Thousands of patients with a common type of blood cancer could benefit from a new drug combination, while others could see their disease kept at bay for longer.
Research published in the journal Blood shows that the drug tazemetostat – which is already approved for use in patients with one type of B-cell lymphoma – could work better when combined with another targeted drug. It could also work for patients with the most common type of B-cell lymphoma, affecting thousands of patients.
Patients have varying responses to treatment
B-cell lymphoma is a type of cancer that develops when white blood cells called lymphocytes grow out of control.
For patients with follicular lymphoma, treatment can include the drug tazemetostat – but patients have varying responses, and some see their cancer return. Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma, affecting around 5,000 patients in the UK per year – tazemetostat is not approved for patients with this cancer.
Researchers at The Institute of Cancer Research, London, have been searching for a way to increase the numbers of patients who respond to tazemetostat and keep cancers under control for longer.
They worked as part of the SPECIFICANCER team funded by Cancer Research UK and the Mark Foundation for Cancer Research, through Cancer Grand Challenges (a global initiative co-founded by Cancer Research UK and the National Cancer Institute in the US).
The SPECIFICANCER team have previously shown that drugs such as tazemetostat can be more effective for other hard-to-treat cancers such as triple-negative breast cancer and colorectal cancer, when used in combination with other drugs.
DOT1L interacts with the drug
The researchers at The Institute of Cancer Research (ICR) first knocked out genes in B-cell lymphoma cells, in the presence and absence of tazemetostat, and found that DOT1L is needed to interact with the drug to block cell growth.
They discovered that combining tazemetostat with a DOT1L inhibitor drug called pinometostat, that is already in clinical trials, can shrink follicular lymphoma tumours in the lab that have developed resistance to tazemetostat.
The researchers then tested the combination in DLBCL cells and found that the new drug combination could also stop tumours from growing in this group of patients.
The cells treated with the combination of drugs had more genes switched on linked to growth inhibition and cell death, as well as immune functions than those treated with one drug alone.
New drug combination shrinks tumours
In mice, the drug combination significantly blocked DLBCL tumour growth, with no major side effects. After 15 days, tumours left to grow on their own had tripled in size and those treated with tazemetostat alone had also almost reached this size. Those treated with the DOT1L inhibitor alone had almost doubled, whilst those treated with the drug combination had shrunk.
Tazemetostat targets EZH2 – an enzyme that is overexpressed and hyperactive in a number of cancers, including B-cell lymphoma, melanoma and prostate cancer. EZH2 inhibitors on their own have had mixed results in clinical trials – including in those for B cell lymphoma. The researchers believe that this new combination targeting both EZH2 and DOT1L may therefore be beneficial for a range of cancers, to overcome treatment resistance.
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'Combining drugs... is an important tool in our arsenal'
Dr Van Nguyen, Postdoctoral Training Fellow at The Institute of Cancer Research, London, and study co-author, said:
“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.”
Professor Kristian Helin, Chief Executive at The Institute of Cancer Research, London, and study lead, said:
“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.
“For some types of blood cancer, we have shown that combining the targeted drug tazemetostat with an inhibitor of the DOT1L enzyme could shrink tumours that have stopped responding to tazemetostat treatment alone. 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, and I look forward to seeing clinical trials designed to test this combination in patients.”
'Attack cancer from different angles'
Director of Cancer Grand Challenges, Dr David Scott, said:
"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.”