Nav: Home

Researchers pinpoint why lymphoma patients may become resistant to specific therapy

May 15, 2019

TAMPA, Fla. and BOSTON - With more targeted therapies being approved each year for cancer, the development of drug resistance to these agents is a growing concern. It has often been assumed that drug resistance is due to the presence or development of additional genetic alterations; however, it is now clear that resistance mechanisms are more complicated. Researchers from Moffitt Cancer Center and Dana-Farber Cancer Institute have discovered a mechanism of drug resistance to Venetoclax®, also known as ABT-199, a BCL-2 targeting drug commonly used to treat chronic lymphocytic leukemia and acute myeloid leukemia. Their findings, published in the journal Cancer Cell, also suggest a possible co-treatment strategy to overcome this resistance.

BCL-2 is a protein that promotes cell survival and is highly deregulated in numerous malignancies. This deregulation can be overcome by treatment with Venetoclax. However, many patients who initially respond to the drug eventually develop resistance and tumor recurrence. The team of researchers led by Jianguo Tao, M.D., Ph.D and Jun Qi, Ph.D., wanted to determine how the BCL2 inhibitor resistance develops in B-cell lymphomas, such as mantle cell lymphoma (MCL) and double-hit lymphoma (DHL), in order to find strategies to overcome and prevent its occurrence.

They created model cell lines that were resistant to Venetoclax and compared these cells to the parental cell lines that maintained drug sensitivity. The scientists found that ABT-199 resistance was dependent on both genetic mutations and non-mutational changes. Many patients with hematologic malignancies have an amplification of part of chromosome 18. The researchers discovered that during ABT-199 treatment, rare subpopulations of cells lose this genetic amplification and can survive from drug treatment. Interestingly, this region of chromosome 18 contains the BCL-2 gene, which is the target of ABT-199. This loss of the ABT-199 target and other cell death regulators on chromosome 18 contribute to the survival of these cell populations, which eventually can develop into drug resistance cells.

The researchers also demonstrated that the resistant cells developed non-mutational changes involving transcriptional reprogramming. "Certain regions of the DNA called super-enhancers became activated or deactivated in the resistant cells, leading to either a downstream loss or gain in protein expression, which ultimately contributed to cell survival. The study, for the first time, unified genetic alteration and non-genetic adaptive response as a driving force for drug resistance evolution to therapy," said Tao, senior member of the Department of Laboratory Medicine and Hematopathology at Moffitt Cancer Center.

The transcriptional reprogramming was dependent on a protein called CDK7. These observations suggested that targeting CDK7 may be an effective strategy to prevent Venetoclax resistance. The researchers conducted a chemical screening of a set of small molecule inhibitors further confirmed this hypothesis by showing that combination treatment with ABT-199 and the CDK7-targeting inhibitor THZ1 prevented the emergence and maintenance of ABT-199 resistance in models of MCL and DHL. The patient samples assessment further proved the clinical relevance of this study, which can unveil the drug resistance mechanism in patient care in the future.

"Disabling CDK7 in combination with ABT-199 is an attractive means to provoke tumor regression of otherwise refractory lymphoma, and such a combination strategy could be applied across a broad spectrum of hematological malignancies," said Qi, assistant professor in medicine at the Department of Cancer Biology Dana-Farber Cancer Institute and Harvard Medical School.
-end-
The study was supported in part by grants from the National Cancer Institute (CA179062, CA134807, CA137123, POQ-CA066996-19, P50-CA100707-15, CA211336, P30-CA076292), the Lymphoma Research Foundation, Incyte Corporation, the Leukemia and Lymphoma Society and by the Cortner-Couch Chair for Cancer Research from the University of South Florida School of Medicine.

About Moffitt Cancer Center

Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 50 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, clinical trials, prevention and cancer control. Moffitt is the No. 6 cancer hospital in the nation and has been listed in U.S. News & World Report as one of the "Best Hospitals" for cancer care since 1999. Moffitt devotes more than 2.5 million square feet to research and patient care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,500 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.

About Dana-Farber Cancer Institute

From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world's leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report's Best Hospitals for both adult and pediatric cancer care.

Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women's Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston's Longwood Medical Area.

Dana-Farber is dedicated to a unique 50/50 balance between cancer research and care, and much of the Institute's work is dedicated to translating the results of its discovery into new treatments for patients in Boston, and around the world.

H. Lee Moffitt Cancer Center & Research Institute

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:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Jumpstarting Creativity
Our greatest breakthroughs and triumphs have one thing in common: creativity. But how do you ignite it? And how do you rekindle it? This hour, TED speakers explore ideas on jumpstarting creativity. Guests include economist Tim Harford, producer Helen Marriage, artificial intelligence researcher Steve Engels, and behavioral scientist Marily Oppezzo.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".