MD Anderson Develops Drug IACS-10759 from Concept to Phase I

An MD Anderson-developed drug looks to be effective in overcoming ibrutinib resistance in mantle cell lymphoma. The University of Texas, MD Anderson Cancer Center led a study demonstrating how a small molecule drug discovered at the institution may help overcome resistance to treatment with ibrutinib in patients with mantle cell lymphoma.

Known as IACS-10759, it was the first therapy to be developed from concept to clinical trial by MD Anderson’s Therapeutics Discovery division, a unique drug-discovery engine created to answer unmet patient needs. IACS-10759 is currently in Phase I clinical trials for acute myeloid leukemia as well as for solid tumors and lymphoma. Recent results from the latest study, as reported in EurekAlert!, were published online in Science Translational Medicine.

The recent study investigated the link between metabolic reprogramming and cancer cell growth, metastasis and therapeutic resistance, using three different patient-derived xenograft mouse models and genome analysis specimens.  Metabolic reprogramming is an emerging hallmark of tumor biology of which cancer cells evolve to rely on two key metabolic processes: glycolysis and oxidative phosphorylation (OXPHOS)—to support their growth and survival.

Michael Wang, MD and professor of Lymphoma as well as study lead noted, “to investigate the therapeutic effects of IACS-10759, we developed an ibrutinib-resistant B-cell lymphoma mouse model using tumor cells isolated from cerebrospinal fluid from a patient who did not respond to multiple therapies including ibrutinib.” He continued, “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.”

Ibrutinib was approved by the U.S. Food and Drug Administration in 2013 for treatment of relapsed/refractory mantle cell lymphoma and is now used as a front-line therapy. The drug has demonstrated anti-tumor activity with an overall response rate of 68 percent and median survival duration of 18 months.

Given that the one-year survival rate is 22 percent after relapse on ibrutinib, there is an urgent need to identify alternate therapeutic options for mantle cell lymphoma, according to co-senior author Linghua Wang, Ph.D., assistant professor of Genomic Medicine, who 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.

Lead Research/Investigator

Michael Wang, MD