Duke researchers have discovered a new combination of drugs that is more effective than chemotherapy at killing acute myeloid leukemia cells in mice. The findings could eventually lead to a new treatment for the aggressive form of cancer.
Kris Wood, a cancer biology researcher at Duke University, published his lab’s findings in Nature Cancer, one of the most prestigious journals in the field. The paper — the culmination of seven years of research — details the mechanism cancer cells use to evade a cancer medication called selinexor and a strategy for blocking it.
Acute myeloid leukemia is a particularly grisly form of cancer that starts in the bone marrow and rapidly spreads through the bloodstream. The five-year survival rate for adults hovers around 30%.
Patients with AML are generally prescribed chemotherapy so potent that they can only receive the drugs for days at a time before the body needs to recover.
“It’s so intense that if you’re over about 65 years old and you’re diagnosed with AML, they won’t even give it to you,” he said. “And by the way, there’s no other effective treatments.”
Selinexor had been approved to treat other types of cancers but when the drug was used on AML in clinical trials, researchers found it to be less effective.
“What we discovered is that this drug has been promising in trials but has not been a home run,” he said.
Wood and his lab set out to investigate why the drug wasn’t working as well.
Using a gene-editing tool called CRISPR, Wood discovered that the drug was unintentionally activating a series of chemical reactions that allowing cancer cells to survive harsh conditions.
“A light bulb went off in our heads,” he said.
They reasoned that the drug would work better if they could block those reactions, effectively cutting the cancer cell’s lifeline. So they paired selinexor with another cancer medication currently in clinical trials called ipatasertib.
Years of experiments proved not only that their hypothesis was correct but also that the two drugs used together worked even better than chemotherapy in mice. The drug combination was twice as effective as chemotherapy by some measures.
Furthermore, because the medications are potentially milder than chemotherapy, patients could theoretically take the drug therapy for several months or years, reducing the risk of cancer reemerging.
The discovery is still far away from impacting the way AML patients are treated. The drug therapy must undergo years of clinical trials to ensure it’s safe and effective in humans. Few trials make it to final approval.
Whether these drugs even have the opportunity to enter clinical trials also depends on cooperation from the companies that manufacture them.
“Getting two companies to collaborate on a trial like this is not trivial.,” Wood said. “I think that there is a real appetite to trying to make this work, even though it’s complex and difficult.”
Wood has a personal reason to persevere. Hidden in the dense pages of his paper is a short acknowledgment of a dear friend.
“We dedicate this work to the memory of our friend, Kimberly Brigati Wang, and her courageous fight against AML,” the paper reads.
The sentimental message is unusual for a pharmacology paper, which often measures diseases in proteins and cells, rather than lives lost. But for Wood, the science and humanity of cancer are closely intertwined.
Brigati Wang was diagnosed with AML in 2014 and died shortly after from chemotherapy complications. The loss spurred Wood to spend years of his scientific career understanding AML.
When his friend died, Wood was starting up his lab in Duke, which focused on cancer cell signaling.
“We could sort of study whatever cancer type we want because the principles apply,” he said. “I felt that if I could choose anything, this would be a compelling one for me.”
After Wood’s paper was published last week, he sent a copy to Wang’s family — as he always does — along with a short paragraph explaining the dense scientific jargon.
“They are super happy and thrilled every time,” he said. “I do want them to know that her life is continuing to lead to good things in the world.”
by: Teddy Rosenbluth
posted on: The News & Observer