Often, you don’t have to know how something works – what’s important is that it works. Few of us are versed in the chemical reactions involved in the transformation of chocolate chip cookie dough into a nice, gooey batch, after all.

But that’s not how it usually goes in cancer medicine, where scientists have delved into the inner workings of cells to understand the ways in which cancer outfoxes the body’s natural defenses.

Let’s delve in a new leukemia drug

They did such delving for a drug called venetoclax as related to chronic lymphocytic lymphoma (CLL), the most common type of leukemia. They found that venetoclax worked by blocking a protein that CLL cancer cells generate and exploit to stop a process called apoptosis, which would otherwise trigger the cancer cells to die.

Venetoclax  also seemed to be effective in another type of leukemia – acute myeloid leukemia, or AML, a nasty blood cancer that strikes mainly the elderly. Scientists assumed the drug worked the same way in AML as it did in CLL. What works for a chocolate chip cookie should work for a sugar cookie, after all.

It took a University of Colorado School of Medicine team and a clinical trial at UCHealth University of Colorado Hospital at the Anschutz Medical Campus (UCH) to demonstrate otherwise – and open up a promising new avenue in how we treat leukemia. In the process, the team showed that a combination of venetoclax and low-dose chemotherapy starkly improves the prospects of those with AML. The FDA agreed, approving the drug for AML in November 2018.

Journal club

The story starts more than a decade ago, when Dr. Daniel Pollyea was doing his fellowship in hematology and oncology at Stanford University. Fellows were expected to pick out a journal article, digest it, and summarize it for faculty during a “journal club.”

“You had to stand up there, present an article, and then get pummeled with questions and criticism,” Pollyea said. “So you had to know that paper as well as any paper you’d ever read before.”

Pollyea chose a paper by a team led by Craig T. Jordan, a PhD cancer biologist and, as Pollyea described him, “one of the world’s top experts on leukemia stem cells.” Jordan was at the University of Rochester at the time.

Not forgotten

In 2011, Pollyea came to the CU School of Medicine, where he’s now director of Leukemia Services and sees patients at UCH. A couple of years later, Jordan joined the CU faculty, where he’s now chief of the Division of Hematology.

Pollyea hadn’t forgotten that journal article and had continued to follow Jordan’s work. He sat down with Jordan and they agreed to build CU into the world’s top authority on the biology of leukemia stem cells. They would get there by combining the work of Jordan’s lab with clinical trials to translate lab discoveries into treatments for patients. Pollyea would lead those trials, with funding from the Leukemia & Lymphoma Society providing key support (during the 2019 baseball season, Colorado Rockies’ home runs landing on UCHealth’s “Hit the Mitt for Charity” sign in Coors Field’s left-field stands benefit the society).

“The leukemia stem cell population is the root cause of AML and the source of relapse,” Pollyea said, adding that killing AML stem cells would be “akin to pulling the root up with the weed. You could actually eradicate the disease and not just stun it.”

Chink in the armor

Jordan’s lab had found something surprising with venetoclax. As Pollyea described it, venetoclax caused the AML stem cells to more or less starve to death. The sugar cookie was in fact different than the chocolate chip cookie.

Normal cells can burn different types of fuel, depending on what’s available – sugar, fat, or the amino acids broken down from proteins. AML stem cells, Jordan’s team found, run only on protein – and they showed, for the first time, that venetoclax stops protein metabolism in those stem cells. So in addition to chemotherapy, which uses chemicals to kill cancer cells as well as healthy cells; and immunotherapy, which uncloaks cancer cells so the immune system can attack them; the CU School of Medicine team discovered what looks to be a unique general approach to killing cancer. Call it starve-the-stem-cells therapy.

Studying the new leukemia drug

A clinical trial Pollyea led bore that out with patients. The drug took effect quickly, and 67 percent of the 145 patients involved went into remission, with median survival of more than 17 months. (Only about 20 percent of patients only on the accompanying chemotherapy – the standard treatment – go into remission, and median survival is less than a year).

Jordan and Pollyea continue to work on new recipes, as it were. The FDA’s November 2018 approval of venetoclax for AML was limited to patients ages 75 and over. New studies now happening at UCHealth – and only at UCHealth – aim to change that. One of them considers patients 60 and over; the other is for patients as young as 18.

“It’s the only setting in the world where a younger patient would be allowed not to receive standard intensive chemotherapy,” Pollyea said.

Funding the future

The Leukemia & Lymphoma Society is helping support both new studies.

“LLS is our critical partner,” Pollyea said. “They are just an incredible funding agency that really understands the science and I think recognizes the best approaches – the most novel and sometimes the riskiest approaches – that may not have any other funding source.”

A combination of medical creativity and high-risk, high-reward funding is just what it will take to tackle blood cancers that are anything but cookie-cutter.