Last March, Abby Finkenauer spoke to the House of Representatives about her personal experience with endometriosis and the profound impact that this disease has on patients; those who have been diagnosed, and those who live in chronic pain without knowing that endometriosis may be the cause. Then serving as Iowa’s Democratic representative, Finkenauer introduced an amendment that was approved by the House in July to double the 2019 funding allocation to endometriosis research. Finkenauer’s efforts have helped build critical awareness for the severity of this disease, as well as the pressing need for increased investment in biomedical research to find a cure.
Well before this momentous increase in congressional funding, Dr. Tanya Petrossian, PhD, was working at the forefront of disease-modifying therapeutics for endometriosis. Dr. Petrossian is the founder and CEO of Endocyclic Therapeutics, where she brings her unique research background and personal experiences to bear on a problem that has long been neglected within the biomedical research community: finding small-molecule therapeutics, specifically targeted to endometriotic tissue, that will leave healthy tissues intact and prevent the recurrence of endometriotic lesions.
Dr. Petrossian’s work at EndoCyclic is supported by a Small Business Innovation Research Grant from the National Institute of Child Health and Human Development (NICHD), a highly competitive grant that puts her research on a fast track to phase I and II clinical trials. This grant also fosters collaborations with academic research labs to accelerate projects considered high-priority by the NIH. Through the course of the drug discovery and development process, Dr. Petrossian has worked closely with Dr. Katherine Burns, PhD, at the University of Cincinnati College of Medicine, whose lab studies how environmental toxicants can interact with the immune and endocrine systems to influence the development and progression of endometriosis.
Endometriosis is an intensely painful but relatively common condition that impacts the lives of millions of patients and their loved ones in the U.S. alone, but a lack of research funding and effective treatment options have left many clinicians at a loss as to how to help patients manage the disease. Surgery is currently the main diagnostic measure for endometriosis, and for many people, even receiving a diagnosis is a major barrier to care that can take years—up to a decade, for some. Finding metabolic or chemical biomarkers that are unique to endometrial lesions could go a long way toward helping more women reach a timely diagnosis. But as Dr. Burns points out, traditional clinical approaches to disease are heavily focused on whether or not that disease is treatable. Most of the courses of treatment available to doctors today are limited to hormonal therapies or pain management strategies that don’t address the root causes of the pathology.
A major drawback to broad-spectrum hormonal approaches is that they affect many other aspects of a patient’s physiology. This often comes with intolerable side effects that leave people at a loss for better treatment options; frequently, multiple invasive surgeries to remove the lesions are the only solution.
This is what sets EndoCyclic’s compounds apart: they aren’t hormones or immune modifiers, but instead are highly specific to endometriotic tissue. As Dr. Petrossian explains, hormones act by making physiological changes that may help dampen some of the symptoms of endometriosis. These compounds, on the other hand, act more like a supplement to the body’s natural developmental pathways, finely tuning the molecular processes that go awry and lead to lesion growth. Similarly to the way cancer progresses, certain growth pathways in endometriotic lesions are switched on when they shouldn’t be. The compounds that the company is looking at now specifically target these pathways to help regulate them. “They’re mimicking what the body should be doing,” says Petrossian, and importantly, adds Burns, “in this case they’re not turning off other much-needed pathways.”
Dr. Petrossian and Dr. Burns each bring unique skill sets to the project, and their combined expertise enhances the ingenuity behind EndoCyclic’s approach. Dr. Petrossian’s experience in biochemistry, cancer biology, and bioinformatics lend invaluable molecular insight to the drug development process; and in Dr. Burns’ lab, she is able to observe how candidate molecules behave in vivo. Dr. Burns’ lab developed a model for studying the disorder that recapitulates the way the disease manifests in humans, leading to the formation of lesions that are visually indistinguishable from those that arise in human patients.
The availability of reliable disease models is a crucial component of the drug development pathway. Before a drug makes it to the bedside, it must first be rigorously tested in both cells and animals at the bench, so that researchers can gain insight into how the drug functions in living systems and what its potential side effects may be. One concern associated with hormonal treatments is that they disrupt the menstrual cycle and may interfere with the ability to become pregnant. Promisingly, Dr. Burns says her research team observes normal hormonal cyclicity in their animal model of the disease, even with high doses.
According to Dr. Petrossian, the results of preliminary toxicology and drug metabolism studies are also promising.
Because of its specificity, EndoCyclic’s molecules may have real potential to not only treat existing lesions and reverse the disease, but also prevent its recurrence. “The compound acts in two ways,” Dr. Burns says, “It prevents the proliferation of lesions and induces apoptosis,” which is a type of programmed cell death normally undergone by cells that have suffered damage that the body can’t repair. The drug takes advantage of our natural defenses against immune invaders, signaling to the innate immune system to home to the cells that are set to self-destruct and clearing them from the body.
What’s also exciting about EndoCyclic’s molecular approach is that they’ve identified several different molecules that could work at different stages of the disease. “We’re focusing on one, but we have some others in the pipeline—some that slow and halt growth, some that kill, and some that do both,” Dr. Petrossian explains. Due to its slow progress and tendency to recur after surgery over several months, endometriosis is extremely complicated to treat with one surgery. But finding ways to keep these lesions from regrowing could be of enormous benefit to patients who have struggled for years with repeated rounds of surgery and recurrence. Other work funded by the NICHD at the NIH has propelled the diagnostic side of endometriosis research forward, taking advantage of novel genetic screening tools to look for unique biomarkers specific to endometrial lesions. This could one day permit diagnosis on the basis of a simple blood test, rather than a surgical procedure.
Dr. Burns says a separate grant from the Endometriosis Foundation of America will allow them to explore the preventive potential of these drugs, as well as their therapeutic capabilities. The preliminary data they can gather with the help of this grant will pave the way for future funding to move these compounds through the drug discovery and clinical trial pathways.
Expanding the diagnostic and therapeutic toolbox for endometriosis will provide relief for the millions of people who suffer from this chronic, incapacitating condition. But part of the work of managing the disorder is erasing the stigma that goes with it. Many patients are told that painful periods are normal, or are discouraged from continuing to seek treatment when doctors are at a loss as to what to do for them. Hormonal and pain management therapies are superficial interventions that ignore the reality of this disease and don’t address its underlying causes. For many who endure this condition, it is a fixture in their daily lives that requires careful planning and management of their time to accommodate unpredictable pain levels from day to day.
As Dr. Burns and Dr. Petrossian explained based on their own personal experiences with endometriosis, what many fail to understand is how difficult the disorder makes it to survive in a traditional job. For people living with endometriosis, simple acts like preparing a meal, going for a run, or holding a newborn infant can all be sources of unmanageable pain. Hopefully, as more research efforts are directed toward diagnosing, preventing, and treating the disease, it will become easier to not only raise awareness among clinicians and the public, but empower patients to advocate for themselves.