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Q&A with Professor Frank McKeon

By Lisa Merkl

Texas is on its way to becoming home to some of the most exceptional cancer expertise in the country. The University of Houston is very much part of that equation. Thanks to a sizeable grant from the Cancer Prevention Research Institute of Texas (CPRIT), UH was able to recruit pioneering cancer specialist Frank McKeon, M.D., Ph.D. In addition to the $6 million provided by CPRIT, UH is committing $4.6 million toward his hire. Before coming to UH and establishing the Somatic Stem Cell Center, he previously was affiliated with Harvard Medical School and, most recently, the Genome Institute of Singapore. McKeon offers insight into his research and vision for the future.

Q. Why did you come to Houston?

A. My wife, Wa Xian, and I were in Boston for a number of years and then went down to Singapore, but as the family started to grow, we wanted to get back to the U.S. It’s very clear to us that Houston already has the largest medical center in the world, and the efforts and innovation are incredibly focused on extending that to a wide array of technologies and discoveries that leverage all those institutions, including the University of Houston. It’s clear that Houston is the fastest growing center right now. The other two big ones – Boston and the San Francisco Bay Area – are pretty established at this point, but Houston still remains the Wild West with probably the greatest dynamic range right now for growth.

Q. What drives your research?

A. I work together with my wife, who is at the Institute of Molecular Medicine at UT Health, and we’ve been developing technologies for looking at organ-specific stem cells. These are stem cells that reside in all of our tissues, and there’s not much known about them. The challenges in identifying appropriate stem cells are quite broad, such as in addressing chronic lung diseases, liver fibrosis and end-stage organ disease in need of transplants. We need a cell-based treatment for all of these. It’s also very important to develop disease models that faithfully reflect the disease pathology, which we don’t currently have.

Then there’s the problem of cancer. With cancer, we need to better understand the small number of cancer cells that actually contribute to a tumor and should be targeted, as well as an even smaller fraction of cancer stem cells that give rise to resistant disease. We know how to kill 99 percent of most cancer cells, but we don’t know how to get rid of the remaining fractional component of resistant cells.

Another area of particular interest in our lab is looking at precursors of major lethal cancers. The reason for going after precursors is that they typically exist for 20 years before an aggressive metastatic cancer arises. In some cases, we can see these precursors. For instance, with an endoscope, we can see a precursor for esophageal cancer, called Barrett’s esophagus. We can keep an eye on these abnormal cells, but they’re not cancer cells and we don’t know how to kill them. They’re the visitors that come before and have the potential to get loose, so we need ways of killing them, but it’s a different realm than killing cancer cells, because they’re more like normal cells. The question then becomes how to identify the ones with high risk. The same scenario takes place with ovarian, pancreatic and gastric cancers. Typically, cancers arise from these precursor lesions that take two decades before becoming cancer. So, we have this window of two decades to stop a cancer, but we’re not paying attention to it in current practice.

The central focus of all these questions is how to clone stem cells. If you can clone them, you can start to look at organ regeneration. Even cancers have stem cells. You can deconstruct a tumor into its various stem cell components, identify the ones you know how to kill, as well as the subset you don’t know how to kill, and figure out how to do it.

Q. What role does your CPRIT grant play in this?

A. CPRIT supports this notion that cancers take decades to become dangerous and that many of us have these precursor lesions that are not going to kills us, but they may someday. Most cancers have at least a two-decade window where these precursor lesions are slowly developing, and they’re not malignant nor classically cancerous, but they have stem cells in them that keep them regenerating and growing in abnormal ways, slowly acquiring mutations. We’re taking an unusual approach to cancer, but it’s a preventative approach. We need to understand these precursors and stop them in their tracks, rather than waiting until they get to be something that is a real medical management problem, such as trying to stop a metastatic cancer, which is very tough. We’ve cloned a few of them for Barrett’s esophagus, as well as pancreatic and gastric cancers. We’re now delving in to what kinds of mutations they have and how closely they resemble cancer.

Take Barrett’s esophagus, for instance. Three million Americans have this condition and only about 5 percent of them will develop a difficult-to-treat cancer. What we don’t understand is which ones will progress to a cancer and which ones will stay indolent. In our study, we cloned the stem cells from each of these precursor lesions from each patient and looked at the complete genomic analysis.

We recently finished a study analyzing 12 patients’ stem cells from Barrett’s esophagus. In two of the patients, we saw mutations that looked very similar to cancer, yet were not classically cancer cells. That tells us those cells need to be dealt with. The other 10, however, had no mutations whatsoever, yet they already formed this identifiable columnar-shaped precursor lesion. With the latter group, the condition is not likely to progress to anything life threatening, so we wouldn’t want to overtreat. We can’t take all three million Barrett’s esophagus patients with just this one precursor lesion that could lead to esophageal cancer and throw everything at them. Overtreatment creates tremendous problems for patients. The key is finding out whose condition is on the verge of turning into a lethal cancer and which ones can relax.

Q. How will your research benefit with this move to Houston and UH, in particular?

A. The collaboration opportunities are endless. Here on campus in the Science and Engineering Research Center alone, there are some of the best chemists and biomedical engineers in the world just one floor up. We want to work with them to develop drugs for these stem cell models of disease, whether it’s cancer, inflammatory bowel disease or COPD. Another avenue we want to investigate is with the researchers studying nuclear receptors and cell signaling, who play a key role in the maintenance of the immaturity of these stem cells. Then, there’s the genomics efforts going on around the university, whether they’re our biology and biochemistry colleagues right next door or the researchers across campus in the Health and Biomedical Sciences Building. Then, of course, if we go nearby to the Texas Medical Center, there is tremendous firepower in nanotechnology, engineering and chemical engineering. This is where this work is going to go. We can provide the stem cells, but it needs the microfluidics and computational efforts. There’s just so much here at the University of Houston and in Houston, in general, augmented by the largest medical center in the world. The direction UH is taking toward having a larger medical presence is just perfect. I see this as very exciting.

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