions, respectively. Both have a side effect of altering chromatin packing density.
When Backman combined these chromatin protection therapeutic (CPT) compounds with chemotherapy, his PWS microscope showed “something remarkable.”
“Within two or three days, nearly every single cancer cell died because they could not respond,” says Backman. “The CPT compounds don’t kill the cells; they restructure the chromatin. If you block the cells’ ability to evolve and to adapt, that’s their Achilles’ heel.”
More testing needed
Backman cautions that there is a “big difference between cell cultures and humans,” so much more testing is needed before the technique can become a viable approach for cancer treatment. But CPT/chemotherapy testing produced the same results in seven different types of cancer in cell cultures, which Backman sees as “very promising.”
It’s possible that the same technique could work for other complex diseases, such as Alzheimer’s disease and atherosclerosis. Or, conversely, it could make normal cells more adaptable, effectively turning them into stem cells to repair brain and spinal cord damage. The modulation should theoretically be reversible, as well; a neuron could not only be reprogrammed, but also reversed by removing the stimulus and allowing it to go back to its normal state.
“If chromatin is software,” Backman says, “then we are saying there is room to write new codes.”