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- Epigenetic therapy in urologic cancers: an update on clinical trialsPublication . Faleiro, Inês; Leão, Ricardo; Binnie, Alexandra; De Mello, Ramon Andrade; Maia, Ana Teresa; Castelo-Branco, PedroEpigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.
- The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancerPublication . Faleiro, Inês; Apolónio, Joana; Price, Aryeh J.; De Mello, Ramon Andrade; Roberto, Vânia; Tabori, Uri; Castelo-Branco, PedroAim: We explore the biomarker potential of the TERT hypermethylated oncologic region (THOR) in pancreatic cancer. Materials & methods: We assessed the methylation status of THOR using the cancer genome atlas data on the cohort of pancreatic cancer (n = 193 patients). Results: THOR was significantly hypermethylated in pancreatic tumor tissue when compared with the normal tissue used as control (p < 0.0001). Also, THOR hypermethylation could distinguish early stage I disease from normal tissue and was associated with worse prognosis. Discussion: We found that THOR is hypermethylated in pancreatic tumor tissue when compared with normal tissue and that THOR methylation correlates with TERT expression in tumor samples. Conclusion: Our preliminary findings support the diagnostic and prognostic values of THOR in pancreatic cancer.
- Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancerPublication . Leão, Ricardo; Lee, Donghyun; Figueiredo, Arnaldo; Hermanns, Thomas; Wild, Peter; Komosa, Martin; Lau, Irene; Mistry, Mathew; Nunes, Nuno Miguel; Price, Aryeh J.; Zhang, Cindy; Lipman, Tatiana; Poyet, Cédric; Valtcheva, Nadejda; Oehl, Kathrin; Coelho, Hugo; Sayyid, Rashid; Gomes, Ana Melo; Prado e Castro, Ligia; Sweet, Joan; Vinagre, João; Apolónio, Joana; Stephens, Derek; Faleiro, Inês; Fadaak, Kamel; Richard, Patrick O.; Kulkarni, Girish; Zlotta, Alexandre R.; Hamilton, Robert J.; Castelo-Branco, Pedro; Tabori, UriIn urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh /TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.