Know Your Investigator

Sep, 2020

Dr. Chadi Nabhan recently caught up with Dr. Emil Lou, Associate Professor of Medicine in the Division of Hematology, Oncology and Transplantation, and Medical Director of the Clinical Trials Office – Solid Tumor Unit of the Masonic Cancer Center at the University of Minnesota. He is also a member of the Caris Precision Oncology Alliance™. The interview took place in July 2020.

Here are excerpts of the interview:

NABHAN: What got you into oncology, and specifically what led you to want to focus more on GI oncology?

LOU: In my high school and college days I developed a strong interest in becoming a scientist. I was already focused on cancer biology at that point but the physiology and biology of disease was really what I was mostly interested in. My motivation stemmed from not only the scientific aspect, but also from the personal experiences I had when some family members and close family friends died of cancer. Because I was initially a biology major in college and became interested in things that were more relevant to human physiology, I switched my major to biochemistry. Once I learned that there was such a thing as a physician-scientist pathway, I chose this route because to me it was the best of both worlds – I’d be able to be a basic scientist, exploring the scientific background of cancer biology, and I’d also be able to treat patients. This would all allow me to work toward applied research that would be meaningful for the human condition. In the end I wound up pursuing a combined MD/PhD degree with the intent of becoming an oncologist because of my fascination in cancer biology. There was also the humanistic side of caring for patients, which is combined with biology; both are critical and very complementary. As an oncology fellow at Memorial Sloan-Kettering, I rotated in clinic with many renowned expert GI oncologists, including Dr. David Kelsen, Dr. Eileen O’Reilly, and Dr. Ghassan Abou-Alfa, and others, all of whom made a very favorable impression upon me.

NABHAN: Right now, you’re at the University of Minnesota. Tell us how you spend your day – what does a day in the life of Emil Lou look like?

LOU: Sometimes scattered, sometimes more focused, but definitely diverse and never a boring moment. I self-identify as a physician scientist because it provides a lot of heterogeneity. I find the physician-scientist career pathway very stimulating as it affords me the opportunity to wear several hats. I’m in clinic two half-days per week, and outside of the clinic a large part of my responsibility and passion is running my lab. And a little fun fact is I’m also formally fellowship-trained and board certified in neuro-oncology. Over the past few years, my entire clinical focus has been in gastrointestinal oncology with a special clinical and translational focus on pancreatic and colorectal cancers. I also have a strong and growing interest in expanding novel translational research opportunities including genomic correlation of GI cancers by working with Caris and the POA. In addition, last summer I took on the position of Medical Director of our Cancer Center’s Clinical Trials Office-Solid Tumor Unit (STU). That role has been very educational and enriching for my career as well, and further expanded translational research opportunities.

NABHAN: What area of GI oncology is your lab focused on?

LOU: During my fellowship at Memorial Sloan-Kettering I was on the lab track in a cell biology lab. It was then that I made an observation that there were long protrusions connecting cells at long distances. The analogy I commonly use is that these protrusions are like skyways connecting buildings. The field ended up naming these things “tunneling nanotubes.” Our group was the first to demonstrate that these unique structures were present in intact tumors from patients, first in mesothelioma and lung cancers, and then in several other cancer types as well. I have focused on identifying their role in cancer for more than a decade now.

Most of my research is focused on the overarching issues of how cancer cells become chemo-resistant, more invasive, and what role cell communication plays in stimulating these processes. We have found that these nanotubes create actual cellular networks composed of cells reaching out to each other and creating vast clusters of cells that then synchronize to become more invasive and chemoresistant. This work connects very well with my interests as a translational scientist and a GI oncologist. For example, mutant RAS is prominent in ~20% of all cancers, is especially prominent in colorectal cancers, and is extremely prevalent in pancreas cancer. Today there’s more recognition than there was a few years ago that there’s intertumoral heterogeneity, even within tumors from a single patient, but how that heterogeneity comes about has not been well defined. So we postulate that these tunneling nanotubes are facilitating the communication of major drivers of cancer and resistance, including RAS. One example of GI cancer specific work we completed in my lab was published last June (Desir et al., Cancers 2019). It was the first demonstration that KRAS actually shuttles from cell-to-cell from cells that are harboring mutant KRAS to colon cancer cells that have wildtype RAS. That transfer actually induces a change in morphology in the phenotype of the cells to make them more invasive and likely to be chemoresistant. We think this functions primarily as part of a broader tumoral communication network that allows these drivers of resistance to amplify the signal throughout the tumor and other tumors, including spinoff metastatic tumors. We published a separate study in pancreas cancer in 2018 that showed these tunneling nanotubes are dense in other aggressive cancers like pancreas cancer, and linked to the fact that chemotherapy is a form of stress to pancreatic cancer cells. These cells reacted to chemotherapy as a stimulus for a stress response marked by production of more tunneling nanotubes, which then led to the acceleration of intercellular communication amongst these cancer cells. This and similar findings have opened up new avenues of exploration that forces us to reexamine our strategies and tactics in the clinic. I thought, “Wow, chemotherapy and the other ways we treat cancer may actually be detrimental, at some point, by producing a counterproductive response at the cellular and molecular levels that upgrade and worsen their invasive and metastatic potential, from a therapeutic standpoint, and buttress the tumor cells against future treatment options.” That’s how cells and the tumors are reacting to our best-intentioned treatments to attack them at the clinical level. There might be better underlying cellular explanations as to why these tumors become so aggressive and difficult to treat, and the explanation may lie, at least in part, with cellular, in addition to molecular, causes.

NABHAN: How do you summarize how the treatment of GI cancers has transformed over the years and where do you see it heading?

LOU: The evolution of GI oncology over the last decade centers upon improved sophistication of identification of genomic markers, better stratification, and more widespread availability of the necessary testing technology. The RAS issue is a great example of a paradigm where from the time of my initial training there was so little understanding of its implications for tailoring treatment options, and even more importantly to avoid unnecessary harm to patients in the case of patients with colorectal cancers harboring mutant RAS. The relation between RAS and EGFR mutations was less known. The knowledge emerged that there’s a subset of tumors that would react to these EGFR inhibitors as long as KRAS were not mutated. However, there are a number of variants of KRAS that do not act uniformly. A few years ago my colleagues and I reported a case of a patient with a missense mutation in KRAS whose tumors actually responded to EGFR inhibition. Although the alteration is relatively rare, it provides food for further scientific thought in terms of tumor heterogeneity and for the notion that not all RAS mutations are equal.

My answer of where we are and where we need to go is predicated more on how immersed we are in the field of molecular oncology. In addition, the twin in parallel that needs to be better recognized and will be better recognized is cellular heterogeneity. There’s recognition of heterogeneity as something that is well established when you go to basic science meetings and talk to basic scientists… and I live and breathe tumor microenvironment heterogeneity, but there’s so little recognition at the clinical level about heterogeneity and how to even attack this because we think of cancer as this great enemy. As an example, we give chemotherapy to pancreatic cancer cells in the lab and it reacts by forming the nanotube-based cellular networks to galvanize itself against the very drug we gave to try and kill the cancer. I think that overall with heterogeneity, recognition of cellular factors as well as the molecular factors are really going to be crucial to improving rational clinical trial design in the years to come. I think the “Holy Grail,” so to speak, is tailoring therapy to each individual patient. My hope is that in 5 or 10 years from now we’ll have achieved some that.

NABHAN: Do you see genomic sequencing becoming more mainstream, where all patients are going to have this? Do you think it’s going to be selected based on management? How do you see sequencing playing out in 5 to 10 years?

LOU: As a molecular and cellular biologist, I realize I have an internal bias and interest. But I also qualify that with some technical limitations that hopefully will improve tissue preparation and processing within the next 5 to 10 years. For any specimen that’s sequenced, the genomic profile is only as accurate as the quality of the specimen received. Also, from the scientific perspective of the tumor microenvironment, the genomic profile depends on what portion of the tumor is received, and to some extent probably whether it is a primary tumor specimen vs. metastatic. You can only work with what you have and for the safety of the patient in obtaining the tissue, but I think that’s something where if we’re not already there with universal genomic profiling, we need to be, at least to identify the genomic fingerprint as a starting point. Cell-free liquid-based testing and its ability to complement tissue-based testing, has advanced a lot in the past few years. As a clinician, I find it a potentially useful tool, but as a scientist I find value also in understanding genomics in the context of the tumor microenvironment and its architecture. There are great strides to be made in both.

For now and in the years to come, obtaining accurate genomic profiling will be crucial to the process of identifying actionable mutations once our ability to identify targeted drugs and integrate them into randomized trials catches up to our ability to identify molecular targets. Recent advances in cholangioracinoma is an example where identifying FGFR2 in some tumors can lead to significant therapeutic implications. With tumor-agnostic classifications, we are finally recognizing molecular subtypes as part of mainstream oncology in addition to the organ sites of origin. It is an exciting time to be a molecular oncologist!

NABHAN: What changes have you made in taking care patients during COVID19?

LOU: Early in the pandemic, I benefited from discussions with a number of prominent GI oncologists who generously shared ways they were adapting to the quickly shifting landscape. The set of tips was so useful for all of us that we compiled them into a document we published in April in JCO Practice Oncology to share with others: (https://ascopubs.org/doi/full/10.1200/OP.20.00239).

Our institution, like many, shifted very quickly to virtual telemedicine visits. If the patient doesn’t have video capability, we’re otherwise doing phone visit; all of which is done as much as possible to avoid or minimize the risk of this patient population being exposed to COVID. From the position of a clinical trials director, we really had to significantly modify our strategies when we had a pause of clinical trials to try and reestablish our clinical trials portfolio – and that’s been a challenge. But from a day-to-day practice, the virtual visit scenarios have really changed how we practice. I believe many positive changes to practice, including prominently telemedicine, will be well integrated with standard of care and clinical trials practice for years to come.

NABHAN: What do you do for fun when you’re not in the lab and not seeing patients?

LOU: Outside of work, my wife and I really enjoy traveling with our children and seeing different cultures firsthand. We’ve tried to instill in them our love of travel and have taken them internationally with us the past few summers. I studied in France twice as a student, so I have a special affinity for France and visiting Europe. The past three summers I was playing summer lacrosse in two different weekend leagues, but again due to COVID the league has been suspended this summer. Coming back to a sport I had played many years ago has really reawakened my interest to be proactive and forced me to get me out of the house and exercise more!

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Dr. Emil Lou

Associate Professor of Medicine in the Division of Hematology, Oncology and Transplantation, and Medical Director of the Clinical Trials Office – Solid Tumor Unit

Masonic Cancer Center at the University of Minnesota