Decades ago, patients who were diagnosed with acute myeloid leukemia, a rare cancer of the bone marrow and blood, were told there was nothing doctors could do for them.
In part due to pioneering research by two University of Michigan researchers, research into the field of how protein interactions that drive leukemia growth can be stopped has expanded, and patients today have better care options.
The U.S. Food and Drug Administration this year approved a once-daily drug called KOMZIFTI that was developed by the researchers, Jolanta Grembecka and Tomasz Cierpicki, who are associate professors in UM’s Department of Pathology. It helps to treat acute myeloid leukemia, which is an aggressive, fast-growing blood cancer that can affect anyone but is most commonly found in people aged 60 years and older.
“Drug discovery is a complex, resource-intensive endeavor that demands significant time and investment,” said Douglas Hurst, the scientific director of biochemistry and immunology of cancer at the American Cancer Society. “ACS is proud to have played a significant role in this FDA-approved treatment by providing early-stage research grants to both Drs. Grembecka and Cierpicki. These critical foundational studies helped set the stage for this success.”
The cancer society provided early-stage research grants to both UM researchers, said Ashley Noonan, a spokesman for the American Cancer Society.
It wasn’t a simple process for the pair, who met at Poland’s Wroclaw University of Technology. Both researchers are from Poland and immigrated to the United States in the early 2000s to continue their research at the University of Virginia, where they realized there was potential to develop a way to block the interaction that led to leukemia growth.
“Eighteen years ago, we were researchers at the University of Virginia, and we finished our training there as postdoctoral fellows,” Grembecka said. “At the time, there was a biological validation that menin might be a good protein to inhibit in certain leukemia subtypes.”
The research, they said, wouldn’t have happened if they had stayed in Poland.
“One of the reasons why we are in the United States and not in Poland, we came here and we could see our future with complete freedom,” Cierpicki said. “We could see how we can drive science and with the funding that at least used to be extensive.”
Leukemia is a form of cancer involving white blood cells, which normally fight infections. The bone marrow produces an excessive amount of abnormal white blood cells, which then don’t function properly and lead to symptoms such as persistent fatigue, recurrent nose bleeds, bone pain and a sudden loss of weight.
While leukemia is associated with childhood cancers, it can develop at any age, according to medical experts. Nearly 67,000 new cases of leukemia are expected in the United States this year, according to the National Cancer Institute, and over 23,500 individuals are expected to die.
About 13.8 of every 100,000 men and women in Michigan were estimated to have leukemia in 2017-21, which is slightly below the U.S. rate of 14.1, according to a database kept by the National Cancer Institute and the U.S. Centers for Disease Control and Prevention. Michigan’s leukemia mortality rate for 2018-22 was 6.4 deaths for every 100,000 people, which was higher than the national average of 5.9 deaths.
Development of the treatment
The process to develop a drug that could be clinically tested was long and sometimes frustrating, Cierpicki said.
And Cierpicki and Grembecka were setting off on an essentially uncharted path when they began their research. While scientists had an idea that blocking the interaction that caused leukemia to grow was possible, they didn’t yet know how exactly to do so and what that would entail.
“When we started working on this whole idea that we could develop, not even drugs but some chemical tool or compounds that would block this protein and test if this would change the development of leukemia,” Cierpicki said. “At this stage, not much was even known about this.”
Grembecka said the pair were the first to characterize the menin-protein interaction that could be blocked by small molecules. From the first rounds of medicinal chemistry, the treatment was tested in acute myeloid leukemia cells and then in mouse models of the disease.
“To get to the clinical candidate, you have to go through hundreds, or in this case, probably more than 2,000 molecules to very carefully make sure you are not missing a valuable compound that might be your clinical candidate, especially at later stages,” Grembecka said.
The University of Michigan agreed to a licensing agreement with San Diego-based drug developer Kura Oncology in December 2014. Working with a smaller company was crucial, Cierpicki said, because it wouldn’t have many different developments ongoing, and the pair’s research might be less prioritized. Instead, a small company built around one particular technology was what the researchers wanted with Kura Oncology.
Phase one of the clinical trials began in September 2019, and the research team worked alongside Kura Oncology to develop the treatment that was eventually approved by the FDA.
An ongoing trial using KOMZIFTI, along with the drugs venetoclax and azacitidine, found that 86% of newly diagnosed acute myeloid leukemia patients achieved complete remission from the cancer, Kura Oncology and Japanese specialty drug developer Kyowa Kirin Co. Ltd. announced in a Dec. 8 press release. But some blood cell lines may not have fully recovered in the patients, the drug developers reported.
The work isn’t done, though, the UM researchers said. Leukemia cells can become drug resistant, and the researchers are continuing to develop new generations of drugs that can address this reality and potentially other forms of leukemia and solid tumors.
“This keeps us busy,” Grembecka said.
Research at universities
The researchers said they loved their time in Poland and visit often. But for their work, a place like the United States was necessary.
“These drugs are less often being developed in Europe, for example,” Cierpicki said. “Sometimes it happens, but I think here, there are still many more opportunities, and we hope it will stay like that.”
The support and resources American universities provide for the development of medical breakthroughs cannot be understated, especially for a research giant like UM that spends over $2 billion a year on research, they said. Their offices are adjacent to the Rogel Cancer Center and the UM hospital, which was yet another draw for them.
“What is very unique about this academic system, you get the freedom to drive your research,” Cierpicki said.
Despite the support the researchers get from the university, hours must be spent applying for grants from federal institutes, like the National Institutes of Health, Grembecka said. Since 2011, menin inhibitor research at the university has been approved for millions in federal grants, federal award disclosure data shows.
“We are constantly applying for grant funding to the NIH foundation, different opportunities,” Grembecka said. “Obviously, this is not a 9-to-5 type of job, but we are passionate about science and especially drug discovery.”
The research being done at universities allows patients access to better treatment and care, said Betsy King-McDonald, the communications manager for the Blood Cancer Foundation of Michigan.
“Every 90 minutes, someone in Michigan learns they have blood cancer,” King-McDonald said in an email. “Blood cancers like lymphoma, acute myeloid leukemia, and others are not only hard to treat, but also extremely expensive. Fighting for a family member’s life shouldn’t have to put a strain on a family’s livelihood.
“So, when research advances make these cancers even a little easier to treat, that benefit ripples out into every aspect of a patient’s life. From greater financial resiliency to better mental health outcomes, every dollar invested in research helps ease the real, practical burdens of fighting cancer right alongside the medical ones. It’s a breakthrough worth celebrating.”
