ImetelChat

Describes role of telemerase inhibition in gastrointestinal cancers, such as esophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and pancreatic cancer.

Stefen Heeg, Medical Center – University of Freiburg, Freiburg, Germany
(DovePress October 2015)

Abstract:
Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities.
../..
Current telomerase-based therapies do either target telomerase directly to inhibit its enzyme function or use telomerase as an antigen to elicit antitumor immunity. Preclinical and early clinical trials have revealed promising results in gastrointestinal cancers and might provide novel therapeutic options in the future.

Link to the full article: https://www.dovepress.com/variations-in ... ticle-PGPM

Fish, Interesting review article, what to you think about this: <<Preclinical and early clinical trials have revealed promising results in gastrointestinal cancers and might provide novel therapeutic options in the future.>> Early clinical trials in GI tumors?? Where?? A clinical trial means it was given to a person either for pharmacologic studies in a healthy "volunteer" or a patient to test therapeutic effect. What GI tumors have been targeted here other then in vitro or in animal models? This statement is suspect IMO. Not that trials aren't contemplated (esophageal, pancreatic etc-we have seen non clinical support for multiple cell types) but what early clinical trial have "revealed promising results?" Your thoughts? Regards, bp

Intriguing, indeed. Guess this needs some further investigation. Maybe I'll track the authors email and ask him. On the other hand, it seems a serious article so the information must have come from somewhere.

It always good to start with the references which the author has published in connection to his article. And it happens that Heeg has used a wealth of information, mainly consisting of scientific and pre-clinical research. I just went through his list of 95 references and selected a few which seem to directly relate to has statement. I also dropped him a line so we may get some additional asnwers if we are lucky.

Btw: take a closer look at reference 84 about hepatoma (Gryaznov involved!). It is very interesting (now added to imetelstat.info)

About telomerase:
19. Johnson JE, Varkonyi RJ, Schwalm J, et al. Multiple mechanisms of telomere maintenance exist in liposarcomas. Clin Cancer Res. 2005; 11(15):5347–5355.
20. Queisser A, Heeg S, Thaler M, von Werder A, Opitz OG. Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis. Cancer Genet. 2013;206(11):374–386.
26. Heeg S, Hirt N, Queisser A, et al. EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis. Cancer Sci. 2011;102(2):351–360.
54. Gocha AR, Nuovo G, Iwenofu OH, Groden J. Human sarcomas are mosaic for telomerase-dependent and telomerase-independent telomere maintenance mechanisms: implications for telomere-based therapies. Am J Pathol. 2013;182(1):41–48.
58. Zhao Y, Gao Y, Chen Z, Hu X, Zhou F, He J. Low frequency of TERT promoter somatic mutation in 313 sporadic esophageal squamous cell carcinomas. Int J Cancer. 2014;134(2):493–494.
60. Finley JC, Reid BJ, Odze RD, et al. Chromosomal instability in Barrett’s esophagus is related to telomere shortening. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1451–1457.
61. Lord RV, Salonga D, Danenberg KD, et al. Telomerase reverse transcriptase expression is increased early in the Barrett’s metaplasia, dysplasia, adenocarcinoma sequence. J Gastrointest Surg. 2000;4(2):135–142.
65. Basu N, Skinner HG, Litzelman K, Vanderboom R, Baichoo E, Boardman LA. Telomeres and telomere dynamics: relevance to cancers of the GI tract.
68. Naito Y, Takagi T, Handa O, et al. Telomerase activity and expression of telomerase RNA component and catalytic subunits in precancerous and cancerous colorectal lesions.
72. Bertorelle R, Rampazzo E, Pucciarelli S, Nitti D, De Rossi A. Telomeres, telomerase and colorectal cancer. World J Gastroenterol. 2014;20(8):1940–1950.
79. Mizumoto K, Tanaka M. Detection of telomerase activity in patients with pancreatic cancer. Methods Mol Med. 2005;103:199–205.
87. Greten TF, Forner A, Korangy F, et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer. 2010;10:209.
88. Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer. 2006;95(11):1474–1482.
91. Lin WH, Yeh SH, Yang WJ, et al. Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice. Int J Cancer. 2013;132(6):1451–1462.

About imetelstat:
83. Wu X, Smavadati S, Nordfjäll K, et al. Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks. Biochim Biophys Acta. 2012;1823(12):2130–2135. ==== is already on imetelstat.info===
84. Djojosubroto MW, Chin AC, Go N, et al. Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology. 2005;42(5):1127–1136. === now added to imetelstat.info===
85. Joseph I, Tressler R, Bassett E, et al. The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res. 2010;70(22):9494–9504. ==== is already on imetelstat.info===

Fish, thanks, hope you can track down some answers. I am familiar with most of these articles from my research over the years and was always disappointed that indications in vitro never translated to treatment of horrible diseases like hepatoma and pancreatic cancer. I could only conclude that these indications were not pursued because of drug toxicity concerns. Perhaps combo therapy will alleviate some of the toxicity by allowing lower dosing. In any case there was something that stopped pursuit of these indications that has not been shared with us otherwise why did things stop dead in the research and clinical world? Some of the disappointments were undoubtedly related to the Okarma/Kelsey solid tumor failures. I believe all of this will be revisited with combo therapy under the guidance of Janssen but the timeline will be long. Please let us know what you find out. I suspect the statement about early clinical studies in GI tumors was just sloppy editing but it would be great if the statement really had merit. bp

To clarify: when I said "research" I meant library research not lab research, I am just an observer and a student here. bp

BP, I got a reply of Dr. Heeg. I will paraphrase his answer. He says that the sentence that you are mentioning is in the introduction of the manuscript and refers to the data from hTERT immunotherapies and PARP inhibitors as shown in table 1 of the article. He confirms that most of these "promising effects" have not been found in later clinical trials as outlined in the manuscript. He also says that there is no strong evidence from clinical trials and that maybe this was a unintentionally a little overstated. However, he says, there are hints that these therapies might be effective, maybe in combination, maybe with some sort of ALT-inhibition, in the future.

So this pretty aligns to your comments on the article.

Thanks Fish.