A groundbreaking study from the University of Cambridge suggests a novel therapeutic combination that could revolutionize the treatment landscape of B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer and one that poses significant treatment challenges for adult patients. This innovative approach promises not only enhanced efficacy but also a dramatic reduction in the harsh side effects that often accompany current chemotherapy regimens, paving the way for kinder and more targeted interventions.
B-ALL is a pernicious cancer characterized by an overproduction of immature B-cells, a vital component of the immune system responsible for antibody production. These malignant cells proliferate within the bone marrow, crowding out healthy blood cells and disseminating to other organs, including the brain, where they can evade conventional therapies. The disease commonly afflicts children, accounting for about 40% of all childhood cancers, but it also affects adults, in whom treatment outcomes are typically poorer.
Current standard-of-care approaches for B-ALL involve lengthy and intensive chemotherapy protocols spanning over two years, which, while often effective in younger patients, carry profound toxicities. Patients endure severe side effects such as immunosuppression leading to infections, bruising, bleeding, nausea, hair loss, and long-term complications affecting the nervous system, joints, and cardiac function. Alternative therapies like bone marrow transplants and CAR-T cell therapy have emerged but present their own challenges, including severe side effects, high costs, and complex logistics.
In a paper published in Nature Communications, a team led by Dr. Simon Richardson and Professor Brian Huntly has unveiled a promising new strategy employing a combination of two oral agents: venetoclax and inobrodib. Venetoclax, already approved for a related blood malignancy, acute myeloid leukemia (AML), functions by inhibiting the BCL2 protein, a key regulator of apoptosis or programmed cell death in cancerous B-cells. However, venetoclax alone shows inconsistent effectiveness against B-ALL, prompting researchers to explore mechanisms underlying resistance.
Their investigations centered on the CREBBP gene, which when mutated or inactivated, contributes to disease progression and chemotherapy resistance. CREBBP plays a crucial role in cellular metabolism and gene expression regulation. Astonishingly, the team discovered that inactivating CREBBP rewires the fat metabolism pathways within malignant B-cells. This metabolic shift sensitizes cells to death by ferroptosis — a form of programmed cell death distinct from apoptosis. Ferroptosis involves the iron-dependent peroxidation of lipids in cell membranes, which, when unchecked, leads to catastrophic cellular damage and demise.
To exploit this vulnerability, the Cambridge researchers utilized inobrodib, an inhibitor of CREBBP developed by CellCentric, a Cambridge spinout company. Through CREBBP inhibition with inobrodib, the cancer cells undergo metabolic rewiring that diminishes their ability to prevent lipid damage. When combined with venetoclax’s blockade of BCL2, this dual insult induces ferroptotic cell death in B-ALL cells, including those harboring mutations that confer resistance to venetoclax alone.
Experimental models using human and mouse B-ALL cells demonstrated that this combination therapy powerfully eradicated malignant early-stage B-cells. Notably, the therapy maintained effectiveness against genetically resilient leukemia cells, highlighting its potential to overcome existing treatment barriers. Professor Huntly emphasized the significance of these findings, noting that venetoclax and inobrodib have been safely combined in early trials for AML, bolstering hopes for rapid translation into clinical trials for B-ALL patients.
This therapeutic innovation carries several clinical advantages. Because the drugs are administered orally, the treatment paradigm could be less invasive and more convenient than current protocols. Moreover, the selective targeting of cancerous B-cells with this approach suggests fewer off-target effects, potentially sparing patients the debilitating toxicities commonly associated with chemotherapy and immunotherapies like CAR-T cells—the latter of which can irreversibly deplete normal B-cell populations, impairing immune competence.
Dr. Richardson elaborated on the immune implications, explaining that although B-cells are depleted during administration, the body’s capacity to regenerate healthy B-cells should restore immune function post-treatment. This transient effect markedly contrasts with permanent B-cell aplasia seen in CAR-T cell therapies, making venetoclax and inobrodib a potentially safer therapeutic option.
An important economic consideration accompanies this therapeutic prospect. Venetoclax’s patent expiration in the near future is anticipated to reduce its cost substantially through generics, improving accessibility and affordability for patients and healthcare systems alike. Such developments could democratize use and alleviate financial burdens associated with novel cancer therapies.
The urgency for improved B-ALL therapies is underscored by the real-life experience of survivors like Gill Murphy, who endured aggressive chemotherapy and stem cell transplant for her disease. Her story reveals the profound physical and psychological toll of current treatments, including prolonged hospitalizations and enduring side effects such as fatigue, early menopause, and cognitive challenges. Murphy’s testimony provides a poignant backdrop for the pressing need to develop more tolerable and effective treatments.
Cancer researchers have long sought strategies that not only eliminate malignant cells but also minimize collateral damage to patients’ quality of life. The Cambridge team’s discovery of ferroptosis induction via CREBBP inactivation, combined with BCL2 inhibition, represents a breakthrough in this quest. By harnessing the cancer cell’s metabolic liabilities, this approach exploits a previously untapped cell death pathway, broadening therapeutic horizons.
Despite the promising preclinical data, rigorous clinical trials are essential before this dual-drug approach can become standard treatment. The researchers are actively pursuing funding to initiate clinical trials involving adults and teenagers with B-ALL. Success in these trials could herald a new era of cancer treatment that balances efficacy with safety and patient well-being.
Beyond B-ALL, this research might also illuminate the role of ferroptosis in other hematologic malignancies and solid tumors, inspiring novel drug combinations that trigger ferroptotic cell death in resistant cancers. As scientists deepen understanding of cancer metabolism and cell death pathways, such targeted treatments could transform oncological care globally.
In conclusion, the combination of venetoclax and inobrodib leverages cutting-edge insights into genetic mutations and metabolic reprogramming to strike at the heart of B-ALL survival mechanisms. Its promise lies not only in potentially overcoming drug resistance but in offering a gentler, more precise treatment pathway that could improve survival while mitigating the physical and emotional burdens endured by patients. As research progresses, hopes rise for a future where blood cancers like B-ALL are not just treatable but conquered with compassion and precision.
Subject of Research: Animals
Article Title: CREBBP inactivation sensitizes B cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition
News Publication Date: 20-May-2025
Web References: 10.1038/s41467-025-59531-6
References: Garcia-Gimenez, A, et al. CREBBP inactivation sensitizes B cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition. Nat Comms; 20 May 2025; DOI: 10.1038/s41467-025-59531-6
Keywords: Blood cancer, Leukemia, Cancer
