WEILL CORNELL SCIENTISTS REVEAL HOW THE PROTEIN WORKS AND HOW THE DRUG GUMS IT UP, OFFERING NEW HOPE FOR TREATMENT OF AGGRESSIVE CANCER
Researchers have discovered how an experimental drug is capable of completely eradicating human lymphoma in mice after just five doses. The study, led by researchers at Weill Cornell Medical College, sets the stage for testing the drug in clinical trials of diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, itself the seventh most frequently diagnosed cancer in the U.S.
In the journal Cell Reports, published today online, the scientists describe how the powerful master regulatory transcription factor Bcl6 regulates the genome, ensuring that aggressive lymphomas survive and thrive. They also show how the Bcl6 inhibitor, developed at Weill Cornell, effectively gums up the protein, stopping it from working.
While Bcl6 is active in a number of cancers, including leukemia and breast cancer, work testing a Bcl6 inhibitor is most advanced in DLBCL. “That’s because we desperately need a new strategy to treat this lymphoma — many patients are resistant to currently available treatments,” says the study’s senior investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
Dr. Melnick developed the first BCL6 inhibitors nine years ago, and has continued to improve upon the design of these drugs so they could be used to treat cancer patients. He has since collaborated with colleagues at many institutions in a systemic effort to understand how both Bcl6 and its inhibitor drugs function.
In a study published in March in Nature Immunology, Dr. Melnick and his team reported that it is possible to shut down Bcl6 in DLBCL without affecting its vital role in the T cells and macrophages needed to support a healthy immune system. The protein has long been considered too complex to target with a drug as it also is crucial to proper function of many immune system cells, not just B cells gone bad.
That finding suggested Bcl6 inhibiting drugs may have few side effects, says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
The latest study was designed to understand exactly how Bcl6 promotes DLBCL.
Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are like transcription factors on steroids: their actions regulate thousands of genes in different kinds of cells. Bcl6 can control the type of immune cell that develops in the bone marrow — pushing them to become B cells, T cells, or macrophages — and it has a primary role in the developmental phase of B cells, during which they generate specific antibodies against pathogens.
The researchers found that in order to help B cells produce antibodies against an infection, Bcl6 “builds a huge shopping mall-style complex” that sits on top of a stretch of the genome. By binding onto these genes, Bcl6 deactivates the DNA, stopping genes from producing RNA and proteins. “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there,” Dr. Melnick.
Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome, Dr. Melnick says. “We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”
Bcl6 also has a second, independent function that Dr. Melnick says acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.
The researchers found that in order for DLBCL to survive, Bcl6 needs to maintain both its shopping mall protein complex and keep the train tracks on the path toward B cell division.
To their surprise, they also found that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick says. “There are two identical binding sites on the protein surface.”
Even better, the Bcl6 inhibitor they developed was designed to fit into that same keyhole.
“This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” Dr. Melnick says, adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.
The Latest Bing News on:
- Deep-learning model enables rapid lymphoma detection in PET/CT imageson November 26, 2020 at 4:30 am
Madison have recently developed a deep-learning model that can perform this task automatically. This could free up valuable physician time and make quantitative PET/CT treatment monitoring possible ...
- Global Burkitt Lymphoma Treatment Market Size By End User, By Region 2020 | Overview, Growth, Economics, Demand And Forecast Research Report To 2026on November 25, 2020 at 5:20 am
The latest report as Burkitt Lymphoma Treatment Market acknowledges Size, Application Segment, Type, Regional Outlook, Market Demand, Latest Trends, and Burkitt Lymphoma Treatment Industry Share and ...
- Lymphoma Research at Winship Led by Dr. Jonathon B. Cohenon November 24, 2020 at 2:15 pm
Armed with a family background in oncology, this former Camp Judaea camper is looking for effective cancer treatments at Winship Cancer Institute of Emory University.
- Cancer survivor documents second battle with lymphoma on social mediaon November 23, 2020 at 8:54 pm
A cancer survivor who began the pandemic in remission detailed her relapse and response to her second battle with the disease.
- Silicon Therapeutics Announces Dosing of First Patient in Phase 1 Open-Label Clinical Trial of SNX281 for Advanced Solid Tumors or Lymphomaon November 23, 2020 at 8:30 am
Silicon Therapeutics announces treatment of first patient with its therapeutic candidate SNX281 in a Phase 1 clinical trial.
- Rates of VTE, major bleeding high in primary CNS lymphomaon November 20, 2020 at 10:53 am
For patients with primary central nervous system lymphoma (PCNSL), the incidence of venous thromboembolism (VTE) and major bleeding is high, according to a study published in the November issue of ...
- End of Life Care in Lymphoma Compromised by Late Recognition of Dyingon November 18, 2020 at 5:07 pm
Half of patients with lymphoma are only identified as dying within one day of their death, meaning end of life care is limited, shows a revealing study that explored how such care could be improved ...
- New shingles vaccine may protect lymphoma patientson November 18, 2020 at 9:16 am
Vaccines are often ineffective in individuals with lymphoma, but a new shingles vaccine may change that, according to a new study. Researchers focused on this hard-to-vaccinate group and how best to ...
- Jeff Bridges Has Been Diagnosed With Lymphoma—Here Are the Symptoms to Knowon November 18, 2020 at 7:10 am
“Although it is a serious disease, I feel fortunate that I have a great team of doctors and the prognosis is good.” ...
- Mantle Cell Lymphomaon November 8, 2020 at 4:00 pm
What Is Mantle Cell Lymphoma? Mantle cell lymphoma is a cancer of white blood cells, which help your body fight infections. You may hear your doctor call your condition a type of "non-Hodgkin's ...
The Latest Google Headlines on:
The Latest Bing News on:
TREATMENT OF AGGRESSIVE CANCER
- Mum's appointments cancelled due to Covid is told of cancer over ZOOMon November 26, 2020 at 2:25 am
Kimberley Eccles, 23, from Leyland, Lancashire, was told by doctors she had Rhabdomyosarcoma, a rare tissue cancer, over a Zoom call in August after three appointments were cancelled due to Covid.
- Arizona woman fighting aggressive cancer surprised with dream weddingon November 25, 2020 at 6:22 pm
For Samantha Preston, it was the wedding she always dreamed of even as she undergoes treatment for osteosarcoma.
- African American Men Face Higher Risk of Aggressive Prostate Cancer, but Not Necessarily Deathon November 25, 2020 at 4:22 pm
Multiple studies have suggested African American men tend to have more aggressive forms of prostate cancer, but a new study suggests that may not translate to a higher risk of death.
- New immunotherapy shows promise against rare childhood canceron November 25, 2020 at 11:01 am
A novel CAR T-cell therapy developed by researchers at UCL and designed to target cancerous tumors, has shown promising early results in children with neuroblastoma, a rare form of childhood cancer.
- Lynparza® (olaparib) Receives Health Canada Approval for the Treatment of BRCA or ATM Gene-Mutated Metastatic Castration-Resistant Prostate Canceron November 25, 2020 at 9:52 am
Lynparza is the first targeted treatment approved in biomarker-selected prostate cancer validated by a Phase III trial1 MISSISSAUGA, ON, Nov. 25, ...
- Study aimed at improving breast cancer treatment for Black womenon November 24, 2020 at 9:58 am
An Indiana University Melvin and Bren Simon Comprehensive Cancer Center researcher is identifying the unique biology that may make Black women more susceptible to aggressive breast cancer.
- Israeli scientists: New cancer treatment like using ‘tiny scissors’ to hit cellson November 22, 2020 at 3:25 pm
Israeli scientists say they’ve created a way to treat cancer in mice that is so precise, it’s like using “tiny scissors” to target the cells, according to a report. “This is the first study ...
- Revolutionary CRISPR-based genome editing system treatment destroys cancer cellson November 19, 2020 at 4:00 pm
Researchers have demonstrated that the CRISPR/Cas9 system is very effective in treating metastatic cancers, a significant step on the way to finding a cure for cancer. The researchers developed a ...
- Early treatment with lorlatinib improves survival in some lung cancer patientson November 18, 2020 at 2:02 pm
Lung cancer patients with a specific genetic alteration lived longer and were protected against metastasis to the brain when treated early with the drug lorlatinib (Lorbrena), according to a study led ...
- Al Roker returns to Today with 'terrific news' on prostate cancer treatmenton November 17, 2020 at 7:42 am
Al Roker, the lovable NBC weatherman, returned to the Today show on Tuesday morning to offer an update on his ongoing treatment for prostate cancer. And things are looking up. "I just went to the ...