From bedside to bench and back again

Emil Lou microscope

Masonic Scholar combines clinical experience with research smarts in quest to end cancer drug resistance

One patient who will always stick with Masonic Scholar Emil Lou, M.D., Ph.D., is a 51-year-old man he treated with a rare and incurable form of brain cancer called medulloblastoma.

“This man was in a wheelchair, had multiple dime-sized tumors in the base of his brain that couldn’t be removed, and was experiencing constant nausea and vomiting,” recalls Lou.  

Because medulloblastoma is more common in children, Lou’s team briefly considered what was at the time the standard treatment for kids: surgery, followed by radiation of the entire brain and spine, and then chemotherapy. But “he was so ill that I thought he might die if I gave him chemotherapy,” Lou says.

So Lou and his team began to explore other options.

Knowing from his research that a mutation in a protein called sonic hedgehog is common in adult medulloblastoma patients, Lou dug into the literature and discovered that a recently approved drug, called Vismodegib (Erivedge), was being used to target the mutation in patients with a form of skin cancer called basal cell carcinoma. He also found that the drug had been tested in early-phase clinical trials for patients with medulloblastoma.

Lou obtained the treatment for his patient for compassionate use. Remarkably, after just four months of treatment, he found that the man’s tumors had completely disappeared. Today, nearly four years after his initial diagnosis, he remains cancer free and is in “phenomenal” shape, having made a near-complete recovery.

Without his background in molecular analysis, an approach that underpins much of his work as a physician-scientist, Lou may never have known to try Erivedge and his patient may not be alive today.

Bridging the gap between research and care

Emil Lou isn’t your average doctor.

As a brain cancer expert and gastrointestinal oncologist at the U’s Masonic Cancer Clinic, Lou treats cancers that he describes as some of the “worst of the worst.” And often, many of the available drugs for these cancers fail time and again.

But as a scientist who leads groundbreaking research on molecular and cellular interactions, Lou is also uniquely equipped to find out-of-the-box solutions to some of the most urgent challenges faced by patients like his.

Today, he is combining clinical experience with research smarts to answer one central question: how do the cells and molecules in our bodies contribute to cancer drug resistance and what can we do to intervene?

A challenging path

Emil Lou headshotLou has always been interested in science.

As an undergraduate, he majored in biochemistry because he was interested in a career in cancer research. But around the same time, as he and people close to him began losing loved ones to cancer, he felt a tension between wanting to make research discoveries and wanting to take immediate action to make a difference in patients’ lives.

“I was torn by the idea that if I discovered something in the lab, I might not be able to do anything about it if I wasn’t a physician,” he recalls.

So Lou set out to merge his passions for research and care as an M.D. / Ph.D. student at Upstate Medical University in Syracuse, New York, and later as a postdoctoral fellow at Memorial Sloan Kettering Cancer Center.

At a time when few students were pursuing combined degrees and even fewer were interested in cancer care, his path was challenging, to say the least.

“When I first started medical school, there were three of us who wanted to be oncologists. Classmates took pity on us because of how depressing they thought the field was,” says Lou. “At the same time, going to school for dual M.D. and Ph.D. degrees was an endeavor that often took seven to ten years to complete.”

But Lou stuck with it and after gaining extensive research expertise in cellular and molecular biology, along with years of clinical training and experience in treating gastrointestinal and brain cancers, he is thrilled with how far the field has come.  

“There’s been a revolution in improving our understanding of what drives aggressive cancers at the cellular and molecular levels, and that knowledge has led to smarter approaches to designing drugs that work effectively. Research has really changed how we treat cancer in the clinic, rather than just in theory,” Lou reflects.

“Melanoma and lung cancer are perfect examples," he continues. "Metastatic forms of these diseases were incurable and basically death sentences a decade ago, but now every few months the FDA’s approving another drug, and these drugs are working effectively.”

Digging in on drug resistance

Today, Lou runs a thriving lab and clinic at the U that allow him to marry cancer research and patient care. He focuses on patients with gastrointestinal cancers—including pancreatic, colorectal, stomach, and esophagus cancers—and sometimes treats those with brain cancer or brain metastasis.

At any given time, his lab leads around half a dozen studies.

Most of them focus on the most drug-resistant cancers that are difficult to treat and are informed by patients he is either treating or has treated at the Masonic Cancer Clinic. And all of them dig into the cellular and molecular mechanisms that might stop a cancer treatment from being effective.

Because of their commitment to connecting real patient cases to their lab-based research, Lou and his team have made important discoveries that are shaping how some of the most challenging cancers are treated. Recent examples of their success include:

  •  Discovering a rare mutation in the RAS gene associated with aggressive forms of colorectal cancer. Mutations of this gene prevent two commonly used colorectal cancer drugs from working. Because of this finding, doctors now test for this mutation to better customize each colorectal cancer patient’s treatment regimen. This finding also has significant implications for treating cancer more broadly because RAS mutations are present in 30 percent of all cancers, including 40 percent of colorectal cancers and 95 percent of pancreatic cancers. Currently, there is no clinically available drug that successfully targets RAS. “If we can better identify mutant forms of RAS, we can begin to develop more effective approaches to preventing the progression of these cancers,” says Lou. “Finding a way to block RAS would be a big game-changer.”
  •  Finding that hypoxia, or a low-oxygen tumor environment, increases connections between large volumes of ovarian cancer cells that are resistant to chemotherapy. These cellular connections, studied extensively by Lou over the past decade and known as tunneling nanotubes (TNTs), pass along signals or molecular “cargo” that may speed the spread of cancer. To learn more about TNTs, see the following section.

Next steps: cellular connections in cancer’s spread

Today, Lou continues to apply what he knows about cellular and molecular communication to the quest for better cancer therapies.

He is especially focused on one big idea: that distant cells create connections between each other to speed the spread of cancer and that disrupting these connections could lead to better patient outcomes.

Eight years ago, during his postdoctoral fellowship, Lou and his team became the first in the world to prove that these connections between distant cells, known as tunneling nanotubes (TNTS), exist in human tumors.

“Initially, we found TNTs in an aggressive lung cancer called mesothelioma,” explains Lou. “Over time, we expanded our investigations and detected TNTs in other tumors such as sarcoma, pancreatic, colorectal, and ovarian cancers. We consistently found that all of these tumors have TNTs and that they are probably using these connections to communicate messages or signals that allow tumors to grow more effectively.”

Now, having confirmed the existence of TNTs in cancer, Lou has made it his mission to unearth how they facilitate cancer’s spread.

His team has spent the last six years perfecting reliable methods for analyzing TNTs and is paving the way as a world leader in studying TNTs in cancer drug resistance.

In 2014, for example, they became the first group in the world to report that TNTs spread microRNAs, small genetic codes associated with cancer drug resistance, across vast networks of cancer cells, making these cells even more destructive. “We and others have proven that this is an important function of TNTs,” explains Lou. “We now know that they cause microRNA to move rapidly from cell to cell, basically infecting other cells and making them drug resistant.”

And this discovery is just the tip of the iceberg. “It took five years to get down to the right techniques for studying TNTs,” he says. “We’re finally at the point where we’re rolling up our sleeves to fully understand what they do. Now the fun begins.”

Building from the ground up: the impact of Masonic support

Lou, who has been a Masonic Scholar for six years, will be the first to admit that it has not been easy to get his research off the ground, especially when it has come to moving into uncharted territory with the study of TNTs.

“When I first started applying for jobs, senior researchers were warning me against pursuing this line of research, saying it was too risky because it was so new and unproven,” he recalls.

But six years ago, Lou joined the U’s faculty after he presented a compelling roadmap of where he was hoping to go with his research on cancer drug resistance and TNTs, in particular.

He has since built a robust translational research program from scratch, something he could never have done without Masonic support.

“During my first few years, I needed to develop methodologies for studying drug resistance and build a brand new lab from the ground up,” Lou says. “Because some of our research was so untested, receiving support from the Masons was the only way I was able to do this. The door would have been completely shut without it.”

“Now, because we’ve laid this foundation, we’re in a much stronger position. Editorials about our research have been written up in journals like Nature and because of our work, other groups have approached me as a physician-scientist for ideas that could help combat drug resistance,” he continues. “We’re gaining momentum and riding the wave. The Masons should know that none of this would have been possible without their ongoing support. My research team and I are extremely grateful.”

Watch a recent episode of Exploration Health, which features Lou’s efforts to stop stomach cancer.

Web figure

Cellular skyways

In perfectly Minnesotan fashion, Masonic Scholar Emil Lou likens tunneling nanotubes (TNTs), the long, tunnel-like extensions that he has shown connect distant cancer cells, to skyways.

“Imagine two buildings that are not immediately next to each other, but connected by a protected skyway,” he explains. “If the weather is frigid, you don’t need to put on your winter clothes to walk from one building to another, and as long as you keep walking, with virtual certainty, you will make it to the other side.”

“Cells do this too by creating TNTs as a form of cellular social networking,” he continues. “They form these tunnels to protect themselves and to reach out and touch other cells, passing signals or molecules to one another. The end result is an amplified signal that makes surrounding cells more invasive and more likely to become resistant to drug therapy.”  

Photo credit: Lou E, Fujisawa S, Morozov A, Barlas A, Romin Y, Dogan Y, et al. (2012) Tunneling Nanotubes Provide a Unique Conduit for Intercellular Transfer of Cellular Contents in Human Malignant Pleural Mesothelioma. PLoS ONE 7(3): e33093. Link

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