Researchers at The Institute of Cancer Research, London, have identified a promising drug combination strategy that could significantly expand treatment options for patients with B-cell lymphoma, particularly those who have developed resistance to existing therapies. The study, published in the journal Blood, demonstrates that combining tazemetostat with the DOT1L inhibitor pinometostat can overcome treatment resistance and potentially benefit thousands of patients with the most common form of B-cell lymphoma.
Addressing Treatment Resistance in B-Cell Lymphoma
B-cell lymphoma develops when white blood cells called lymphocytes grow out of control. For patients with follicular lymphoma, tazemetostat is an approved treatment option, but patient responses vary significantly, with some experiencing cancer recurrence. The situation is more challenging for patients with diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell lymphoma affecting around 5,000 patients in the UK per year, as tazemetostat is not approved for this indication.
The research team, working as part of the SPECIFICANCER initiative funded by Cancer Research UK and the Mark Foundation for Cancer Research through Cancer Grand Challenges, sought to identify ways to increase the number of patients who respond to tazemetostat and extend the duration of cancer control.
Mechanistic Discovery and Preclinical Validation
The researchers employed gene knockout studies in B-cell lymphoma cells to identify key molecular interactions. They discovered that DOT1L is essential for tazemetostat's ability to block cell growth. This finding led them to test the combination of tazemetostat with pinometostat, a DOT1L inhibitor already in clinical trials.
In laboratory studies, the combination successfully shrank follicular lymphoma tumors that had developed resistance to tazemetostat alone. When tested in DLBCL cells, the drug combination also demonstrated the ability to halt tumor growth. Cells treated with the combination showed increased activation of genes linked to growth inhibition, cell death, and immune functions compared to single-agent treatment.
Dramatic Preclinical Efficacy Results
The most compelling evidence came from mouse studies, where the drug combination significantly blocked DLBCL tumor growth without major side effects. After 15 days of treatment, control tumors had tripled in size, and those treated with tazemetostat alone had nearly reached the same size. Tumors treated with the DOT1L inhibitor alone had almost doubled, while those receiving the combination therapy had actually shrunk.
Dual-Target Approach to Overcome Resistance
Tazemetostat targets EZH2, an enzyme that is overexpressed and hyperactive in multiple cancers, including B-cell lymphoma, melanoma, and prostate cancer. However, EZH2 inhibitors have shown mixed results in clinical trials as monotherapies. The researchers believe that simultaneously targeting both EZH2 and DOT1L may provide benefits across a range of cancers by overcoming treatment resistance mechanisms.
Dr. Van Nguyen, postdoctoral training fellow at The Institute of Cancer Research and study co-author, explained the clinical significance: "Tazemetostat is a promising drug but unfortunately, many patients' cancers either do not respond or they start growing again quickly. It's exciting to see that combining it with a DOT1L inhibitor could allow thousands more people to benefit from the treatment."
Clinical Translation Prospects
Professor Kristian Helin, chief executive at The Institute of Cancer Research and study lead, emphasized the broader therapeutic implications: "We need to have more treatment options available to patients that will keep their cancer at bay for longer – and overcome cancer's ability to adapt, evolve, and become drug resistant. Combining drugs which have different mechanisms of action is an important tool in our arsenal to do this."
The research demonstrates particular promise for expanding tazemetostat's utility to DLBCL patients, who currently cannot access this targeted therapy. Professor Helin noted: "We have also shown that the drug combination could work for patients with diffuse large B-cell lymphoma – which has not previously responded to tazemetostat treatment. Expanding the use of a drug which is already clinically approved will hopefully mean that more patients can benefit sooner."
Dr. David Scott, director of Cancer Grand Challenges, highlighted the innovative approach: "This bold and collaborative research from the SPECIFICANCER team exemplifies the kind of innovation Cancer Grand Challenges was created to support. By combining existing treatments in new ways, the team has been able to successfully treat B-cell lymphoma in pre-clinical models. This approach allows us to attack cancer from different angles, overcoming drug resistance and offering patients a faster route to better outcomes."
The research team anticipates that clinical trials will be designed to test this combination in patients, potentially offering a faster path to improved outcomes given that both drugs are already in clinical development or approved for other indications.
