A study at The University of Texas MD Anderson Cancer Center demonstrated how a small molecule drug discovered at the institution may help overcome resistance to treatment with ibrutinib in patients with mantle cell lymphoma.
The drug, IACS-10759, 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.
Results from a study exploring the drug's effectiveness in ibrutinib-resistant mantle cell lymphoma were published in the May 8 online issue of Science Translational Medicine.
The 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 specimens. Metabolic reprogramming is an emerging hallmark of tumor biology in which cancer cells evolve to rely on two key metabolic processes - glycolysis and oxidative phosphorylation (OXPHOS) - to support their growth and survival.
"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," said Michael Wang, M.D., professor of Lymphoma & Myeloma and study lead. "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."
Clinical trials nationally have focused on the PI3K/AKT/mTOR pathway in relapsed and/or refractory lymphoma, but clinical success thus far has been limited. Wang's team showed evidence that glutaminolysis and OXPHOS appear to be a prominent energy metabolism pathway in ibrutinib-resistant mantle cell lymphoma cells.
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.
MD Anderson study team members included Liang Zhang, Ph.D.; Yixin Yao, Ph.D.; Yang Liu, Ph.D.; Hui Guo, Ph.D.; Makhdum Ahmed, M.D., Ph.D.; Taylor Bell; Hui Zhang; Elizabeth Lorence; Maria Badillo; and Krystle Nomie, Ph.D., all of the Department of Lymphoma & Myeloma; Shaojun Zhang, Ph.D.; Guangchun Han, Ph.D.; Xingzhi Song, Ph.D.; Jianjua Zhang, M.D., Ph.D.; Giulio Draetta, M.D., Ph.D.; and Andrew Futreal, Ph.D., of the Department of Genomic Medicine; Shouhao Zhou, Ph.D., of the Department of Biostatistics; Yuting Sun, Ph.D.; Emilia Di Francesco, Ph.D.; Tim Heffernan, Ph.D.; and Philip Jones, Ph.D., of the Institute for Applied Cancer Science and Center for Co-Clinical Trials; Lan Pham, Ph.D., of the Department of Hematopathology; and Philip Lorenzi, Ph.D., of the Department of Bioinformatics and Computational Biology. The Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences also participated in the study.
The study was funded by the National Institutes of Health (P30 CA016672, 1S10OD012304-01, and R21 CA202104); the Cancer Prevention and Research Institute of Texas (RP130397); T. Gary Rogers; the Kinder Foundation; the Cullen Foundation; the Leukemia and Lymphoma Society; and the Institute for Applied Cancer Science at MD Anderson. Wang reported no competing interests.
The study was also supported with funding from the B-Cell Lymphoma Moon Shot™, part of MD Anderson's Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives. The Moon Shots Program also supports the platforms of the Therapeutics Discovery division.
Science Translational Medicine