Craig Jordan, PhD, has spent more than 20 years developing better treatments for acute myeloid leukemia (AML), a rapidly progressing cancer of the blood and bone marrow that can spread to other parts of the body, including the lymph nodes, liver, spleen and central nervous system.
In October, Jordan — CU Cancer Center member and chief of the hematology division in the CU School of Medicine — was awarded a 2020 National Cancer Institute Outstanding Investigator Award, a seven-year grant that supports investigators with outstanding records of productivity in cancer research to embark upon new projects of unusual potential in cancer research and provides more than $5.9 million in research funding.
Jordan and his team will use the funds to continue their research into the role of leukemia stem cells in AML and its treatment. For Jordan, it’s a journey that began more than 20 years ago when he was a new assistant professor at the University of Kentucky.
“I started out my career working on normal blood formation, but my office happened to be right next door to a young investigator who was also a new assistant professor and a leukemia doctor,” Jordan says. “Between my scientific background and her clinical work, we became good friends and collaborated on projects early on. That switched me over from studying the growth of normal blood cells to the leukemia world.”
Targeting stem cells
When he came to the CU School of Medicine in 2013, Jordan was deep into his work on leukemia stem cells, which he likens to the root of a weed growing in your backyard. If you pull the weed but don’t get all of the root out, the weed will grow back. The same goes for stem cells in leukemia, and he had a good idea of how to eradicate them.
“When I got into the leukemia field in the late ’90s, the main drugs that were used for AML, even at that point, were already pretty old,” he says. “Standard chemotherapy started in the early ’70s, so we had 25 years or so of the same drug regimen that didn’t work very well, but it was all we had.”
Taking the job at CU was an amazing opportunity to advance the hematology division’s research program, Jordan says.
“With support from the Department of Medicine and the CU Cancer Center, we built a world class team of investigators. Treating any kind of cancer is a complex problem, so it really takes a village. Our team of physicians, leukemia biologists, drug experts, and clinical trials investigators is the best I’ve ever seen”.
Jordan’s research team quickly found that the existing drugs weren’t much help against leukemia stem cells, so they started comparing regular stem cells and leukemia stem cells to look for differences they could specifically target. They eventually discovered that a protein called Bcl-2 was key to the way in which leukemia stem cells create energy.
“All cells, cancer or normal, have a basic need to make energy for growth and survival,” he says. “We discovered that leukemia cells use Bcl-2 to control energy output from mitochondria. Normal cells make energy in ways that do not require Bcl-2. Imagine running a car engine on ethanol vs. diesel fuel. In both cases the engine is providing power to turn the wheels, but the fuels are different. It’s not a bad analogy for leukemia vs. normal stem cells. They both need the mitochondria to make energy, but the way they run the engine, so to speak, is a little different.”
Finding the right drug
Because Bcl-2 also prevents the biological process called programmed cell death, it already was of interest to drug manufacturers. They understood that if they could create a drug that targets Bcl-2, it would cause cancer cells to die more quickly. But Jordan knew that such a drug would also be helpful in treating AML, as it would cause leukemia stem cells to die due to lack of energy.
In 2014, Jordan began working with one such drug, venetoclax, which was recently approved by the FDA for treatment of AML in older patients who are unfit for intensive chemotherapy. Jordan stresses that venetoclax is no magic bullet, as most patients who take it eventually relapse, but for those older patients, it can make a huge difference.
“Venetoclax is much less toxic than conventional chemotherapy,” Jordan says. “One of the big problems with chemotherapy is it kills tumor cells, but it kills normal cells too.”
Patients can get really sick from standard chemotherapy, he says, and patients who are older or have other health conditions often can’t tolerate it.
“The great thing about venetoclax is it’s much more specific,” he says. “It kills most tumor cells and very few normal cells, so it’s tolerated much better. It puts about 70% of patients into remission, but the catch is that most of them don’t stay in remission. In other words, we haven’t completely killed all the leukemia root. But if you’re an older patient and can go into remission for a few years with a drug that doesn’t make you horribly sick, that’s a big step forward. It’s also a great starting point for building more sophisticated approaches to leukemia treatment.”
The research continues
Armed with the NIH award, Jordan and his research team plan to spend the next few years figuring out how to make venetoclax even more effective, experimenting with secondary drugs that can be administered with venetoclax to make it better at killing leukemia stem cells.
“If you look at the history of most cancer treatments, it’s rare that progress is made overnight from fatal to cured,” he says. “It’s almost always gradual. You do a little better and a little better, so it’s incremental progress that you make. AML has been stalled for decades where 20% or less of people would survive because previous drugs failed to kill the root of disease, the leukemia stem cells. Now we’ve made an important improvement with venetoclax, as this drug more effectively targets leukemia stem cells, thereby increasing the length of remission. Our ultimate goal is to create therapies that are so effective that the leukemia stem cells are completely destroyed.”
