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:
- Global Hodgkin's Lymphoma Drugs Market 2020 analysis with Key Players, Applications, Trends and Forecasts by 2025on July 13, 2020 at 5:50 pm
Global “Hodgkin's Lymphoma Drugs Market” Report mainly includes sales, revenue, trade, competition, investment, ...
- Malignant Lymphoma Market By Current Industry Status,Growth Opportunities, Top Key Players, Target Audience And Forecast To 2027on July 13, 2020 at 11:05 am
The lymphatic system runs throughout our bodies. Cancers that develop anywhere in body’s lymphatic system are called ...
- What you need to know about lymphoma, the UK’s fifth most common canceron July 13, 2020 at 9:00 am
I want you to think about cancer for a moment. If you are a woman, it is likely that breast cancer will be the first type to spring to mind. For men it will probably be cancer of the prostate or bowel ...
- 'No Question' Patients with Follicular Lymphoma Can Benefit from FDA's Approval of Tazverikon July 13, 2020 at 8:20 am
The Food and Drug Administration’s recent approval of Tazverik (tazemetostat) for the treatment of adults with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation ...
- Merck's Keytruda Gets Priority Review for Lymphoma Indicationon July 10, 2020 at 8:15 am
FDA grants priority review to Merck's (MRK) regulatory application seeking label expansion of Keytruda as second-line treatment for relapsed or refractory classical Hodgkin lymphoma.
- Number of Cases of Breast Implant-linked Lymphoma in the UKon July 8, 2020 at 11:16 pm
As of April 2020, there have been 68 cases of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) reported in the UK. This figure includes cases where the original implantation did not ...
- Lymphoma Research Foundation Scientific Advisory Board Gains New International Leaders in Lymphomaon July 8, 2020 at 9:25 am
The Lymphoma Research Foundation (LRF) – the nation's largest non-profit organization devoted exclusively to funding innovative lymphoma research and serving the lymphoma community through a ...
- Analysis Identifies Predictors of Survival in Older Patients With Mantle Cell Lymphomaon July 7, 2020 at 7:02 am
Data from an analysis of approximately 1,200 patients with mantle cell lymphoma collected across 12 treatment centers presented at the 2020 ASCO Virtual Scientific Program demonstrated that ...
- Evolving insights into the genomic complexity and immune landscape of diffuse large B-cell lymphoma: opportunities for novel biomarkerson July 3, 2020 at 8:38 am
Recently, comprehensive genomic analyses have allowed a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering novel opportunities in patient risk stratification and ...
- Global Hodgkin's Lymphoma Market: Opportunity Analysis and Forecast to 2029 - ResearchAndMarkets.comon July 3, 2020 at 2:02 am
Opportunity Analysis and Forecasts to 2029" report has been added to ResearchAndMarkets.com's offering. The World Health Organization (WHO) classifies HL into two main types: classical HL (CHL) and ...
The Latest Google Headlines on:
The Latest Bing News on:
TREATMENT OF AGGRESSIVE CANCER
- Cancer In The Age Of COVID: Black Breast Cancer Survivors Speak Outon July 14, 2020 at 4:38 pm
- Two new studies highlight possible treatment options for patients with neuroendocrine tumorson July 14, 2020 at 4:31 pm
Two new studies led by Renuka Iyer, MD, Section Chief for Gastrointestinal Oncology at Roswell Park Comprehensive Cancer Center, highlight possible new treatment options for patients with ...
- Ashion Analytics receives Medicare coverage for GEM ExTra® assay for cancer patientson July 14, 2020 at 8:56 am
GEM ExTra, Ashion Analytics's flagship clinical assay, detects tumor-specific mutations, allowing physicians to make the best-available treatment recommendations for patients with advanced solid ...
- New findings about the development of brain tumors could lead to more effective treatmenton July 14, 2020 at 5:18 am
If the cells maintain their stem cell characteristics, particularly aggressive forms of cancer develop ... provide us with a starting point for new treatment strategies." It also explains why ...
- IRICoR and the Quebec Breast Cancer Foundation: Joint $3M investment for new treatmentson July 14, 2020 at 4:42 am
In this context, IRICoR and the Quebec Breast Cancer Foundation (QBCF) have joined forces to fund research on breast cancer, a cancer that affects a large and vulnerable population. Today, they ...
- Novel drug could enable the immune system to attack ovarian canceron July 13, 2020 at 2:58 pm
Immunotherapy is the future of cancer treatment. Our combination of drugs should promote ... But these findings indicate a genetic superhighway that leads right to this highly aggressive disease," Dr.
- How a Couple Got Each Other Through Canceron July 13, 2020 at 2:05 am
What happens when the parents of a young daughter have consecutive bouts of cancer? They close ranks — and reach out.
- Genentech Provides Update on Phase III Study of Tecentriq in Women With Advanced-stage Ovarian Canceron July 12, 2020 at 10:00 pm
Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the Phase III IMagyn050 study showed that the addition of Tecentriq ® (atezolizumab) to Avastin ® (bevacizumab ...
- TGen identifies immune effects of drug in aggressive ovarian cancer striking young womenon July 9, 2020 at 5:00 pm
"Immunotherapy is the future of cancer treatment. Our combination of drugs should promote ... But these findings indicate a genetic superhighway that leads right to this highly aggressive disease," Dr ...
- Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challengeson July 9, 2020 at 5:31 am
Colon cancer inter-tumour heterogeneity is installed on multiple levels, ranging from (epi)genetic driver events to signalling pathway rewiring reflected by differential gene expression patterns.