09 March 2020

Japanese scientists have revealed a new strategy that has potential for the treatment of a form of non-Hodgkin’s lymphoma which currently has a poor prognosis.

The condition, angioimmunoblastic T-cell lymphoma (AITL), has a five-year survival rate of below 30%. Many patients carry mutations in specific genes, including DNMT3A, TET2, IDH2, and RHOA.

A team of researchers from the University of Tsukuba in Japan set out to investigate the exact role of some of these gene mutations in the development of the disease. In particular, the team were interested in a mutation in the RHOA gene, which occurs in between 50-70% of AITL samples, as well as mutations in TET2. Up to 70% of AITL cases carry mutations in both genes.

The team first created a mouse model of AITL, which carries a mutant RHOA gene and lacks both copies of TET2. They showed that this led to AITL-like symptoms in these mice, and that this process depends on T-cell receptor signalling.

Dasatinib is a multi-kinase inhibitor already used to treat Philadelphia chromosome-positive leukaemias. The researchers suspected that it might interfere with the T-cell receptor signalling pathway. They showed that dasatinib was able to suppress disease progression in their mouse model.

Finally, they carried out an early stage trial of dasatinib with human patients. This phase 1 clinical trial involved five patients with relapsed or refractory AITL after chemotherapy and/or autologous stem cell transplant. One patient withdrew from the trial, but of the four remaining patients, all showed a partial response to dasatinib.

Their study appeared recently in the journal Cancer Research.

Dr Mamiko Sakata-Yanagimoto, who co-led the research with Prof Shigeru Chiba, explains: “Our findings suggest that angioimmunoblastic T-cell lymphoma is highly dependent on T-cell receptor signalling and that dasatinib could be a promising candidate drug for treatment.

Prof Chiba adds: “Currently there are no monotherapies that satisfactorily improve overall survival in relapsed or refractory cases. Our work suggests that targeting the T-cell receptor pathway should be considered in developing angioimmunoblastic T-cell lymphoma treatment strategies.”


Source: Nguyen TB, Sakata-Yanagimoto M, Fujisawa M, Tanzima Nuhat S, Miyoshi H, Nannya Y, Hashimoto K, Fukumoto K, Bernard OA, Kiyoki Y, Ishitsuka K, Momose H, Sukegawa S, Shinagawa A, Suyama T, Sato Y, Nishikii H, Obara N, Kusakabe M, Yanagimoto S, Ogawa S, Ohshima K, Chiba S (2020) “Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma”, Cancer Research, doi: 10.1158/008-5472.CAN-19-2787

 

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