14 May 2019

A new drug could help patients with mantle cell lymphoma when the disease does not respond to treatment with ibrutinib, US researchers have reported.

IACS-10759 is in phase I clinical trials for acute myeloid leukaemia, solid tumours and lymphoma. A new study, published in Science Translational Medicine, has explored the drug's effectiveness in mantle cell lymphoma, which makes up 6-8% of non‑Hodgkin’s lymphomas.

The US study explored the link between metabolic reprogramming and cancer cell growth, metastasis and therapeutic resistance, using three different patient-derived xenograft mouse models and genomic analysis of samples donated by patients.

The one-year survival rate of those whose cancer relapses and does not respond to ibrutinib is 22%. Because of this the researchers say there is an urgent need to develop new options for this hard-to-treat group.

The team from The University of Texas MD Anderson Cancer Center sequenced 21 samples from patients with MCL that was either sensitive or resistant to ibrutinib. They discovered that an increase in oxidative phosphorylation (OXPHOS) was linked to ibrutinib resistance.

They found IACS-010759, a small molecule that inhibits OXPHOS by targeting an energy-generating process in mitochondria, reduced tumour growth and extended survival when administered to mouse models of ibrutinib-resistant MCL.

The researchers hope that OXPHOS could be a new target for ibrutinib-resistant MCL.

Dr Michael Wang, professor of lymphoma and myeloma and study lead at The University of Texas MD Anderson Cancer Center, said: “To investigate the therapeutic effects of IACS-10759, we developed an ibrutinib-resistant B-cell lymphoma mouse model using tumour cells isolated from cerebrospinal fluid from a patient who did not respond to multiple therapies including ibrutinib.

“We showed that metabolic reprogramming toward OXPHOS and glutaminolysis is associated with therapeutic resistance to ibrutinib in mantle cell lymphoma, an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with IACS-10759 results in marked growth inhibition in vivo and in vitro in ibrutinib-resistant, patient-derived cancer models.”

Although clinical trials have focused on targeting the PI3K/AKT/mTOR pathway in relapsed and refractory lymphoma, clinical success has been limited. Professor Wang's team showed that glutaminolysis and OXPHOS are a prominent energy metabolism pathway in ibrutinib-resistant mantle cell lymphoma cells.

Co-senior author Dr Linghua Wang, assistant professor of lymphoma and myeloma, said the study "warrants the exploitation of active cancer metabolic pathways, especially OXPHOS and glutaminolysis, to improve clinical outcomes for mantle cell lymphoma and other lymphomas”.

Further investigation is ongoing and with a Phase I lymphoma trial that will include an ibrutinib-resistant cohort.


Source: Zhang, L., Yao, Y., Zhang, S., Liu, Y., Guo, H., Ahmed, M., Bell, T., Zhang, H., Han, G., Lorence, E., Badillo, M., Zhou, S., Sun, Y., Di Francesco, M.E., Feng, N., Haun, R., Lan, R., Mackintosh, S.G., Mao, X., Song, X., Zhang, J., Pham, L.V., Lorenzi, P.L., Marszalek, J., Heffernan, T., Draetta, G., Jones, P., Futreal, A., Nomie, K., Wang, L., Wang, M. (2019) “Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma”, Science Translational Medicine, available from doi: 10.1126/scitranslmed.aau1167


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