Understanding the processes involved in cancer development are a huge step forward in terms of developing treatment options.  For many types of cancer, that is a painstaking process and after years of research, only a few pathways are discovered. A new study from Pacific Northwest National Laboratory (PNNL) has jumpstarted that process for endometrial cancer, identifying dozens of pathways that lead to cancer development in one study.

Significantly, it looks as if all of the potential steps and genes involved have been explained, and instead of pointing a flashlight at a problem, these researchers have simply turned on the light. Tens of thousands of genomic and protein interactions have been documented, occurring at different times, documenting steps that play out over years in patients’ bodies.

This unprecedented look at endometrial cancer, commonly known as uterine cancer, offers insights to how physicians might be able to better identify which patients will need aggressive treatment and which won’t; clues on why certain treatments are not effective with some patients populations; and suggestions for currently approved drugs to target proteins CDK12, SMARCA4 and PML.

“This is like the Google Earth of endometrial cancer,” said Karin Rodland, one of five corresponding authors of the paper and a cancer biologist at the U.S. Department of Energy’s Pacific Northwest National Laboratory (PNNL). “It’s a very comprehensive portrait of this particular cancer type. We tried to measure everything we possibly could. Then we searched for patterns.”

This study began in 2013, building on The Cancer Gene Atlas, or TCGA, which identified some of the genetic underpinnings of the disease. The study is the fifth publication in a series of studies funded by the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium to tackle the biological pathways involved in cancer. Previously published papers have focused on ovarian cancer and colon cancer.

The team wound up studying 95 uterine tumors and 49 normal uterine tissue samples over the years, measuring the abundance and modifications of a vast number of molecular players, including genes, messenger RNAs, circular RNAs, micro RNAs and proteins. The researchers focused on post-translational modifications, including phosphorylation and acetylation, or where proteins became active or inactive in the cell to understand which pathways impacted cancer development.

“This unique, rich resource of high-quality data about all these molecular players from the same set of samples provides cancer researchers with a precious view of protein activity and regulation,” said Liu.

The team took more than 12 million measurements to understand as much information from their library of tumors as possible. This comprehensive methodology allowed scientists to identify tumors that are not currently classified as aggressive but have the genetic potential to be just as invasive as serous tumors (which grow quickly and are more likely than other tumors to kill patients).

Currently, aggressiveness in endometrial tumors is determined by viewing a histological slide of cells from a sample of tumor, a method that relies on human interpretation of cell phenotypes in a small percentage of cells from a tumor. The team showed that activity levels of certain proteins clearly differentiate more-aggressive from less-aggressive tumors, not just phenotype. For example, the protein beta-catenin, a well-known actor in many types of cancer, interacts with a signaling pathway known as Wnt to evade detection, accumulates in the cell, and deregulates cell division.

“What was a disciplined army of interacting proteins now becomes a mob, wreaking havoc,” said Rodland.

The team also found histone acetylation, the molecular signaling process in which a cell accesses certain portions of DNA on a chromosome for use, happens more often than expected in tumor cells. The team’s measures indicate that ths process is very active in endometrial cancer.

“Imagine a librarian holding a book very tight to the chest, not allowing anyone else to read it,” said Rodland. “If you want to read the book—or in this case, access a gene and turn it on—you have to have a way to loosen the librarian’s grip and open the book.”

In addition to understanding the molecular pathways involved in deregulation, this study analyzes the clinical aspects of this cancer, identifying patients who will or won’t benefit from checkpoint therapy.

Algorithm to Help Guide Treatment

The team created an algorithm to determine when drugs such as pembrolizumab and nivolumab can be used to treat cancer cells that have managed to evade the immune system. Using the immune system as a therapy is one of many ways physicians can spur the body’s natural defenses to fight cancer.

In endometrial cancer, physicians use a measurement known as tumor mutation burden (TMB) to determine which patients are most likely to benefit, but based on the measurements of immune activity in this study, scientists have proposed a new measurement that focused on a patient’s antigen presentation machinery, known as the APM. The APM describes how well the body flags cancer cells and presents them to the body’s immune system for destruction – a key function for checkpoint inhibitors to be effective.

Better insight into exactly who would benefit from the drugs would allow physicians to avoid their use in patients who are unlikely to benefit, sparing those patients severe and unnecessary side effects.

“This work contributes to the personalized medicine we need to deliver for patients who have endometrial cancer,” said Bing Zhang of Baylor College of Medicine, a corresponding author. “Such work will help us to know which patients will benefit most from which therapies.”

The team also discovered that circular RNAs seems to be involved in the transformation tumor cells undergo when they gain metastasis. The transition is called the endothelial-mesenchymal transition, or EMT; researchers believe this is what makes endometrial cancer so deadly.

Having a roadmap is an impressive first step, but in terms of treatments and cures, researchers have a long way to go.

“This is hypothesis-generating research,” said Rodland. “It’s like the Moon mission, where the crew brought back rocks for study by many other scientists. Here, we are providing the raw information for scores of scientists to pore over, to study, and to generate new hypotheses. Eventually we hope this information will lead to clinical trials and perhaps new ways to treat this disease.”