Under the Microscope: Taking a research risk yields a completely new cancer therapy target

Much of today’s cancer research focuses on making current treatments better. While this work is vital to making cancer therapies gentler and more effective, improvements typically come in small increments. For true breakthroughs, researchers need to discover completely new aspects of cancer—including new weaknesses that can be targeted with drugs.

Seth Field, M.D., Ph.D., from Case Comprehensive Cancer Center is hoping his work will lead to this type of breakthrough. He is hunting for new drug targets by studying a piece of cell machinery known as the Golgi apparatus. This organelle carries out the key function of ferrying proteins and lipids produced by the cell through the membrane to the outside of the cell.

With V Foundation funding, Field and his colleagues have discovered a part of the Golgi apparatus that seems to play a role in driving several types of cancer. They are now working to develop new drugs that inhibit this export machinery and might prove useful for treating cancer. If they continue to get positive results, the work could lead to a fundamentally new way to treat cancer.

“The funds we received from the V Foundation have been invaluable,” said Field. “They gave us the flexibility to study processes that we don’t fully understand and allowed us to do research that involves a bit of a risk.”

Following a hunch

In 2006, Field received a V Foundation grant while at the University of California San Diego. The project focused on the role of a phosphoinositide lipid molecule called PtdIns(3,4,5)P3 that was known to be important in cell growth signaling in cancer. The work led to the discovery of new targets of PtdIns(3,4,5)P3 that seem to modulate the activity of downstream cancer signaling.

“This project involved a very well-grounded approach to studying cancer because there was a lot of data that pointed toward this area as being important to study,” said Field. “However, I wanted to look deeper into the fundamental biology in hopes of finding insights that had the potential to generate more of a leap in cancer treatments.”

Following this thread, Field expanded his research to examine other members of the phosphoinositide family whose functions were unknown. He had a hunch that they might play a role in cancer, but they hadn’t been studied enough to tell for sure. Luckily, his hunch paid off, leading to the discovery of a new PtdIns(4)P effector called GOLPH3.

GOLPH3 forms the core of a molecular machine that helps the Golgi package cargo so it can be transported to the plasma membrane. Genetic studies revealed that many of the components of this complex are also oncoproteins that drive human cancers, including breast, lung, colorectal and prostate cancers.

Field and his team have shown that the GOLPH3 complex plays a key role in helping cells survive after DNA damage and that it contributes to cell migration, the process that allows cancer cells to spread. They also found that GOLPH3 enhances the Golgi’s membrane transport operations in a way that promotes cancer.

Funding from the V Foundation provided a financial cushion that enabled us to carry out these high- risk, high-reward experiments. Having funding we could fall back on if things didn’t pan out was extremely valuable in making us feel more comfortable going in this new direction.

Seth Field, M.D., Ph.D.

Finding a new type of treatment

When Field moved to Case Comprehensive Cancer Center in 2019, he used his remaining V Foundation funding to uncover how GOLPH3 helps cells send signals to each other as part of the intricate communication networks that control tumor growth.

His team found that the GOLPH3 pathway can modulate the strength of growth factor signaling, which, in turn, drives cell proliferation in a way that promotes tumor growth. Based on these findings, the team began developing small molecules that could inhibit the GOLPH3 pathway.

“We don’t yet know if we will end up with a game-changing treatment, but we do know that the inhibitors we’re developing are unlike any other approach that has been tried before,” said Field. “So far, laboratory studies have shown that our lead compounds work pretty well and have specificity for cancer over normal cells.”

The inhibitors have not yet been tested in patients, so the jury is still out on whether this approach will work. But because the inhibitors target a different signaling pathway than any current treatments, early laboratory results suggest they could potentially be used in combination with existing therapies or help patients who don’t respond to traditional cancer treatments. In fact, the researchers have already found some evidence that common chemotherapeutic agents work synergistically with some of the inhibitors under development.

Because of the research enabled by the V Foundation, Field has been able to secure several grants from the National Cancer Institute and other funders to continue studying the GOLPH3 pathway and to develop treatments that target it. His findings have also been published in top journals such as Nature and Cell, and he was a recipient of the NIH Director’s New Innovator Award and elected to the American Society for Clinical Investigation.