Agencies / Researchers from the University of Cambridge have developed a new dual therapy that may offer hope for patients with B-ALL acute lymphoblastic leukemia (ALL), the most common cancer in children.
The treatment is expected to improve the chances of recovery and reduce reliance on chemotherapy, which is known for its side effects, according to a new study published in Nature Communications.
Although the study has so far been conducted on laboratory cells and lab mice, the research team is seeking funding to soon begin human clinical trials.
Acute lymphoblastic leukemia
B-ALL acute lymphoblastic leukemia affects more than 500 people a year in the UK, 40% of whom are children.
Although most cases are curable in young people, treatment requires more than two years of intensive chemotherapy, leaving patients vulnerable to infections and severe side effects such as hair loss, nausea and vomiting, bruising and bleeding, as well as long-term complications involving nerves, joints and the heart. For adolescents and adults, the results are often worse.
The researchers developed a combination of two drugs, Venetoclax and Inobrodib. The former is currently used to treat another type of leukemia, but is not always effective against acute lymphoblastic leukemia.
That’s where inoprodib, a new drug developed by Cambridge University’s Cellcentric, comes in.
The drug inactivates the CREBBP gene, changing the way cells consume fat, making them susceptible to a unique type of “programmed cell death” known as ferroptosis, which is different from classic cell death and occurs as a result of damage to cell membranes by oxidized lipids.
The CREBBP gene is responsible for producing a protein that plays a pivotal role in regulating the activity of many genes within cells, by modifying the structure of DNA and facilitating gene transcription.
This protein acts as an important regulator in cell growth and division and is involved in controlling inflammation and immune responses.
In conditions such as B-ALL acute lymphoblastic leukemia, mutations or disruption of the function of this gene can lead to dysregulation of cancer cell growth and increased resistance to chemotherapy, making it a central target in research to develop more effective treatments.
Apoptosis
Ferroptosis is a type of programmed cell death, different from other forms such as apoptosis, characterized by the accumulation of iron and oxidative damage to lipids in cell membranes, ultimately leading to cell disintegration and death.
This type of cell death occurs when a cell fails to protect itself from oxidative reactions that target fats, and iron is a key element in accelerating this process.
It is also important in a number of diseases such as cancer and neurological diseases, and has become an emerging target in the development of new therapies, especially for cancers that show resistance to conventional treatments, such as some types of leukemia.
When inoprodib was combined with venetoclax, effective eradication of B-cell tumor cells, even those that were resistant to treatment, was observed.
Cancerous B cells, a type of white blood cell responsible for producing antibodies, underwent a cancerous transformation, causing them to multiply uncontrollably and form tumors in the lymphatic system.
Genetic mutations
These cells arise as a result of genetic mutations that disrupt the mechanism of apoptosis and cell division, and the most common types include chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and multiple myeloma.
These cells differ from normal B cells in their shape, size and behavior. They lose their ability to perform their immune function properly while continuing to proliferate, disrupting the immune system and causing symptoms such as enlarged lymph nodes, anemia, and an increased risk of infection.
Treatment depends on the type and stage of the tumor and includes chemotherapy, immunotherapy, and stem cell transplantation in some cases.
Although the study is still in its early stages, and only on mice, the results are very encouraging.
“A Major Advantage”
The big advantage of this approach is that it does not completely eliminate B cells as some modern therapies, such as CAR-T cell therapy, do, allowing the body to reproduce them after treatment stops, thus minimizing the risk of long-term damage to the immune system.
The story of Jill Murphy, who was diagnosed with this type of cancer in 2013, highlighted the intense suffering that patients go through. Thinking her symptoms were caused by a simple anemia, she was diagnosed with leukemia and spent weeks in the hospital receiving chemotherapy, living with the harsh consequences of hair loss, nausea, and not being able to see her baby due to her weakened immune system.
“I was treating the disease as a project to be accomplished, but over time the fear became greater, and there were long nights without sleep,” Jill said.
After undergoing a stem cell transplant, she achieved a cure, but now lives with what she describes as a “new normal” with lasting side effects such as fatigue, diabetes, and cognitive issues.
However, Jill has found new meaning in her life, becoming an ambassador for the Leukemia Society in the UK, passing on her experience and supporting other patients, emphasizing that the treatment situation today is much better than it was 12 years ago.
Clinical trials
The Cambridge team is aiming to launch clinical trials soon, capitalizing on the expected lower cost of Venetoclax, with “generic versions of the drug” coming to market, which could make the treatment more available.
The Cambridge Cancer Research Hospital, in partnership with Addenbrooke’s Hospital Trust, aims to accelerate the pace of medical discoveries and spread their benefits to cancer patients across the UK.
