29 March 2018

A mechanism of therapy resistance in aggressive diffuse large B-cell lymphoma has been revealed by Swiss scientists - suggesting potential treatment targets.

The researchers from the Ecole Polytechnique Federale de Lausanne (EPFL), say the treatment, which targets lymphoma signalling at its root, could be effective in a broad group of patients.

Writing in the latest edition of Blood, the team says that one of the driving forces behind non-Hodgkin lymphomas is the over-activation of a receptor on the surface of B cells.

The receptor normally stimulates the growth of B-cells only when it is needed, but in non-Hodgkin lymphoma, the growth signal is unable to switch off, which results in the uncontrolled growth of B-cells.

Recent studies have tried to block the signal by inhibiting the activation of the B-cell. One of those saw ibrutinib being tested in clinical trials to treat the aggressive diffuse large B-cell lymphoma (DLBCL).

While the drug was found to block the enzyme BTK (Bruton’s tyrosine kinase), it is successful in only to a sub-group of DLBCL patients.

The team at EPFL worked to identify why there is resistance to ibrutinib. When they used tumour cells from DLBCL patients, the researchers found that the inactivation of BTK in resistant tumours triggered over-activation of alternative signals promoting tumour cell survival and proliferation.

The team, including Elena Battistello, who led the project targeted the enzymes LYN, FYN, and BLK, which initiate the propagation of the signals.  Blocking these enzymes completely stopped the B-cell receptor pro-tumorigenic signals and strongly impaired tumour growth in all of the DLBCL patient-derived tissues that the team tested.

“The three enzymes can be promising therapeutic targets for a diverse and broad group of DLBCL patients” the researchers say.

Source: Battistello E, Katanayeva N, Dheilly E et al. Pan-SRC kinase inhibition blocks B-Cell Receptor oncogenic signaling in Non- Hodgkin Lymphoma. Blood. 22 March 2018; doi: 10.1182/blood-2017-10-809210

Link: http://www.bloodjournal.org/content/early/2018/03/21/blood-2017-10-809210?sso-checked=true


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