Therapeutic impact of Telomerase Inhibitor Imetelstat: A Literature Review
DOI:
https://doi.org/10.35882/ijahst.v3i2.238Abstract
The immortal phenotype of cancer cells is a significant trait, and in the vast majority of malignancies, the enzyme telomerase is essential for sustaining the cancer cells' limitless capacity for replication. The absence of telomerase expression and the lack of an immortal phenotype in normal adult tissues suggest that telomerase is a prospective therapeutic target for the treatment of a variety of tumor forms. At every cell division, telomeres will shrink if telomerase is not active. Apoptosis, cell senescence, and chromosomal instability are initiated when the telomeres become critically short. Telomeres are stabilized in the majority of rapidly expanding cancers by reactivating telomerase. In numerous tumor forms, it has been demonstrated that telomerase inhibition inhibits the development of cancer cells. Telomerase inhibitors have been discovered over the past 10 years as a result of substantial basic research into the mechanisms regulating telomeres, which may offer a potent, nearly universal cancer treatment approach. A short-chain oligonucleotide called imetelstat [GRN163L, Geron Corporation] has a high affinity and specificity for the RNA component of telomerase's template region [hTR or hTERC]. Researchers conduct an examination of articles that are in accordance with the issue to be studied. Articles used in literature review are obtained through the database of international journal providers through PubMed, we investigated clinical studies and discussed what happened in these clinical studies and the extent of the effectiveness of imetelstat in treatment of cancer. Articles proved that imetelstat could enhance cancer treatment. Articles proved that Imetelstat is promising therapeutic agents for cancer treatment. In this review, we suggest that formulating and following treatment, Further studies are needed to determine the related mechanisms to enhance Imetelstat efficacy.
Downloads
References
W. Lu, Y. Zhang, D. Liu, Z. Songyang, and M. Wan, “Telomere-strucutre, function, and regulation,” Exp Cell Res, vol. 319, pp. 133–141, 2013.
M. A. Giardini, M. Segatto, M. S. da Silva, V. S. Nunes, and M. I. N. Cano, “Telomere and telomerase biology,” Prog. Mol. Biol. Transl. Sci., vol. 125, pp. 1–40, 2014.
P. Fragkiadaki et al., “Telomere length and telomerase activity in osteoporosis and osteoarthritis,” Exp. Ther. Med., vol. 19, no. 3, pp. 1626–1632, 2020.
P. Martínez and M. A. Blasco, “Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins,” Nat. Rev. Cancer, vol. 11, no. 3, pp. 161–176, 2011.
T. Trybek, A. Kowalik, S. Góźdź, and A. Kowalska, “Telomeres and telomerase in oncogenesis,” Oncol. Lett., vol. 20, no. 2, pp. 1015–1027, 2020.
D. Shore and A. Bianchi, “Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase,” EMBO J., vol. 28, no. 16, pp. 2309–2322, 2009.
T. Bourgeron, Z. Xu, M. Doumic, and M. T. Teixeira, The asymmetry of telomere replication contributes to replicative senescence heterogeneity. Sci Rep. 5:153262015. View Article : Google Scholar : PubMed/NCBI.
M. T. Hemann, M. A. Strong, L. Y. Hao, and C. W. Greider, “The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability,” Cell, vol. 107, no. 1, pp. 67–77, 2001.
M. Pedram, C. N. Sprung, Q. Gao, A. W. I. Lo, G. E. Reynolds, and J. P. Murnane, “Telomere position effect and silencing of transgenes near telomeres in the mouse,” Mol. Cell. Biol., vol. 26, no. 5, pp. 1865–1878, 2006.
J. D. Robin et al., “Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances,” Genes Dev., vol. 28, no. 22, pp. 2464–2476, 2014.
M. A. Jafri, S. A. Ansari, M. H. Alqahtani, and J. W. Shay, “Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies,” Genome Med., vol. 8, no. 1, p. 69, 2016.
H. J. Sommerfeld, A. K. Meeker, M. A. Piatyszek, G. S. Bova, J. W. Shay, and D. S. Coffey, “Telomerase activity: a prevalent marker of malignant human prostate tissue,” Cancer Res., vol. 56, no. 1, pp. 218–222, 1996.
K. Meeker et al., “Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis,” Cancer Res., vol. 62, no. 22, pp. 6405–6409, 2002.
F. P. Barthel et al., “Systematic analysis of telomere length and somatic alterations in 31 cancer types,” Nat. Genet., vol. 49, no. 3, pp. 349–357, 2017.
K. Chiba et al., “Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism,” Science, vol. 357, no. 6358, pp. 1416–1420, 2017.
Seimiya H., Muramatsu Y., Ohishi T., Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Cancer Cell. 2005;7:25–37. doi: 10.1016/j.ccr.2004.11.021. [PubMed] [CrossRef] [Google Scholar] [Ref list]
Seimiya H., Oh-hara T., Suzuki T., Naasani I., Shimazaki T., Tsuchiya K., Tsuruo T. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991. Mol. Cancer Ther. 2002;1:657–665. [PubMed] [Google Scholar] [Ref list]
Frink R.E., Peyton M., Schiller J.H., Gazdar A.F., Shay J.W., Minna J.D. Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner. Oncotarget. 2016;7:31639–31651. doi: 10.18632/oncotarget.9335. [PMC free article] [PubMed] [CrossRef] [Google Scholar] [Ref list]
Fujiwara C., Muramatsu Y., Nishii M., Tokunaka K., Tahara H., Ueno M., Yamori T., Sugimoto Y., Seimiya H. Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. Sci. Rep. 2018;8:14827. doi: 10.1038/s41598-018-33139-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar] [Ref list]
Chiappori A.A., Kolevska T., Spigel D.R., Hager S., Rarick M., Gadgeel S., Blais N., Von Pawel J., Hart L., Reck M., et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann. Oncol. 2015;26:354–362. doi: 10.1093/annonc/mdu550. [PMC free article] [PubMed] [CrossRef] [Google Scholar] [Ref list]
A. N. Guterres and J. Villanueva, “Targeting telomerase for cancer therapy,” Oncogene, vol. 39, no. 36, pp. 5811–5824, 2020.
T. Lapidot et al., “A cell initiating human acute myeloid leukaemia after transplantation into SCID mice,” Nature, vol. 367, no. 6464, pp. 645–648, 1994.
P. Greenberg et al., “International scoring system for evaluating prognosis in myelodysplastic syndromes,” Blood, vol. 89, no. 6, pp. 2079–2088, 1997.
P. J. Mason, D. B. Wilson, and M. Bessler, “Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance,” Curr. Mol. Med., vol. 5, no. 2, pp. 159–170, 2005.
M. Al-Hajj and M. F. Clarke, “Self-renewal and solid tumor stem cells,” Oncogene, vol. 23, no. 43, pp. 7274–7282, 2004.
M. F. Clarke and M. Fuller, “Stem cells and cancer: two faces of eve,” Cell, vol. 124, no. 6, pp. 1111–1115, 2006.
J. H. Ohyashiki, G. Sashida, T. Tauchi, and K. Ohyashiki, “Telomeres and telomerase in hematologic neoplasia,” Oncogene, vol. 21, no. 4, pp. 680–687, 2002.
J. Mascarenhas et al., “Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis,” J. Clin. Oncol., vol. 39, no. 26, pp. 2881–2892, 2021.
A. Tefferi et al., “A pilot study of the telomerase inhibitor imetelstat for myelofibrosis,” N. Engl. J. Med., vol. 373, no. 10, pp. 908–919, 2015.
G. M. Baerlocher et al., “Telomerase inhibitor imetelstat in patients with essential thrombocythemia,” N. Engl. J. Med., vol. 373, no. 10, pp. 920–928, 2015.
D. P. Steensma et al., “Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a phase II study,” J. Clin. Oncol., vol. 39, no. 1, pp. 48–56, 2021.
A. A. Chiappori et al., “A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer,” Ann. Oncol., vol. 26, no. 2, pp. 354–362, 2015.
P. A. Thompson et al., “A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children’s Oncology Group Phase I Consortium Study [ADVL1112],” Clin. Cancer Res., vol. 19, no. 23, pp. 6578–6584, 2013.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Mohamed Ziedan
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-ShareAlikel 4.0 International (CC BY-SA 4.0) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
