By: Christine des Garennes
Several days following the Federal Drug Administration’s approval of a new cancer drug, Erik Nelson (ACPP) was still processing the news.
“It hasn’t sunk in yet that this is actually happening,” he said from his breast cancer research lab in Burrill Hall. “This is why I get up every morning: to hopefully impact a patient's life.”
Nelson, associate professor in the Department of Molecular & Integrative Physiology in the School of Molecular & Cellular Biology at the University of Illinois Urbana-Champaign, and members of his lab study how hormones and metabolic factors impact cancer progression with the goal of creating better treatments. Developing a therapeutic does not happen overnight. It involves years, possibly decades, of foundational research, collaboration across disciplines, lab studies and clinical trials, not to mention brainstorming among colleagues around the literal or proverbial water cooler.
When he was a postdoctoral researcher at Duke University, Nelson was part of the team that discovered a drug, then called RAD1901, might have unique benefits in treating breast cancer patients. That drug, known generically as elacestrant, was recently approved for treatment of postmenopausal women or adult men with certain types of advanced or metastatic breast cancer. It’s the first new endocrine-related therapy approved in 20 years and the first orally available selective estrogen degrader, allowing patients to take a pill at home instead of traveling to clinics for injections. The drug will be marketed as Orsderdu.
“To have been a part of an effort where we started at the bench that is now an FDA-approved drug—first-in-class—that will hopefully really improve patients’ lives is a truly humbling experience for me, and really, one of the milestones of my career,” Nelson said.
In the lab of Donald McDonnell at Duke, Nelson studied how a cholesterol break-down product might impact bone and osteoporosis. He and another senior scientist, Suzanne Wardell, had been tasked by Radius Pharmaceuticals to investigate a drug’s potential for treatment of hot flashes in postmenopausal women. In early clinical trials, researchers found that at low doses the drug seemed to prevent hot flashes. But as the dosage increased, it made the hot flashes worse. Wardell and Nelson conducted biochemical assays and found that at high doses, the drug degraded the estrogen receptor; the estrogen receptor being a key driver for ~60-70% of breast cancers.
“I also started thinking that this same compound might have effects in breast cancer research since it was behaving like an anti-estrogen,” Nelson said. “That was really unique biology. And at the time, basically we were just talking around the water cooler and figuring out what we could do with this really interesting pharmacology.”
We can do better
One in eight women will be diagnosed with invasive breast cancer in the U.S., according to the Centers for Disease Control and Prevention. Metastatic breast cancer, the most advanced state of breast cancer, is when cancer has spread beyond the breast to bones, lungs, and other areas of the patient’s body. The drug fulvestrant, approved by the FDA in 2002, works to slow or stop the progression of breast tumors fueled by estrogen. However, it needs to be administered in large doses via injection into a patient’s muscles. It also doesn't have very high circulating values, meaning it doesn’t go where it should go in the body at the concentrations it should be, Nelson said.
“Here we are [in 2013] with a drug of similar class to fulvestrant, but it was being developed for hot flashes, which meant that it probably got across what we call the blood-brain barrier. So we put two and two together and thought, well, hey, maybe this could be positioned as a new orally available degrader of the estrogen receptor, allowing patients to take it for metastatic breast cancer.”
Prolonging a patient’s life and improving their quality of life has always been in the forefront of Nelson’s mind. Like many around the world, his family had been affected by cancer. His great aunt had recurrent breast cancer and undergone a radical mastectomy, a painful surgery that left her disfigured. She told family members if the cancer were to come back, she didn’t want to undergo any more treatment. Nelson was sixteen years old at the time and he found the decision difficult to comprehend until he saw the results of the invasive procedure, which involves removing breast tissue and underlying tissue.
“We can do better,” he said to himself on the car ride home from a visit.
As an undergraduate student at the University of Calgary, he joined an endocrinology lab. There he found his passion in studying and asking questions about hormone-related research. That led to a PhD in comparative endocrinology in Calgary, followed by his postdoctoral years at Duke.
He arrived at the U of I in 2014, drawn by the Department of Molecular & Integrative Physiology and School of Molecular & Cellular Biology’s long track record of cancer research, especially into the nuclear receptors he was interested in studying. As it happens, one of his colleagues, Benita Katzenellenbogen (CGD), Swanlund Professor of Molecular and Integrative Physiology, would have a connection to the development of elacestrant. The drug is approved for treatment of metastatic breast cancer where there’s a mutation in the estrogen receptor. These mutations turn the estrogen receptor into a state of “always on.” In the 1990s, Katzenellenbogen characterized how these mutations activated the estrogen receptor. Around the same time, Suzanne A W Fuqua at Baylor College of Medicine first found some of these mutations in human breast tumor samples.
Since joining the U of I faculty, Nelson has collaborated with faculty in MCB and units and disciplines across campus: engineering, food science, human nutrition, and more. He also has appointments with IGB and with the Cancer Center at Illinois.
“As we started our lab here, we found that immune cells are particularly susceptible to perturbations in cholesterol homeostasis and cholesterol metabolism. That was really intriguing to us because in theory, the immune system has the capacity to attack and eradicate cancer. If we can figure out how to turn the immune system on in just the right way, we should be able to engage it in a cancer patient and have that take care of the cancer completely.”
“The problem is cancer cells have figured out how to turn off the immune system or even worse, use it to help them rather than eradicate them.”
In recent years members of the Nelson Lab have been focused on how cholesterol homeostasis and cholesterol metabolism can be used to retrain the immune system into attacking cancer cells rather than helping them. And they have been making some progress toward achieving this goal. (Read more.)
“I have an amazing team of graduate students, postdoctoral associates, research technicians, and several undergraduate researchers. Together we all share the same vision of treating and eventually eradicating this disease altogether. And it's my pleasure to oversee what they're doing and help guide them towards the best experiments and how to interpret data.”
Cancer research advocates also continually inspire him. He meets monthly with the Cancer Research Advocacy Group, which is comprised of cancer survivors and those affected by cancer.
“They tell me what needs are not currently being met in the clinic and educate us on what it is really like taking current cancer treatment. Our goal is to research ways to fill those gaps.”
Looking ahead to the next stage of his research enterprise, Nelson aims to develop molecules and biological products, or biologics such as antibodies, to treat specific cancer subtypes. In the future, a patient and their doctor can review the data about the disease, their specific situation and really personalize the treatment approach.
“We need to develop more therapies and more treatment options for patients so that they do have choice and they can choose the drug that's going to give them the best quality of life and hopefully the longest,” Nelson said.
By: Christine des Garennes
Photos By: and video by Jennifer Lask