Cancer Chemotherapy Resistance Stopped By Chromatin Regulation

Researchers at Northwestern University have developed a new approach to treating cancer that effectively changes the physical structure of chromatin and blocks the cell’s ability to modify global gene expression patterns and evolve resistance to therapy.

The researchers, led by Vadim Backman, Ph.D., the Walter Dill Scott Professor of Biomedical Engineering at Northwestern’s McCormick School of Engineering, tested the macrogenomics engineering approach using two immunologic drugs that are marketed for noncancer indications, but which also change the packing density of chromatin. Combining the two drugs with existing chemotherapeutics successfully wiped out nearly 100% of seven different types of laboratory-grown cancer cells.

“If you think of genetics as hardware, then chromatin is the software,” Prof. Backman explains. “Complex diseases such as cancer do not depend on the behavior of individual genes, but on the complex interplay among tens of thousands of genes. By targeting chromatin, we can modulate global patterns in gene expression.”

The researchers report their findings in Nature Biomedical Engineering, in a paper entitled, “Macrogenomic Engineering via Modulation of the Scaling of Chromatin Packing Density.”

Cancer cells have a persistent ability to survive multiple forms of treatment, such as radiotherapy, immunotherapy, and chemotherapy. Even if treatment does kill the bulk of a tumor, a few cells can survive and proliferate. “How does cancer jump through so many hoops to survive?” Backman queries. “It’s a highly improbable event, if you think about it. But there is one thing that all cancers do. 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.”

How cancers develop, propagate, and survive doesn’t depend on just a few genes, Backman suggests. “Think of the number of mutations that have been documented in cancer,” he says. “We’re talking about thousands. Just changing one gene is not going to give you cancer, and it’s not going to cure cancer either. But we can rewrite the software by using chromatin engineering to manipulate the genetic code.”
Chromatin is a polymer chain comprising proteins and DNA that packages the cell’s genetic material efficiently into chromosomes and ensures that all the required genes can be accessed. The physical properties of chromatin are also known to play an important role in controlling which genes are expressed. So, while gene expression is regulated by events such as transcription factor binding affinity, “the transcription of these genes into mRNA will also depend on local physical forces,” the researchers write.

The Northwestern University–led researchers used a combination of imaging techniques, simulations, systems modeling, and cell-based studies to demonstrate that in cancer cells predictable changes in gene expression are linked to the physical packing density of chromatin.

One of the techniques they exploited, known as partial wave spectroscopic (PWS) microscopy, was developed by Backman’s lab last year and makes it possible to examine chromatin in living cells, in real time, at unprecedented resolution. They combined results from their imaging techniques with molecular dynamics simulations to model how chromatin reacts to stimuli. The results indicated that the more disordered, or heterogeneous, the chromatin packing density, the more likely cancer cells were to survive. In contrast, the greater the packing density order, the greater the likelihood that treatment would kill the cancer cells.

“Just by looking at the cell’s chromatin structure, we could predict whether or not it would survive,” Backman said. “Cells with normal chromatin structures die because they can’t respond; they can’t explore their genome in search of resistance. They can’t develop resistance.”

Backman’s team reasoned that by controlling chromatin packing density it should be possible to regulate the expression and transcription of multiple genes simultaneously and effectively control how biological systems behave. The team screened existing drugs to find compounds that could modify the nuclear environment and reduce the cell’s ability to change its chromatin packing density.

Two of the compounds identified, celecoxib and digoxin, are marketed immunologic drugs used to treat arthritis and heart conditions, respectively, but they also both reduce intranuclear variations in chromatin packing density. Although neither of the compounds, which the team termed chromatin protection therapies (CPTs), were effective in killing cancer cells on their own, when they were combined with chemotherapy “something remarkable” happened, Backman states. “Within two or three days, nearly every single cancer cell died because they could not respond,” he comments. “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.”

The reported studies were carried out in cultured cancer cells, and work is now progressing in animals. “…we have demonstrated that macrogenomic engineering can control the transcriptional activity of many genes simultaneously and can be applied to the selection of adjuvant compounds to increase the efficacy of chemotherapeutic agents in vitro,” the authors write.

Backman’s team suggests that the same chromatin targeting approach might also be applied to other diseases. “Here, we have described a physiochemical framework that maps the collective behaviour of multiple genes simultaneously on the basis of chromatin’s physical nanoenvironment…the approach paves the way for the study and treatment of diseases—such as Parkinson’s disease, atherosclerosis and autoimmune disorders—that are governed by the complex interplay of dozens of genes.”

It may even be possible to find ways of reversing the effect to increase cells’ plasticity and give them properties similar to stem cells, for regenerative medicine approaches. “Genetic changes are permanent, but this type of modulation is more like software,” Backman claims. “By definition, it’s reversible. You could reprogram a neuron, and then remove the stimulus and allow it to go back to its normal state. If chromatin is software, then we are saying there is room to write new codes.”

Macrogenic engineering could also feasibly be used to complement gene-editing techniques, the researchers suggest. Gene editing targets individual genes within the linear genetic code, whereas regulating chromatin packing density affects global patterns of gene expression. “Pairing gene editing and macrogenomic engineering may allow for the hitherto unachieved capacity to control the overall behaviour of biological systems.”