On YMB jakao a frequent poster and cheerleader for Geron posted a link to an interesting article:
"Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner" If you google it, it comes up. Dr. Jerry Shay who has done considerable research in this area is one of the authors. It may be that giving imetelstat early in the disease and for a long time (this is not news and has been discussed previously) may be required for effect. Maybe Okarma will be vindicated! Too bad the early trials in NSCLC failed, perhaps we will see better combo trials in screened patients with short telomeres. bp
Hat tip to jakao YMB for the following link
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Fishermangents
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Re: Hat tip to jakao YMB for the following link
Great post and great article! Here is the link:
http://www.impactjournals.com/oncotarge ... ath[]=9335
For those who don't want to use the link, here's the abstract:
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Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner
Robin E. Frink et al
Received: December 04, 2015 Accepted: April 27, 2016 Published: May 12, 2016
Telomerase was evaluated as a therapeutic oncotarget by studying the efficacy of the telomerase inhibitor imetelstat in non-small cell lung cancer (NSCLC) cell lines to determine the range of response phenotypes and identify potential biomarkers of response. A panel of 63 NSCLC cell lines was studied for telomere length and imetelstat efficacy in inhibiting colony formation and no correlation was found with patient characteristics, tumor histology, and oncogenotypes. While there was no overall correlation between imetelstat efficacy with initial telomere length (ranging from 1.5 to 20 kb), the quartile of NSCLC lines with the shortest telomeres was more sensitive than the quartile with the longest telomeres. Continuous long-term treatment with imetelstat resulted in sustained telomerase inhibition, progressive telomere shortening and eventual growth inhibition in a telomere-length dependent manner. Cessation of imetelstat therapy before growth inhibition was followed by telomere regrowth. Likewise, in vivo imetelstat treatment caused tumor xenograft growth inhibition in a telomere-length dependent manner. We conclude from these preclinical studies of telomerase as an oncotarget tested by imetelstat response that imetelstat has efficacy across the entire oncogenotype spectrum of NSCLC, continuous therapy is necessary to prevent telomere regrowth, and short telomeres appears to be the best treatment biomarker.
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(will be uploaded to imetelstat.info soon)
http://www.impactjournals.com/oncotarge ... ath[]=9335
For those who don't want to use the link, here's the abstract:
-------
Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner
Robin E. Frink et al
Received: December 04, 2015 Accepted: April 27, 2016 Published: May 12, 2016
Telomerase was evaluated as a therapeutic oncotarget by studying the efficacy of the telomerase inhibitor imetelstat in non-small cell lung cancer (NSCLC) cell lines to determine the range of response phenotypes and identify potential biomarkers of response. A panel of 63 NSCLC cell lines was studied for telomere length and imetelstat efficacy in inhibiting colony formation and no correlation was found with patient characteristics, tumor histology, and oncogenotypes. While there was no overall correlation between imetelstat efficacy with initial telomere length (ranging from 1.5 to 20 kb), the quartile of NSCLC lines with the shortest telomeres was more sensitive than the quartile with the longest telomeres. Continuous long-term treatment with imetelstat resulted in sustained telomerase inhibition, progressive telomere shortening and eventual growth inhibition in a telomere-length dependent manner. Cessation of imetelstat therapy before growth inhibition was followed by telomere regrowth. Likewise, in vivo imetelstat treatment caused tumor xenograft growth inhibition in a telomere-length dependent manner. We conclude from these preclinical studies of telomerase as an oncotarget tested by imetelstat response that imetelstat has efficacy across the entire oncogenotype spectrum of NSCLC, continuous therapy is necessary to prevent telomere regrowth, and short telomeres appears to be the best treatment biomarker.
-------
(will be uploaded to imetelstat.info soon)
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Fishermangents
- Site Admin
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Re: Hat tip to jakao YMB for the following link
Bio, I am not sure which failure you are referring to, but I found this:
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A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.
Chiappori et al, Feb 2015, published by Oxford University Press
RESULTS:
Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145).
CONCLUSIONS:
Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.
link: http://www.ncbi.nlm.nih.gov/pubmed/25467017
link to CT site: https://clinicaltrials.gov/ct2/show/NCT01137968
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In this trial imetelstat was used as maintenance therapy. It provided a slight benefit, but not significant enough. It would be interesting what cause the large differences with the Frink 12 May 2016 study, which reported such positive results.
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A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.
Chiappori et al, Feb 2015, published by Oxford University Press
RESULTS:
Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145).
CONCLUSIONS:
Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.
link: http://www.ncbi.nlm.nih.gov/pubmed/25467017
link to CT site: https://clinicaltrials.gov/ct2/show/NCT01137968
-------
In this trial imetelstat was used as maintenance therapy. It provided a slight benefit, but not significant enough. It would be interesting what cause the large differences with the Frink 12 May 2016 study, which reported such positive results.