Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks—DNA methylation, histone modifications, chromatin remodeling, and microRNA—can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.
Key Points• MRD eradication is a desirable end point in chronic lymphocytic leukemia.• Early MRD eradication may prompt treatment discontinuation.The high complete remission rate with first-line combined fludarabine, cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal residual disease (MRD)-negative status as a treatment end point. We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR. MRD was prospectively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment. After course 3 and at final response assessment, 17% and 43% of patients were MRD negative in bone marrow, respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses (MVAs). MRD-negative status was independently associated with significantly longer progression-free survival (PFS) and overall survival (OS) in MVA (P 5 .03 and .02, respectively). This association was confirmed also on landmark MVA at the time of MRD assessment (P 5 .04 and .05, respectively). MRD-negative patients had comparable PFS and OS, independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment. This trial was registered at www.clinicaltrials.gov as #NCT00759798. (Blood. 2014;123(24):3727-3732)
A B S T R A C T PurposeTo evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and MethodsPatients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m 2 intravenously (IV) daily ϫ 3 (days 4 to 6), and cytarabine 1.5 g/m 2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. ResultsAfter a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. ConclusionThe combination of vorinostat with idarubicin and cytarabine is safe and active in AML.
Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.
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