Investigational Drug May Help Drug Resistance in Mantle Cell Lymphoma Treatment

A small molecule drug may help to overcome resistance to Imbruvica (ibrutinib) in patients with mantle cell lymphoma (MCL), according to preclinical study findings from The University of Texas MD Anderson Cancer Center.

“There is potentially a new therapeutic option for these patients that had very limited options previously,” said Dr. Krystle Nomie, from the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with CURE.

The Food and Drug Administration approved Imbruvica for the treatment of patients with relapsed/refractory MCL in 2013. While the drug has demonstrated antitumor activity with an overall response rate of 68% and a median duration of response of about 18 months, the one-year survival rate is 22% after patients relapse on it, “prompting an urgent need to identify alternative therapeutic options that will benefit this patient population,” the researchers wrote.

“These patients only live from four to eight months. The existing therapies cannot cure them, and they have very low efficacy in this population. These patients are dying every day, so the unmet clinical need is very urgent,” added Dr. Michael Wang, M.D., study lead and professor of lymphoma and myeloma at MD Anderson.

Therefore, the researchers explored the link between metabolic reprogramming — where cancer cells evolve to rely on two key metabolic processes to support their growth and survival – and cancer cell growth, metastasis and therapeutic resistance to Imbruvica in MCL.

Using the investigational drug IACS-10759 (currently in phase 1 clinical trials for acute myeloid leukemia as well as for solid tumors and lymphoma), the researchers saw noticeable growth inhibition in vitro and in vivo in Imbruvica-resistant patient-derived cancer models, suggesting “that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies,” they wrote.

“We now know that we can target this pathway to essentially kill the resistant cells,” added Nomie. “It was unknown that this was an actionable target in ibrutinib-resistant cell lymphoma.”

She added that, based on these preclinical trial findings, the researchers plan to add an Imbruvica-resistant MCL cohort to one of the ongoing trials at MD Anderson to test the efficacy of IACS-10759 in the clinic.

“The future of MCL programs are continuing the progression of new discoveries — targeted therapies, immunotherapies and cell therapies,” said Wang. “What is even more exciting will be precision medicine – sequencing the DNA and proteins to find the disease resistance mechanisms in each patient and using precision medicine to treat each patient individually.”