Nav: Home

Discovery could lead to better treatment for leukemia

August 09, 2018

Previous research has revealed that patients with acute myeloid leukemia who also have a particular mutation in a gene called NPM1 have a higher rate of remission with chemotherapy. About one-third of leukemia patients possess this favorable mutation, but until now, how it helps improve outcomes has remained unknown.

Scientists from the University of Illinois at Chicago report on how this mutation helps improve sensitivity to chemotherapy in patients in the journal JCI Insight.

The protein coded for by the NPM1 gene affects the location and activity of another protein called FOXM1. FOXM1 activates other cancer-promoting genes and has been found to be elevated in cancer cells. The presence of FOXM1, especially at high levels, is a strong predictor of worse treatment outcomes and decreased survival in patients with cancer. When the NPM1 gene is mutated, FOXM1 can't activate additional oncogenes, so patients with this mutation tend to respond better to chemotherapy. A drug that targets and incapacitates FOXM1 in patients without the beneficial NPM1 mutation may help improve the efficacy of chemotherapy.

Acute myeloid leukemia (AML) is a cancer of the bone marrow. In AML, stem cells that would normally differentiate into blood cells instead multiply unchecked and fail to develop into mature blood cells. Patients with AML have a high risk of death from uncontrolled infection, fatigue easily and get organ damage because they lack adequate numbers of oxygen-carrying red blood cells. They are also at high risk for dangerous bleeding because of low numbers of cells that help with blood clotting. It has been known that patients with a mutation in the NPM1 gene have a better response to standard chemotherapy, with up to 80 percent of patients being cured compared to just 40 percent for patients without the mutation.

In previous studies, researchers at UIC led by Andrei Gartel, associate professor of molecular genetics, discovered that one of the roles of the NPM protein is to stabilize FOXM1 and keep it in the nucleus where it can activate other cancer-promoting genes.

Gartel and his colleagues determined that when the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell's cytoplasm, where it can't interact with DNA. This may explain why patients with this NPM1 mutation have a much better response to chemotherapy and are less likely to relapse.

In their current study, Gartel and his colleagues further explored the relationship between NPM1 and FOXM1 in patients with AML.

The researchers analyzed bone marrow cells taken via biopsies from 77 patients with AML and found that the presence of FOXM1 in the cells' nuclei was a strong predictor of poor treatment outcome for individual patients.

"When we then looked in the patients' medical records, we saw that those with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance and lower survival rates compared to patients without FOXM1 present in the nucleus," said Dr. Irum Khan, assistant professor of clinical medicine in the UIC College of Medicine and first author on the paper.

In mice engineered to overproduce FOXM1 that were caused to develop leukemia, following treatment with cytarabine, a drug commonly used to treat AML, the mice had more residual disease compared to control mice with AML and normal levels of FOXM1.

"Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients' FOXM1 levels and their treatment outcomes," said Khan.

Next, the researchers demonstrated that they could produce a therapeutic response in patient AML cells grown in the lab using a novel oral drug called ixazomib, which is approved to treat another form of cancer called multiple myeloma. In the current paper, Gartel and his colleagues show that ixazomib works in part by suppressing FOXM1.

When the patient cancer cells were treated with ixazomib plus standard chemotherapy drugs used to treat AML (cytarabine and anthracyclines) the cells showed a higher death rate compared with standard chemotherapy alone. "Ixazomib produced a synergized chemotherapeutic response when added to standard chemotherapy," Gartel said. "We believe this is caused by ixazomib inhibiting the activity of FOXM1."

"There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don't have this beneficial mutation often face," said Khan. "Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory."
-end-
Marianna Halasi, Anand Patel, Rachael Schultz, Nandini Kalakota, Yi-Hua Chen, Nathan Aardsma, Li Liu, John Crispino, Nadim Mahmud and Olga Frankfurt of the University of Illinois at Chicago and Northwestern University are co-authors on the paper.

This research was supported by National Institutes of Health grants R21CA194608-02 (ALG), KL2TR002002-02 (IK) and a research grant from Takeda (IK).

University of Illinois at Chicago

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

The Truth about Cancer: What You Need to Know about Cancer's History, Treatment, and Prevention
by Ty M. Bollinger (Author)

The Emperor of All Maladies: A Biography of Cancer
by Siddhartha Mukherjee (Author)

The Cancer-Fighting Kitchen, Second Edition: Nourishing, Big-Flavor Recipes for Cancer Treatment and Recovery
by Rebecca Katz (Author), Mat Edelson (Author)

Anticancer: A New Way of Life
by David Servan-Schreiber MD PhD (Author)

Chris Beat Cancer: A Comprehensive Plan for Healing Naturally
by Chris Wark (Author)

F*ck Cancer: A totally inappropriate self-affirming adult coloring book (Totally Inappropriate Series) (Volume 4)
by Jen Meyers (Author)

The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies
by Dr. Nasha Winters ND FABNO L.Ac Dipl.OM (Author), Jess Higgins Kelley MNT (Author), Kelly Turner (Foreword)

The Biology of Cancer, 2nd Edition
by Robert A. Weinberg (Author)

The Cancer Revolution: A Groundbreaking Program to Reverse and Prevent Cancer
by Leigh Erin Connealy (Author)

Tripping over the Truth: How the Metabolic Theory of Cancer Is Overturning One of Medicine's Most Entrenched Paradigms
by Travis Christofferson (Author), Dominic D'Agostino (Foreword)

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Dying Well
Is there a way to talk about death candidly, without fear ... and even with humor? How can we best prepare for it with those we love? This hour, TED speakers explore the beauty of life ... and death. Guests include lawyer Jason Rosenthal, humorist Emily Levine, banker and travel blogger Michelle Knox, mortician Caitlin Doughty, and entrepreneur Lux Narayan.
Now Playing: Science for the People

#492 Flint Water Crisis
This week we dig into the Flint water crisis: what happened, how it got so bad, what turned the tide, what's still left to do, and the mix of science, politics, and activism that are still needed to finish pulling Flint out of the crisis. We spend the hour with Dr Mona Hanna-Attisha, a physician, scientist, activist, the founder and director of the Pediatric Public Health Initiative, and author of the book "What the Eyes Don't See: A Story of Crisis, Resistance, and Hope in an American City".