Drugging the “undruggable” targets in GI cancers

Science Talks Podcast with white microphone on a dark blue background, surrounded by white icons representing various science fields/tools
Tucson native Dr. Rachna Shroff discusses her translational work to treat GI cancers.
Dr. Brittany Uhlorn, BIO5 Institute

Gastrointestinal cancers collectively represent one of the greatest public health challenges, accounting for more than one-quarter of all global cancer cases and more than 35% of all cancer-related deaths. Many of these cancers, including pancreatic and biliary, have been historically hard to treat. Dr. Rachna Shroff, Associate Dean of clinical and translational research and chief of GI medical oncology at the UArizona Cancer Center, discusses her genomic profiling approach to developing personalized treatments for cancer patients. She also shares how she supports other researchers and clinicians in connecting their findings at the bench and bedside to discover new therapies through her role as director of the Arizona Clinical Trials Network.

You're a leading expert in GI cancers, specifically in biliary cancer. Tell us a bit more about these diseases and where your passion for studying and treating them stems from.

GI cancers are a global problem. They’re increasing in incidence, and not just for colorectal cancer, which has been a very common and high cause of cancer related mortality in this country, but also for diseases like biliary tract cancers, liver cancer, and those of the upper GI like gastric and esophageal cancers. 

My interest in GI cancers came purely from finding the right mentorship. When I was in my fellowship at MD Anderson Cancer Center in Houston, there were leading experts and fantastic physicians taking care of GI cancer patients. Being in their clinics and learning how they were bringing novel drugs to these patients through their clinical trials is really what drew me into the GI cancer space. 

The other reason is that at the end of the day, unfortunately, the outcomes are quite grim for a lot of GI cancers. As somebody who knew that she wanted to do clinical trials and drug development, this seemed like a space where there was a huge need for more people working, thinking, and trying to be creative about novel clinical trial designs to help improve the outcomes for these patients. 

GI cancers are a very heterogeneous group, so to say that I specialize in GI cancer, that includes the esophagus all the way down to the colorectal and anal areas. That's a lot of different tumors – somewhere from 13 to 17, depending on how you classify the tumors. 

I decided to create a niche for myself to become an expert in treating these patients and in coming up with clinical trials for these patients. My focus has been in pancreatic cancer and biliary tract cancers, which are cancers that start in the bile ducts, or the plumbing of the liver. 

What's been great about the interest that I have in biliary tract cancers is that it coincided with this revolution in next generation sequencing and understanding the importance of the genomic landscape of these tumors. It's translated into potential targeted personalized therapies for these patients. It's been a really nice melding together of science and clinic in terms of my two passions, along with writing and designing clinical trials.

You mentioned that the incidence of these cancers is on the rise. What accounts for that?

The rising incidence is two-fold, specifically for biliary cancers. 

First, we're getting better at classifying them. They're a little bit hard to diagnose, but now through improvements in pathology and histology, as well as things like next generation sequencing and profiling, we're getting better at radiographically characterizing these tumors. 

The other factor contributing to increased cancer incidence in both the pancreas, as well as biliary cancers, is lifestyle. We know that the risk factors for these diseases are things like obesity, metabolic syndrome, diabetes for pancreas cancer, and liver cirrhosis for biliary tract cancers. In this country, there's an increasing incidence of fatty liver disease and nonalcoholic steatohepatitis, which are all risk factors not only for developing cirrhosis and primary liver cancer, or hepatocellular carcinoma, but also for developing biliary tract cancer. 

How might you take the genetic profile of a patient or group of patients to create a personalized therapy?

GI cancers are becoming so exciting for clinical trialists because they’re becoming the model for precision medicine and precision oncology. In fact, the American Society of Clinical Oncology named the breakthrough of 2020 as the concept of molecular profiling and genomic profiling of GI cancers because it has led to so many more FDA drug approvals for our patients. 

The concept is that we know that cancer is caused by mutations. Some of these are germline mutations that increase your risk of developing a hereditary syndrome that can be associated with things like colorectal cancer or pancreas cancer, but more commonly, there are somatic mutations that are acquired over your lifespan. A lot of tumors have overlapping somatic mutations that are not necessarily targetable with drugs. 

KRAS is a very commonly mutated protein found in a number of different tumors, and about 90% of pancreatic cancers have KRAS mutations. Historically this has been an undruggable mutation, but now we're seeing a fantastic wave of inhibitors that are being used in lung cancer. 

When it comes to biliary cancers, we found just by simply prospectively profiling and doing next generation sequencing on patient samples, anywhere from 30 to 40% of patients with biliary tract cancers actually have potentially targetable molecular alterations. 

From this knowledge, we’ve gone from having zero FDA approved drugs to in the last two years to a potential of three. It's revolutionary for these patients, and it's really amazing to see the rapidity with which this trajectory has changed.

It's rewarding work because then you see it implemented in clinic, there's nothing like it. You see patients who historically had survivals that were nothing to write home about, and now you have multiple drugs to be able to offer them. To see in real time how that impacts the patients that you're treating every day is incredibly fantastic.

Tell me more about the clinical trial enterprise and your role in it. 

The mission of the Clinical Research Program at the Cancer Center is to translate University of Arizona science into patients and to translate that to our clinic. What's been great to see in the last few years is there's been a fantastic momentum in that direction. Last year, we accrued more patients to clinical trials than we have in our entire history. 

My job as the director of the clinical trials office is to help support the infrastructure that is needed to make sure that all our clinical investigators can open the trials that they want, that they can put patients on trials, and that we have the people, legwork and support to be able to do that in a compliant and safe way. 

How does your clinical work - practicing medicine and being with the patients - help translate to the research and clinical trial aspects of your career?

My mentor at MD Anderson gave me what I think is the best advice, and I give it to all the fellows and trainees that I meet. 

When I first started on faculty at MD Anderson, I'd been a fellow there, so I was a little impatient to get a trial going. I was this eager beaver that would come to his office and say, “Give me something!” 

He told me that number one, it's a marathon, not a sprint. Drug development and clinical research take a lot of time from start to finish. But he also said that the first thing that I needed to do was to learn how to take good care of these patients. Every single clinical trial and every single clinical research question is born out of the clinic, so until you understand the gaps and the needs and the opportunities for clinical research in GI cancer patients, you're not going to think of the clinical trial question.

He's right. That was the best advice I could have been given. 

Being in clinic is where I'm reminded daily that yes, we've made progress, but we have leaps and bounds to go. And it reminds me of where the needs are. For instance, immunotherapy has been such a revolution in the world of cancer treatment, and it's changed the face of melanoma. It's changed the face of lung cancer. It's even changed the face of gastric and esophageal cancers. It has not done that yet for pancreas cancer, and so to me, that is a big gap. One of the things that I focus on is trying to understand how to turn historically cold tumors hot, and make pancreas cancers more sensitive to immunotherapy

You have so many different roles at the university, but outside of work, what hobbies do you have? Why is it so important for you to spend time away from your work and recharge?

My mentor here, Dr. Julie Bauman, always tells me that the “work-life balance” phase is probably wrong. It's really about “work-life integration,” so I’m focusing on that.

I have two beautiful children - a 12-year-old daughter and an eight-year-old son. My husband's also a faculty member at the university as a physician and an allergist. We try to be very aware and cognizant of the need to unplug and disconnect. He tells me that he's better at it than I am, but I recognize that about myself. I recognize that I do have to take my laptop on vacations, just so that I don't have an email hole that I have to dig myself out of, but we love to travel. Pre-COVID, traveling was a great way for us to really unplug, recharge, and to spend quality time together. 

I use exercise as my endorphin-charging type of activity. I try to start all my days with some sort of workout. I also dance - I've been a dancer ever since I was a little kid here in Tucson.

Overall, the most important thing has been to make sure that work doesn't take me away so much from my family time. My kids are at that funny age, so we like to try to spend as much time together as we can.

About the University of Arizona BIO5 Institute
The BIO5 Institute at the University of Arizona connects and mobilizes top researchers in agriculture, engineering, medicine, pharmacy, data and computational science, and basic science to find creative solutions to humanity’s most pressing health and environmental challenges. Since 2001, this interdisciplinary approach has been an international model of how to conduct collaborative research, and has resulted in disease prevention strategies, innovative diagnostics and devices, promising new therapies, and improved food sustainability.

LAND ACKNOWLEDGEMENT We respectfully acknowledge the University of Arizona is on the land and territories of Indigenous peoples. Today, Arizona is home to 22 federally recognized tribes, with Tucson being home to the O’odham and the Yaqui. Committed to diversity and inclusion, the University strives to build sustainable relationships with sovereign Native Nations and Indigenous communities through education offerings, partnerships, and community service.