Dr. Amengual on Novel Therapeutics in Lymphoma

Jennifer E. Amengual, MD
Published: Tuesday, Jan 21, 2014

Jennifer E. Amengual, MD, assistant professor of medicine and developmental therapeutics, member, Center for Lymphoid Malignancies, Columbia University, discusses the development of novel agents for subtypes of diffuse large b-cell lymphoma.

The understanding of molecular pathogenesis of diffuse large b-cell lymphoma has lead to the identification of three main subtypes: the germinal center subtype, the ABC subtype, and type 3 or primary mediastinal, Amengual says.

Amengual says most of the work lately has focused on developing novel therapeutics for the ABC subtype, which has a worse prognosis than the germinal center subtype. Because ibrutinib and lenalidomide have started to change the treatment of ABC subtype lymphoma, the focus has now shifted to develop novel agents for the germinal center subtype of diffuse large b-cell lymphoma.

It’s been shown that BCL6, which drives the subtype, can be modulated through acetylation, Amengual says. Treatment with HDAC inhibitors can shift the balance between suppressing the oncogene BCL6 and by activating a tumor suppressor such as P53.

In preclinical models of diffuse large b-cell lymphoma, Amengual says, physicians were able to enforce acetylation of BCL6 and P53, which leads to induction of apoptosis. This was validated in mouse models and was then translated to a clinical trial of patients with relapsed/refractory lymphoma. It was found that in a heavily pretreated cohort of patients, there was a 24% overall response rate with the treatment with HDAC inhibitors vorinostat and niacinamide, Amengual says.

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Jennifer E. Amengual, MD, assistant professor of medicine and developmental therapeutics, member, Center for Lymphoid Malignancies, Columbia University, discusses the development of novel agents for subtypes of diffuse large b-cell lymphoma.

The understanding of molecular pathogenesis of diffuse large b-cell lymphoma has lead to the identification of three main subtypes: the germinal center subtype, the ABC subtype, and type 3 or primary mediastinal, Amengual says.

Amengual says most of the work lately has focused on developing novel therapeutics for the ABC subtype, which has a worse prognosis than the germinal center subtype. Because ibrutinib and lenalidomide have started to change the treatment of ABC subtype lymphoma, the focus has now shifted to develop novel agents for the germinal center subtype of diffuse large b-cell lymphoma.

It’s been shown that BCL6, which drives the subtype, can be modulated through acetylation, Amengual says. Treatment with HDAC inhibitors can shift the balance between suppressing the oncogene BCL6 and by activating a tumor suppressor such as P53.

In preclinical models of diffuse large b-cell lymphoma, Amengual says, physicians were able to enforce acetylation of BCL6 and P53, which leads to induction of apoptosis. This was validated in mouse models and was then translated to a clinical trial of patients with relapsed/refractory lymphoma. It was found that in a heavily pretreated cohort of patients, there was a 24% overall response rate with the treatment with HDAC inhibitors vorinostat and niacinamide, Amengual says.




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