Therapy for non-small cell lung cancer using dual EZH2 inhibition and chemotherapy
Inventors: Carla Kim, Christine Fillmore
Invention Types: Therapeutics, Diagnostic/Prognostic
Research Areas: Allergy/Respiratory/Pulmonary Disease, Oncology/Hematology
Keywords: Biomarker, Cell Line, Drug Discovery, Gene expressionFor More Information Contact: Wong, Adrienne
Precision medicine is widely heralded as the future for more effective cancer therapies. Trained as geneticists, members of the Kim Laboratory at Boston Children’s Hospital have discovered a useful combination of drugs for the very complex disease of non-small cell lung cancer. While critics of precision medicine have raised concerns that this approach will take decades, the Kim Lab has a potentially groundbreaking treatment right now.
Epigenetic mechanisms such as histone modifications are important for the regulation of gene expression programs in metastatic and chemotherapy resistant cancer cells. High expression of EZH2, a histone-modifying enzyme of the Polycomb Repressive Complex 2 (PRC2), is observed in lung non-small cell lung cancers, correlating with high tumor grade and poor prognosis. The focus of the Kim Lab research was to find a way to incorporate the epigenetic therapy, namely inhibition of the enzyme EZH2, with current chemotherapies. These studies link, for the first time, mutations common in lung cancer to targeted epigenetic therapies. For most targeted, or precision therapeutics so far, the mutational status of the drug target is considered. Importantly, the genetic mutations that were biomarkers for drug efficacy were not in the gene coding the target of the epigenetic therapy. This is a new layer to precision medicine for cancer, where considering mutations in genes other than the drug target may become very important.
This study, published in Nature this January, shows that treatment with EZH2 inhibitors caused differential sensitivities to the chemotherapeutic agent etoposide; some cell lines were sensitized and others were protected from the chemotherapy treatment. Mutations in BRG1 (SMARCA4), EGFR, or B-RAF were identified as biomarkers that responsiveness to combination EZH2 inhibitor and chemotherapy treatment. Based on these findings, dual EZH2 inhibition and chemotherapy may be a viable treatment for these specific genetic subsets of lung cancers. These drugs already exist: VP-16 is orally bio-available etoposide with full FDA approval, and specific EZH2 inhibitor is in Phase 1 clinical trials for other cancer types. We hope to move forward with more preclinical and clinical testing of this combination, especially given that it could be a precision medicine option for up to 25% of non-small cell lung cancer patients.
• Diagnostic assay to determine/predict sensitivity of lung cancers to dual epigenetic therapeutic agent (ie EZH2 inhibitor) and chemotherapy treatment.
• Combination therapy of EZH2 inhibitor and chemotherapy for treatment lung cancers with BRG1, EGFR, or B-RAF sensitizing mutations.
• Lung cancer patients resistant to standard chemotherapy may be sensitized to treatment by PRC2/EZH2 inhibition.
• Inhibition of the PRC2 complex may disrupt cancer stem cell and resistance gene expression programs, leading to more effective cancer treatment.
• Sponsored research
• License opportunity
Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature. 2015 Jan 28;520:239-42.
Zhang H, Qi J, Reyes JM, et al. Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov. 2016 Sep;6(9):1006-21.
Related Publications: Pat. US 9,895,390 B2
IPStatus: Pat. Pend.