Targeting telomerase in HER2 positive breast cancer: role of cancer stem cells
Monday, Apr 08, 2013, 1:00 PM - 5:00 PM
Hall A-C, Poster Section 39
Poster Board Number:
Jillian Koziel1, Sergei Gryaznov2, Brittney-Shea Herbert1. 1Indiana University School of Medicine, Indianapolis, IN; 2Geron Corporation, Menlo Park, CA
Background: The reverse transcriptase enzyme telomerase is reactivated in 85-90% of malignancies and is a potential target for anti-cancer therapies due to its differential expression between normal and tumor cells. One such therapy involves targeting the template region of telomerase with an antagonistic oligonucleotide, imetelstat, which is currently in clinical trials for breast and other cancers. Imetelstat has been shown to be effective in inhibiting telomerase activity in breast cancer cell lines, as well as inhibiting breast tumor growth and decreasing lung metastases in an in vivo model. HER2 amplification (and/or overexpression) is associated with a more aggressive disease, a greater likelihood of recurrence, and decreased survival compared to breast cancers without HER2 amplification. Recent work has shown that HER2 overexpression increases both the normal and malignant stem/progenitor cell population. This increase in malignant stem cells, known as cancer stem cells (CSCs), drives tumorigenesis and invasion and may explain the aggressive phenotype and drug resistance of this disease. We hypothesize that CSCs have active telomerase and thus may be sensitive to imetelstat treatment, thereby enhancing the effects of therapy for HER2 positive cancers.
Methods: HER2+/- breast cancer cells, grown as mammospheres in culture to enrich for CSCs, were analyzed by flow cytometry for CSC marker expression (CD49f+/EpCAM-, CD44+/CD24-, and ALDH1hi). Mammospheres were analyzed for spheroid forming efficiency, a functional measure of self-renewal potential, and telomerase activity in response to imetelstat treatment.
Results: Imetelstat treatment resulted in inhibition of up to 90% of telomerase activity in mammospheres, similar to adherent cell cultures. The percentage of CSCs based upon analysis of marker expression decreased approximately 30% or 1.4-fold after 5 weeks of imetelstat treatment compared to untreated controls. Imetelstat pretreatment decreased spheroid counts by 84%. The spheroid formation efficiency decreased from 9.36% in the untreated to 1.5% after imetelstat pretreatment, a 6.24-fold decrease. Pretreatment with imetelstat also had a durable inhibitory effect on mammosphere telomerase activity, where over 60% of the enzyme’s activity remained inhibited after one week without additional treatment.
Conclusions: CSCs have active telomerase that can be inhibited using imetelstat. The percentage of CSCs as well as spheroid formation efficiency decreases following imetelstat treatment. The addition of imetelstat to therapy regimens may help decrease metastases and reduce tumor recurrence.
Lets keep in mind that this data is from laboratory samples exposed to high concentrations of Imetelstat over a considerable period of time.
What we are finding is that we cannot achieve these dosing levels in patients without rapidly getting the dose limiting toxicity of thrombocytopenia and neutropenia.
When dosing is reduced and given rest periods to limits DLTs we aren't seeing statisticly significant improvement in the patients in both the Breast and Lung trials. The last CC even disclosed what had been a hoped for benefit in the short Telomere component of the Lung trial turned out upon further examination of the data to be not the case.
Except for data we may receive from the investigator initiated pediatric tumor trial I don't see us getting new data on solid tumor trials for at least several years if ever since the company has focused further near term develoment and resources on hematologic malignancies.
Remember that Imetelstat with Paclitaxol does not work because they both have the same dose limiting toxicities. This does not mean that it does not work with other agents other than paclitaxol.
AACR's Annual Meeting 2013
Presentation Title: Targeting telomerase in HER2 positive breast cancer: role of cancer stem cells
Presentation Time: Monday, Apr 08, 2013, 1:00 PM - 5:00 PM
"The reverse transcriptase enzyme telomerase is reactivated in 85-90% of malignancies and is a potential target for anti-cancer therapies due to its differential expression between normal and tumor cells. One such therapy involves targeting the template region of telomerase with an antagonistic oligonucleotide, IMETELSTAT, which is currently in clinical trials for breast and other cancers. Imetelstat has been shown to be effective in inhibiting telomerase activity in breast cancer cell lines, as well as inhibiting breast tumor growth and decreasing lung metastases in an IN VIVO model...."
mruyog - the reason chip pulled the plug on the breast cancer study was because the significant majority of the patients' tumors had LONG telomeres. it is now understood that imetelstat is ineffective in blocking telomerase when telomeres are long.
Taz, I am shocked!! Here one of the Geron scientist himself says 90% inhibition in mammoshere and 30% reduction in CSCs after a week's treatment! Doesn't this refute what Scarlett stated months bach when he declared the solid-tumor trial had "failed"? Scarlett's stupidity is that he ordered trial's haltage for solid tumors that caused a massive share-price slide!! I had objected to the use of word "failed" then vehemently and do now too!! What are the two bozos up to?
Isn't breast cancer telomerase longer than the short-telomerase testing Geron is doing for NSCLC? No wonder Dr. Klein from Stifel is unhappy with the flawed plan of trials approved by the two bozos!! OR is it Kelsey who screwed up?
mruyog in the phase 2 trial that failed it was due to the dose limiting effects caused by combining it with Paclitaxol. They combined Imetelstat with the wrong drug since both drugs cause the same kind of side effects and thus limit each others use together.