Pralatrexate in Chinese Patients with Relapsed or Refractory Peripheral T-cell Lymphoma: A Single-arm, Multicenter Study.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is associated with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. Pralatrexate, a folate analogue inhibitor, was the first drug approved to treat R/R PTCL. OBJECTIVE: As the distribution of PTCL subtypes differs between populations and few patients in the pivotal trial of pralatrexate were Asian, this study investigated the safety and efficacy of pralatrexate as monotherapy in Chinese patients with R/R PTCL. PATIENTS AND METHODS: In this single-arm, open-label, multicenter study, 71 patients with R/R PTCL (median [range] 2 [1-14] prior systemic treatments) were recruited from 15 centers in China and received pralatrexate IV 30 mg/m2/week for 6 weeks in 7-week cycles (with vitamin B12/folate). The primary endpoint was objective response rate (ORR) per central review (null hypothesis: ORR < 15%). RESULTS: The study's primary objective was met: ORR (95% CI) was 52% (40-64%) (p < 0.001) and responses were observed across pre-specified patient subgroups. Median (95% CI) duration of response was 8.7 (3.3-14.1) months and first response was observed in Cycle 1 for most (84%) patients. Median (95% CI) progression-free survival and overall survival was 4.8 (3.1-8.1) months and 18.0 (10.4-NA) months, respectively. The most common treatment-emergent adverse events were stomatitis (68% [Grade 3/4: 20%]), anemia (49% [Grade 3/4: 24%]) and alanine aminotransferase increase (41% [Grade 3/4: 4%]). CONCLUSIONS: These results demonstrate that pralatrexate may represent a promising treatment option for Chinese patients with R/R PTCL. The ORR of 52% compared favorably with prior studies of pralatrexate in other populations and there were no unanticipated side effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03349333.

MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in vivo by targeting tumor suppressor CHD5.

BACKGROUND: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116(miR-211)) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116(miR-211) cells was upregulated by 16-fold compared to vector control cells (HCT-116(vector)). Exogenous miR-211 directly binds to the 3'-untranslated region (3'-UTR) of CHD5 mRNA, resulting in a 50% decrease in CHD5 protein level in HCT-116(miR-211) cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116(miR-211) cells were significantly higher than HCT-116(vector) cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. CONCLUSION/SIGNIFICANCE: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression of miR-211 promotes tumor cell growth at least in part by downregulating the expression level of the CHD5 tumor suppressor. Our results provide a better understanding of the association of between miR-211-regulated CHD5 expression and CHD5 function in colorectal tumorigenesis.