Call it ground zero in a patient’s battle with cancer: the tumor microenvironment, the tissue around a cancerous cell that gets tricked into doing its bidding. That critical terrain is becoming the focus of a lot of fresh ideas for scientists—and one of them is taking shape today, with the emergence of a startup called XTuit Pharmaceuticals.
After about four years of operating in stealth mode, Cambridge, MA-based XTuit is emerging today with a $22 million Series A round led by New Enterprise Associates. Founding investor Polaris Partners, CTI Life Sciences, Arcus Ventures, and Omega Funds are also taking part in the funding, which will be used to advance the startup’s first drugs—potential therapies for cancer and inflammatory diseases —-into clinical testing.
XTuit is built around the work of researchers at MIT (Bob Langer, who has helped found a slew of Boston-area biotech startups), Massachusetts General Hospital (Rakesh Jain), and the Salk Institute for Biological Studies in La Jolla, CA (Ronald Evans). Alan Crane, a partner at Polaris and a former CEO of Momenta Pharmaceuticals (NASDAQ: MNTA) and later Cerulean Pharma (NASDAQ: CERU), is XTuit’s CEO; Peter Blume-Jensen, a former Merck, EMD Serono, and Daiichi Sankyo executive, is the startup’s chief scientific officer. It’s currently based in the LabCentral incubator in Cambridge, and has six employees, though those numbers will grow substantially this year, according to Crane (pictured above).
XTuit aims to use drugs to normalize what’s known as the “stroma.” Think of stroma as mortar—connective tissue made up of a bunch of different cell types that helps form the structure of organs, and enables them to function properly. These cells go into overdrive when certain diseases take hold. In cancer, for instance, tumors secrete proteins that effectively hypnotize stroma cells into building a thick, firm wall. The hijacked cells also signal abnormally to other cells, compress the tumor’s blood vessels, and create a low-oxygen environment—commonly called the tumor microenvironment—that shields the cancer cells from attacks by drugs or the immune system.
“Through those multiple mechanisms, the diseased tissue really gets a survival and growth advantage,” Blume-Jensen says.
Crane asserts, for instance, that there is a “very strong correlation” between how much haywire stroma a tumor has and how tough it is to treat. An aggressive, deadly cancer of the pancreas, he says, is typically made up mostly abnormal stroma; whereas testicular cancer, which is much more treatable, has ”virtually no stroma.”
Crane says that many of the same stroma problems are present in conditions marked by fibrosis, or internal scarring, such as nonalcoholic steatohepatitis (NASH). In NASH, an increasingly common liver disorder, fat builds up in the liver and causes inflammation and scarring, which, if left unchecked, can leave patients needing liver transplants. NASH is typically caused by sugary and fatty diets, and it’s becoming a big problem in the U.S., where 16 million folks already have the disease, a number expected to grow.
In both cancer and NASH, XTuit’s goal is to calm these stroma cells down, so they behave normally again. The theory goes that by doing this in cancer, drugs that would typically be thwarted by that thick tumor wall and low-oxygen conditions—like immune system boosting “checkpoint inhibitors,” or even chemotherapy—would be able to break through. In NASH, the hope is that the scarring would be reversed. The company has preclinical programs for each, though Crane won’t say how far away they are from human testing—just that the Series A will enable XTuit to get there.
XTuit also isn’t disclosing as of yet how these drugs work, what they are, what they target, or even what kind of cancers the company is eyeing first (though it’s more focused on solid tumors than blood cancers). Crane would only say these drugs home in on a novel target, via a novel mechanism, and impact a master switch, of sorts, that causes stroma to act abnormally and cause all sorts of problems.
Since stroma is all over the body, could this broad effect cause unintended problems in healthy areas? Crane says no, because XTuit’s target is “very highly specific” to diseased tissue, and the company hasn’t seen any unexpected safety problems prop up as of yet. He adds, “We’re normalizing, we’re not eliminating.”
XTuit is jumping into a crowded field for NASH, which has no approved treatments as of yet but plenty in development, led by Intercept Pharmaceuticals’ (NASDAQ: ICPT), experimental obeticholic acid. Despite the competition, Crane believes XTuit brings something novel to the table—rapid reversal of fibrosis. This hasn’t been proven in humans yet, of course, but Crane says in animals, XTuit’s drugs have been able to reverse the fibrosis in sick livers in a matter of weeks.
“[Others] are not really primarily focused on the microenvironment and the fibrosis, they’re focused on other aspects of the disease process and they really only have modest effects on reversing the fibrosis,” Crane says. “And they certainly don’t do it rapidly like this.”
The speed component is key, because it could help XTuit find out quickly, and cheaply, whether its drugs have an effect on human patients. It’s also aiming to use biomarkers to help predict response in cancer patients, hopefully to speed its path forward.
“It enables us on relatively modest resources to get to some very important value-creating milestones,” Crane says.