Translational Research in Cancer Treatments

Translational Research in Cancer Treatments

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Innovative cancer treatments at Harrington Discovery Institute are being led by Seth Field, M.D., Ph.D. Investigator, Harrington Discovery Institute, Director, Harrington Physician-Scientist Programs, Becky Hennessy Endowed Master Clinician in Breast Cancer Genomics, Professor of Medicine/Endocrinology and Senior Attending Physician at University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine. You will learn more about translational research to develop cancer treatments in his lab in this piece.

Translational Research in Cancer Treatments

Author of Blog: Seth Field, MD, PhD

Cancer is a horrible disease. Despite progress in some types of cancer, overall, cancer remains the second leading cause of death in the U.S. It kills indiscriminately, taking old and young alike. And, it affects everyone. I think there is no one that hasn’t been touched by cancer, taking friends, family, or battling it themselves. Clearly, we need to do better – and we are doing just that at Harrington Discovery Institute.

Cancer: A disease of abnormal cell proliferation

Normally, most cells in our body do not proliferate. Instead, proliferation is orchestrated by growth factors that instruct cells when it is time to proliferate. Examples include: (1) during the growth of tissues and organs during embryonic development, (2) during growth from childhood to adulthood, and (3) during wound healing.

These growth factors are small protein molecules that are released from some cells to regulate cell proliferation. Growth factor receptors act as receivers on the surface of cells to detect the presence of growth factors and consequently to trigger cell proliferation.

When growth factors engage a growth factor receptor, the cells will proliferate. Cancer cells have many ways that they can circumvent the requirement for growth factors including,

  • By producing their own growth factors,
  • By having mutations in the growth factor receptor that keeps it stuck in the “On” state to incessantly drive proliferation,
  • And by increasing the production of growth factor receptors so as to amplify their effect.

Growth factor receptors are now validated targets for effective therapeutics in some types of cancers. In HER2-positive breast cancer, the drugs Herceptin and Perjeta act by blocking the HER2 growth factor receptor. Likewise, in EGFR-positive lung cancer, drugs like Iressa, Tarceva, and Tagrisso, block the ability of the EGFR growth factor receptor to send proliferative signals.

Overcoming Limitations to Cancer Treatments: Understanding Cells Identifies New Targets

My lab has been doing research into the inner workings of cells, with the idea that one of the limitations in our ability to treat cancer is because we have a limited understanding of how cells work. It seemed to me, that if we understood better how cells work, we are likely to find new targets for therapeutics to treat cancer.

One of the things we discovered is a key part of how cells move proteins from inside the cell to the surface of the cell, a process called secretion. Watch the video below to see a quick movie of a protein that we have labeled with green fluorescence and we can watch it move from inside the cell to the surface of the cell.

That process of secretion involves a part of the cell called the Golgi apparatus or Golgi complex, or more colloquially, the Golgi. The Golgi looks like a stack of pancakes and acts as the cell’s shipping department. Protein molecules that we refer to as “cargo”, enter the Golgi at one end of the stack. Then, as they move along the stack they are sorted. At the other end of the stack, the cargo gets packaged into shipping containers that we call vesicles, where they are released from the Golgi for delivery to their destination, which for many the destination is the surface of the cell.

Among those cargoes are growth factors and growth factor receptors that go through the Golgi in order to be delivered to the surface of the cell. Their ability to function to drive cell proliferation absolutely depends on them being able to reach the surface of the cell. We discovered the cellular machinery that packages cargo into vesicles, involving a protein called GOLPH3. It turns out that GOLPH3, and all of the proteins that we identified as being part of this process, are all common drivers of cancer.

At least 20%, and maybe as many as 50% of cancers have activation of this GOLPH3 machinery, and it is important in many different kinds of cancers, including lung, breast, prostate, colorectal, pancreatic, and many other cancers.

We also know that interfering with this GOLPH3 cargo packaging machinery shuts down growth factor receptor signaling, and preferentially kills cancer cells. That made us realize that if we could develop drugs that inhibit this GOLPH3 cellular machinery that these drugs might serve as novel therapeutics for cancer.

We developed methods to identify chemical compounds that inhibit the GOLPH3 cargo packaging machinery. We screened 385,000 compounds, and identified 15 inhibitors.

Harrington Discovery Institute Impact: Accelerating to Viable Drugs

I then realized that, like most academic physician-scientists, I didn’t really know how to go from chemical inhibitors to a viable drug. I realized that I needed help from experts, and for that I applied for help from the Harrington Discovery Institute. Fortunately, I was selected for a Harrington Scholar-Innovator Award. The Harrington Discovery Institute’s mission is to accelerate promising discoveries into medicines for unmet needs, so that was the help that I needed. The Scholar-Innovator program is Harrington’s major diseases program, is open to proposals for any type of disease, including many that focus on cancer, like my own.

That award came with a minimum of two years of support, which included monetary support, but, more importantly, set me up with a team of experts with long and accomplished careers in the pharmaceutical industry who could provide advice on every aspect of drug development.

For me, I received advice on medicinal chemistry, which helped us to develop improved chemical compounds that are more potent and have less toxicity. I also learned about how to think about actually giving a drug to a person, and making sure that it actually arrives at the cancer where we need it to act.

Now, in our society, producing a new medicine for use in patients depends on pharmaceutical companies providing resources to fund the enormously expensive clinical trials that are needed to prove safety and efficacy of a therapy. Those companies will only fund those trials if they see that there is a financial incentive, and that depends on having solid protection of the intellectual property. So that is another thing that I learned about from my Harrington advisory team.

So, with the help of my Harrington team, we were able to develop improved compounds that effectively block GOLPH3-dependent secretion, block growth factor signaling, and kill cancer cells, while being well-tolerated by normal cells.

Our compounds show promise and important proof of principle, but are still not good enough to be medicines for use in people. We are working on new approaches to make better drugs.

A Home at Harrington Discovery Institute and a New Home in Cleveland

At the time of my first award from Harrington Discovery Institute, I was a professor of medicine at the University of California in sunny San Diego, where my career was going great. But as I learned more about what the Harrington Discovery Institute is doing, I realized the huge impact that their approach is likely to have on our ability to treat cancer and other diseases. And so, I was able to convince my wife and daughter to leave San Diego and move to Cleveland to join the Harrington Discovery Institute.

I’ve been and continue to be a pretty successful physician-scientist. My lab made many important discoveries, we published big papers in top journals, I won awards, I was well-funded by government agencies and private foundations, and served on many of their advisory boards. But, it was clear to me that what Harrington Discovery Institute is doing is absolutely unique. Many funding agencies provide monetary support. But, that is not sufficient to develop new medicines. Harrington Discovery Institute is unique in providing advice from experts on drug development. That is key.

I am convinced that the Harrington Discovery Institute’s unique approach - to team up academic physician scientists who have brilliant ideas with experts in drug development - that this team approach is the way that we will cure cancer.