Preclinical data on MD Anderson Cancer Center-developed drug offers hope for Imbruvica-resistant mantle cell lymphoma patients
First approved in 2013 for relapsed/refractory mantle cell lymphoma (MCL), J&J’s Imbruvica is now being used as the first line of defense for the rare, incurable form of non-Hodgkin lymphoma. However, some patients do not respond to the treatment — which scientists attribute to underlying intrinsic or acquired drug resistance. Now, researchers at the University of Texas MD Anderson Cancer Center may have developed a drug that could help Imbruvica-resistant patients.
J&J’s $JNJ Imbruvica, known chemically as ibrutinib, has demonstrated anti-tumor activity with an overall response rate of 68% and median survival duration of 18 months in MCL — but the one-year survival rate is 22% after relapse on Imbruvica.
After isolating tumor cells from the cerebrospinal fluid from a patient who did not respond to multiple therapies including Imbruvica, MD Anderson Cancer Center scientists developed an Imbruvica-resistant B-cell lymphoma mouse model to test the therapeutic potential of their drug, IACS-10759.
In the study, the researchers found that inhibiting key metabolic processes that cancer cells depend on for growth and survival — in particular, oxidative phosphorylation (OXPHOS) and glutaminolysis — was associated with therapeutic resistance to Imbruvica in MCL and poor clinical outcomes. The data was published in the journal Science Translational Medicine on Wednesday.
“Inhibition of OXPHOS with IACS-10759 results in marked growth inhibition in vivo and in vitro in ibrutinib-resistant, patient-derived cancer models,” said, Michael Wang, the trial’s lead investigator, in a statement. Oxidative phosphorylation is an efficient method of producing large amounts of ATP, the basic unit of energy for metabolic processes.
Other trials have focused on the PI3K/AKT/mTOR pathway in relapsed and/or refractory lymphoma, but clinical success thus far has been limited. Evidence from this ongoing study suggests glutaminolysis and OXPHOS pathway activity are prominent sources of energy that support proliferation in Imbruvica-resistant MCL cells.
This preclinical data “warrants the exploitation of active cancer metabolic pathways, especially OXPHOS and glutaminolysis, to improve clinical outcomes for mantle cell lymphoma and other lymphomas,” the researchers said.
A Phase I lymphoma trial, which will include an Imbruvica-resistant cohort, will further investigate the potential of the IACS-10759, they added.
The BTK inhibitor Imbruvica — which is approved for four forms of cancer and graft-versus-host disease — generated 2018 sales of about $2.6 billion globally.