How inhibiting one protein could help to treat pancreatic cancer

Targeting an enzyme that makes pancreatic cancer cells more aggressive by silencing some of their genes could make the deadly disease less resistant to treatment.

This was the conclusion of new research from Genentech, a biotechnology company in South San Francisco, CA, which was recently reported in the Journal of Cell Biology.

The study focuses on an aspect of cell biology that is of key interest in cancer research: the “epithelial-to-mesenchymal transition,” a sort of identity change that cancer cells undergo as the disease progresses.

Most cancers begin in cells of the epithelium, which is a type of tissue that consists of densely packed sheets wherein cells are immobile and firmly anchored to each other.

However, as cancer progresses, epithelial tumor cells become more like mesenchymal cells, which are not attached to one another and can migrate, as well as invade other tissues and form secondary tumors there.

Epithelial-mesenchymal spectrum

Another important feature of mesenchymal tumor cells is that — unlike their epithelial equivalents — they are much more resistant to cancer drugs. In addition, they have stem cell properties that allow them to self-renew, differentiate, and drive tumor growth.

Researchers will sometimes refer to this process as movement along an epithelial-mesenchymal spectrum: as cancer progresses, the cancer cells move farther away from the epithelial end and toward the mesenchymal end.

Using laboratory-grown cells, Ira Mellman — Genentech’s vice president of cancer immunology — and others from the Roche subsidiary found a way to push mesenchymal pancreatic cancer cells back toward the epithelial end of the spectrum “on a molecular and functional level.”

“The acquisition of these epithelial characteristics,” explains first author Manuel Viotti, “was sufficient to reduce cell invasion and motility and increase sensitivity to gemcitabine and 5-fluorouracil, two of the most commonly used chemotherapies in human pancreatic ductal adenocarcinoma.”

Pancreatic cancer acquires drug resistance

Pancreatic cancer starts in cells of the pancreas, an organ that lies behind the stomach and is important for digestion and controlling blood sugar. It is one of the 10 cancers that are most common in both men and women.

Although it only accounts for 3 percent of all cancers in the United States, around 7 percent of deaths from cancer are due to pancreatic cancer.

Estimates for the U.S. suggest that around 53,670 people will be diagnosed with pancreatic cancer in 2017, and approximately 43,090 people will die of it.

Because the early stages often go unnoticed, most cases of pancreatic cancer are not detected until the disease has spread. This makes it harder to treat and leaves people with much lower chances of survival compared with many other types of cancer.

The researchers note that existing treatments for pancreatic cancer are largely ineffective once it is advanced, because of “acquired drug resistance, as well as being poorly responsive to immunotherapy.”

Epigenetic regulators

The idea of “priming” pancreatic cancer with an agent that induces cancer cells to move farther away from the mesenchymal end of the epithelial-mesenchymal spectrum and more toward the epithelial end is not new.

A lot of individual proteins that help to control movement along the spectrum have already been identified. But attempts to target them in cancer patients to make their mesenchymal tumor cells move toward the epithelial end of the spectrum have met with little success.

Researchers are beginning to realize that pushing mesenchymal tumor cells along the spectrum toward the epithelial end is a massive task that requires organization of many gene expression changes on a large scale — rather like an orchestra playing many notes at the same time.

Epigenetic regulators are proteins that can orchestrate this complex process. They regulate which of the huge amount of genetic information held in a cell’s DNA can be accessed by the machinery of the cell.

To fit in the tiny space of the cell nucleus, DNA is tightly packed with proteins called histones into a structure called chromatin. Epigenetic regulators control access to DNA by chemically altering either the DNA or the histones of the chromatin structure.

SUV420H2 shows promise

For their study, the Genentech team screened 300 known epigenetic regulators to see which of them could regulate movement along the epithelial-mesenchymal spectrum.

The one that proved most effective was a “histone-modifying protein called SUV420H2.” It caused laboratory-grown mesenchymal pancreatic cells to regain many of the properties of epithelial cells.

In other experiments, they showed that pancreatic cancer cells with low levels of SUV420H2 had much higher levels of expression of epithelial-specific genes than mesenchymal-specific genes.

By contrast, when they increased levels of SUV420H2 in the epithelial-like cells, the team found that they became more mesenchymal-like.

Finally, using tissue samples from individuals with pancreatic adenocarcinoma, they found that SUV420H2 was low in healthy pancreatic tissue, slightly higher in tissue in the early stages of cancer, and much higher in tumor tissue where the cancer had reached an advanced invasive stage and where the cells had lost many of their epithelial properties.

The researchers note that SUV420H2 and other histone-altering enzymes are not difficult to inhibit with drugs, but they point out that more work is needed before we can say whether or not making mesenchymal tumor cells more like epithelial cells will actually benefit cancer patients.

Should that be the case, then using drugs that target SUV420H2 to encourage the epithelial state might help to decrease resistance and make conventional chemotherapies more effective in the fight against pancreatic cancer.

“Priming pancreatic cancers with an epithelial-inducing agent might not only decrease invasion, metastasis, and limit stem cell-like behavior, but may also increase responses to existing cancer drugs.”

Ira Mellman