By Rich Soll, Senior Advisor, Strategic Initiatives at WuXi AppTec (@richsollwx)
Dr. Sandy Markowitz – whose work has transformed our understanding of how colon cancers develop, leading to new ways to assess risk and detect cancers early – is on a mission to turn more of his renowned research into treatments for patients. One way he hopes to accomplish that is through his year-old start-up, Rodeo Therapeutics, whose mission is to make tissue regeneration a reality.
The Seattle-based biotech, which raised a $5.9 million Series A round from Accelerator Corporation in 2017, has been focused on developing a treatment for inflammatory bowel disease. The company is currently working on creating drugs that inhibit an enzyme called 15-PGDH, which has been shown to speed up regenerative processes. Morkowitz co-founded the company with distinguished collaborators Dr. Stanton Gerson, Director of the Case Comprehensive Cancer Center and the National Center for Regenerative Medicine at Case Western Reserve University; and synthetic chemist Dr. Joseph Ready, Bonnie Bell Harding Professorship in Biochemistry at the University of Texas Southwestern Medical Center.
Meanwhile, Markowitz – the Markowitz-Ingalls Professor of Cancer Genetics at the Case Western Reserve University School of Medicine, and the head of the Cancer Genetics Program at Case Comprehensive Cancer Center – continues to spend copious amounts of time in his lab, where he and his team are striving to identify key genetic causes of colon cancer and to develop better ways for prevention, early detection, and treatment of this disease.
Markowitz is also Principal Investigator of the Case GI Cancer SPORE, an NCI Designated Specialized Program of Research Excellence in Gastrointestinal Cancers. The Case GI SPORE, that is one of only three such NCI funded centers in the country, works on an array of projects, including determining the role of the 15-PGDH tumor suppressor pathway in colon cancer and developing new anti-cancer drugs that target this pathway.
In 2017, Markowitz received the NIH Outstanding Investigator Award for making many landmark discoveries in the genetics of gastrointestinal cancers. His research identified two key colon cancer tumor suppressor genes, TGF-beta-II and 15-PGDH, that explain how and why colon cancer develops in certain families in whom the disease is inherited. Markowitz also pioneered the development of the first stool DNA tests for early detection of colon cancer and the first esophagus DNA test for early detection of Barrett’s esophagus (a precursor to esophageal cancer).
I recently had a lively conversation with Markowitz, who explained the strategy behind his translational research, gave kudos to Cleveland’s robust ecosystem for fueling technology and innovation, and shared his insights on how industry is moving toward more impactful science.
Rich Soll: I’d like to start with the GI SPORE program. Can you tell me about the center and its accomplishments to date and how it relates to your research?
Sandy Markowitz: SPORE is an acronym that stands for a specialized program of research excellence, and the NCI creates these across all different cancers. We’re one of three in the country that have been supported to do studies in GI cancers, and this is our seventh year holding that designation. We have commitments to support us at least through year 11.
The purpose of SPOREs is overtly translational. They are meant to make observations that can be directly turned into diagnostics or therapeutics and demonstrated in patients. Our SPORE has given rise to a number of clinical studies, one of which has to do with a discovery and clinical trial demonstration of the diagnostic method for early detection of Barrett’s esophagus. A second has to do with a targeted therapy for PIK3CA mutant colon cancer, where the SPORE has shown these cancers are addicted to glutamine and where we have now initiated a human clinical trial of treating these cancers with an investigational glutaminase inhibitor.
A third program had to do with the 15-prostaglandin dehydrogenase (15-PGDH) pathway where the SPORE initially demonstrated that the pathway plays a key role in the response of colon stem cells to colon damage, and this capacity can be modulated for purposes of cancer prevention as well as for tissue healing. That’s given rise to studies where we’ve shown that you can use this pathway as a predictive biomarker for identifying individuals in whom aspirin is or isn’t effective in reducing colon cancer. It has also given rise to our efforts to drug the pathway, which in our preclinical mouse models, shows benefits for treating colitis and potentially also as a treatment for accelerating the return of bone marrow after a bone marrow transplant, as well as healing other damaged tissues in models of other human disease states.
Rich Soll: How did you first get interested in the 15-PGDH? How does that come into play?
Sandy Markowitz: One of the contributions that my lab made, in fact some years ago, was we discovered the first mutation that inactivated TGF-beta signaling in human cancer, and we showed that the inactivation of TGF-beta is a hallmark of human colorectal cancer.
We’ve been interested in for a very long time in why the TGF-beta pathway is selected out for this exquisite pressure for mutational inactivation in colorectal cancers. So, we did an informatics study to identify downstream effectors of TGF-beta in the gut, and we identified 15-prostaglandin dehydrogenase (15-PDGH). What we found was that TGF-beta turns 15-PGDH on in the gut, and that 15-PGDH is itself a pretty robust tumor suppressor in the gut. One of the ways that it works is by regulating stem cells and their response to injury in the gut. So, we originally discovered 15-PGDH by predicting that it would be an effector of TGF-beta and would provide TGF-beta a mechanism to control a key aspect of gut biology by regulating the response of stem cells to damage.
We also speculated that 15-PDGH inhibition would be protective to mucosal damage. This idea was ultimately proven correct both by knockout studies and by using a small molecule 15-PGDH inhibitor that we identified together with Joe Ready. Our studies with the inhibitor showed that it could protect from tissue damage or could speed the resolution of tissue damage in a variety of different model systems in which we tested it, including protecting from colitis, speeding the recovery of bone marrow after a marrow transplant, and speeding the regeneration of the liver after liver surgery. The inhibitor allowed us to interrogate the 15-PGDH pathway quickly and easily in a bunch of different organs and to show that we had elucidated a pathway that was conserved across multiple tissues and appeared to be just hardwired into control of tissue stem cells throughout the body.
Rich Soll: So, 15-PGDH is uniquely positioned?
Sandy Markowitz: It’s a really interesting pathway. It plays a role in colon carcinogenesis and potentially in colon cancer prevention. But it also plays a very robust role in tissue regeneration. And I think we’re able to separate those two aspects out and take advantage of each one of them in the right context.
Rich Soll: Rodeo was launched with a Series A financing of $5.9 million and you are actively engaged in the program as a founder. Can you tell us more about the company?
Sandy Markowitz: Rodeo is aimed at bringing small molecule15-PGDH inhibitors forward and qualifying them for clinical trials in human beings in the indications that we’ve described in our papers – colitis and IBD, where it would act in a novel way that is not immune suppressive, and in bone marrow transplant for the purpose of speeding the recovery of white counts and neutrophils and preventing many of the lethal complications of bone marrow transplant that arise due to patients being set up for infection because their white cells are absent for many days following the transplant procedure.
Rich Soll: Your interaction with CROs actually predated Rodeo. How has this brought value to you and your research?
Sandy Markowitz: WuXi has been invaluable, essential, indispensable and highly enabling. Before Rodeo, Joe Ready and I were working together to try to advance the chemical biology of 15-PGDH inhibitors, and we had support from several sources, including the SPORE, an NIH program called the National Center for Accelerating Innovation, and from our local drug development efforts at the Case School of Medicine and at University Hospitals Cleveland Medical Center’s Harrington Discovery Institute.
We turned to WuXi very early in that work to take on scale up synthesis of the very first compounds that were developed in Joe Ready’s lab and that were sent to me for biological characterization. WuXi helped us with the scale up synthesis and chiral resolution of those compounds to create the amount of compounds that we needed to do the early biology and early safety studies that we were pursuing with our initial NIH support.
After Rodeo’s formation, that relationship with WuXi grew and deepened. Today, we are leveraging a number of capabilities at WuXi. These include Wuxi’s chemistry and bio-assay capability that are helping us characterize new compounds plus WuXi’s DMPK and the tox capabilities that are helping us further profile the acceptability and the drug-like properties of new compounds. We feel fortunate to be able to partner with WuXi.
Rich Soll: Rodeo is not your first entrepreneurial experience, but it is your first therapeutic company, correct?
Sandy Markowitz: That is correct. My background is as a medical oncologist. So, I have certainly had a strong impetus to try to see if things that we’ve done in the lab can be brought forward in practical ways that could benefit human beings. We’ve actually had a fairly reasonable track record of trying to make these contributions. For example, my laboratory was part of a team was that worked out the genetics of an inherited form of colon cancer called Lynch syndrome. My lab was one of the labs that then showed that there were individuals whose colon cancers weren’t inherited but still developed by targeting and methylating the same genes that are involved in Lynch syndrome. My lab was awarded a patent on a diagnostic test to recognize this form of colon cancer. A number of major diagnostic laboratories, including Mayo, have used the methods of this patent for clinical management of patients and to distinguish this form of colon cancer that is a molecular mimic of Lynch syndrome but does not have the risk of being transmitted to other family members.
That experience led my lab to a more general interest in the diagnostic uses of methylated DNA in colon cancer, and we were one of the first groups to invent a method to be able to detect the presence of colon cancer by testing stool DNA for methylated changes that we identified as diagnostic of cancer. We licensed that technology to Exact Sciences over a decade ago now. Exact Sciences and LabCorp used that technology to create the very first stool DNA test for detecting colon cancer. It was brought onto the market commercially as ColoSure via a joint venture between Exact Sciences and Lab Corp. ColoSure was the predecessor and the forerunner for the current Cologuard test, which is also based on detecting methylated DNA in stool and is now an FDA approved product.
Most recently we’ve taken that concept of using methylated DNA as a way to detect the presence of cancers in the body and have used that to develop a way to detect the early changes in the esophagus that are precursors for esophageal carcinoma. We first developed a DNA methylation-based panel for recognizing changes that are present in esophageal cancers and precancers. We also invented a companion device which is a little swallowable balloon that allows obtaining a sample from a person’s esophagus without having to do an endoscopy. We’ve just created a new startup company called Lucid Diagnostics to commercialize the technology. Lucid is a subsidiary of a company called PavMed, which is a publicly traded company.
So, we’ve had a strong track record in the lab of trying to do translational work and get it into patients; but much of it has been on the molecular diagnostics side. What was new for us with Rodeo was the opportunity to do a therapeutic and see it become a spin-off or start up. And of course, the therapeutic has a real opportunity to make a difference for patients, and we’re really excited about it.
Rich Soll: If you look at the landscape, what kind of changes and trends have you observed in either conducting research or accessing money for research, and how has the environment changed over time?
Sandy Markowitz: Well I would say there is a whole lot more ‘big science’ now than when I first started out, that more and more of the impactful science is being done by collaborative teams that can bring together different ways of looking at a question – they’re molecular, they’re biochemical, they’re pharmacologic, and genetic and informatics. No one person has all those skills and all those capacities. You see papers now with many more authors and with many more technologies being used to look at a problem. Science is bigger in scope than it used to be, which is both more demanding but also a lot more fun.
Science has gotten much more expensive too; to publish a paper in Science is probably a million-dollar investment if not more. And of course, translation from a research bench and toward human beings is more capital intensive. I think there’s a much greater interest now in trying to translate. I think there is much closer relationship now between academia and CROs and pharmaceutical companies than there was when I started out in research.
There’s much more of an interest in the impact that you make with R&D. And again, that creates more opportunities and it also entails dealing with much greater capital needs of translation and of bringing projects to a level of maturity that you can interact with a CRO or a biotech.
Rich Soll: What’s the entrepreneurial environment like at Case Western and what does the local ecosystem also look like?
Sandy Markowitz: Case provided tremendous support for this effort. In the early phases, pre-Rodeo, we had funds that were provided to us by the Case school of medicine which has a program to advance human health that provides funds specifically for translation and commercial efforts. We had funds from University Hospitals Cleveland Medical Center through their Harrington Discovery Institute to encourage drug development and commercialization. We had a mentorship advisory committee from the Harrington of individuals who had been veterans of big pharma to help us understand how one develops a drug and what level of maturity is required for a program in order to make it of interest to biotech entrepreneurs. Plus, we have in Cleveland an NIH funded center, the National Center for Accelerating Innovation, that also invested in us.
For Lucid, we had investments from the Coulter Foundation that has a program at Case to encourage devices and innovation, and we had investment from the state of Ohio whose Third Frontier program encourages development of technology in Ohio. So, it’s really a very rich local ecosystem in terms of a lot of interest in helping people bring technologies forward into the marketplace.
Further, I’m just delighted that we’ve now been afforded the developmental opportunities provided by Accelerator Life Science Partners and by firms such as WuXi AppTec and Johnson and Johnson that are principal stakeholders in Accelerator Life Science Partners.
Rich Soll: What would you say to a young scientist seeking your guidance as they contemplate doing research either academically or in the industry?
Sandy Markowitz: I’d say that the opportunities have never been greater, and that we now have the power of the technology to rapidly do things that we would never thought would be possible to do at all. When I began studying cancer genetics, it could take several years to clone and sequence a gene, and there were only a small number of laboratories in the country that could really do it well. And now, that can be a high school student as a summer project in a laboratory. It can be done in a couple of days by somebody who knows what they’re doing. It’s just remarkable what can be done, and really the only limitation now is the human imagination. There are just marvelous opportunities for creativity. So, I would encourage young scientists to think big, to think about what’s important, what would be the question that if you answered it would really make a difference and have impact on people’s lives? And then to go after answering that question with everything they have.