Novel Drug Combination Shows Promise for B-Cell Acute Lymphoblastic Leukemia with Reduced Toxicity
核心洞察
Cambridge researchers have developed a promising combination therapy using venetoclax and inobrodib that effectively targets B-cell acute lymphoblastic leukemia (搜索) (B-ALL (搜索)), potentially reducing the need for toxic chemotherapy.
The drug combination works by exploiting cancer cell metabolism, triggering ferroptotic cell death even in cells resistant to venetoclax alone, offering new hope for both pediatric and adult patients.
Unlike current treatments that require over two years of chemotherapy or risky procedures like bone marrow transplants, this oral therapy could provide a less toxic alternative while maintaining effectiveness.
Cambridge scientists have discovered that combining two oral drugs—venetoclax and inobrodib—could significantly improve treatment outcomes for patients with B-cell acute lymphoblastic leukemia (搜索) (B-ALL (搜索)), potentially reducing reliance on toxic chemotherapy regimens that currently dominate treatment protocols.
B-ALL (搜索), the most common childhood cancer accounting for 40% of all pediatric cancer cases, affects over 500 people annually in the UK alone. While the disease is curable in many younger patients, current treatments require more than two years of intensive chemotherapy, causing severe side effects including immunosuppression, bleeding, hair loss, nausea, and potential long-term damage to nerves, joints, and the heart. Treatment outcomes are typically much poorer for older children and adults.
"Every week, I see adult patients who are undergoing treatment for this incredibly aggressive form of leukemia, and although the chemotherapy can cure many of them, the side effects are often really challenging. We need to find treatments that are kinder and more effective," said Dr. Simon Richardson from the Cambridge Stem Cell Institute (搜索) and Department of Hematology, University of Cambridge.
Understanding the Science Behind the New Approach
The research, published in Nature Communications, reveals a novel therapeutic strategy developed by Dr. Richardson and Professor Brian Huntly's team. Their approach targets the fundamental biology of B-ALL (搜索), which is characterized by malignancies of early-stage B-cells—immune cells produced in bone marrow that normally create antibodies to fight infections.
In B-ALL (搜索), these cells proliferate uncontrollably, crowding the bone marrow and preventing healthy blood cell development. The malignant cells can also spread throughout the body, including to the brain where they may evade conventional treatments.
The new treatment combines two medications:
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Venetoclax: Already used to treat acute myeloid leukemia (搜索) (AML (搜索)), this drug targets the BCL2 (搜索) protein in B-cells, triggering programmed cell death (apoptosis). However, venetoclax alone has shown inconsistent effectiveness against B-ALL (搜索).
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Inobrodib: Developed by CellCentric (搜索), a University of Cambridge spinout company, this drug switches off the CREBBP (搜索) gene, which when mutated contributes to disease progression and chemotherapy resistance in B-ALL (搜索).
The researchers discovered that inactivating CREBBP (搜索) leads to a rewiring of fat metabolism in B-cells. When BCL2 (搜索) activity is subsequently inhibited by venetoclax, it triggers a different form of cell death called ferroptosis—where cells can no longer protect themselves against damage to membrane fats, causing cellular breakdown.
Promising Preclinical Results
In laboratory studies using human and mouse models of B-ALL (搜索), the combination potently killed early-stage B-cells, even those carrying genetic mutations that made them resistant to venetoclax treatment alone.
"These are very promising findings, and even though our work was only in mice, we're optimistic that we will see similar effects in patients," said Professor Huntly, who also heads the Department of Haematology. "Venetoclax and inobrodib have already been used together in an early-stage clinical trial for AML (搜索), so we know they are safe to use. We now want to trial our approach in adults and teenagers with B-ALL (搜索)."
Advantages Over Current Treatments
This approach offers several potential advantages over existing therapies:
- Both drugs can be administered orally, unlike many current treatments that require intravenous administration
- The treatment specifically targets cancerous B-cells, potentially reducing off-target effects
- While the therapy destroys B-cells during treatment, the body should begin producing them again once treatment stops, making it potentially safer than alternatives like CAR-T cell therapy, which can permanently eliminate B-cell production
- The cost of venetoclax is expected to decrease in coming years with the introduction of generic alternatives, improving accessibility
The Patient Perspective
The need for improved treatments is highlighted by the experience of survivors like Gill Murphy, who was diagnosed with B-ALL (搜索) at age 42 when her daughter was just two years old.
Murphy underwent intensive chemotherapy alongside rituximab, an immunotherapy drug, experiencing severe side effects including vomiting, diarrhea, migraines, hair loss, and extreme fatigue. Due to her immunosuppression, she was often unable to see her young daughter, who had developed infections after starting nursery.
Following her initial treatment, Murphy required a stem cell transplant, a risky procedure that made her extremely ill. "I'd been quite stoic when I was first diagnosed. I treated it as a project, like, 'Right, you've got to get rid of this cancer'. The longer it went on, the more scared I got. There were a lot of sleepless nights... It was really hard."
Although the transplant was successful and Murphy's leukemia is now in remission, she continues to experience long-term effects including chronic fatigue, early menopause, steroid-induced diabetes, cataracts, osteomyelitis, increased susceptibility to infections, and cognitive challenges.
"The doctors I meet all want to see kinder, more targeted treatments," Murphy says. "Anything that we can do to improve treatments so more people can survive their blood cancer and fewer people have to go through incredibly harsh therapies is a win-win."
Next Steps
The Cambridge team is now seeking funding to begin clinical trials in patients. Professor Huntly and Dr. Richardson, who are both Honorary Consultant Haematologists at Addenbrooke's Hospital, Cambridge, are optimistic about translating their findings to the clinic.
The research was largely funded by Cancer Research UK and Leukemia UK (搜索), with additional support from the University of Cambridge and Addenbrooke's Charitable Trust, which are fundraising for a new hospital to transform cancer diagnosis and treatment.
If successful in clinical trials, this dual-drug approach could represent a significant advancement in B-ALL (搜索) treatment, offering new hope to patients of all ages while reducing the physical and emotional toll of current therapies.