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1.
Figure 6

Figure 6. Imetelstat treatment inhibits tumor growth in mice with subcutaneous tumors. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

A. Bioluminescent imaging of the control and treatment group: Mice were injected intraperitoneally with imetelstat twice a week (30 mg/kg) after the tumors became detectable. The tumors were excised at the end of treatment and are displayed below the corresponding animals; B. Chart representing the average photon counts from treated and untreated animals.

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.
2.
Figure 5

Figure 5. Imetelstat penetrates the blood-brain barrier and inhibits telomerase activity in orthotopic xenograft tumors. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

A. Bioluminescent imaging of mCherry/Luc-labeled GBM tumor-initiating cells implanted orthotopically in the brain of nude mice; B. Macroscopic pathology of the mouse brain with the orthotopic tumor indicated by a white arrow. Fluorescent image of the mouse brain shows strong mCherry expression in tumor cells; C. TRAP assay of cells isolated by FACS from intracranial tumors of mice treated with imetelstat. Cell lysates corresponding to 250 cells were used for the imetelstat-treated samples. The internal telomerase amplification standard (ITAS) control is indicated by an arrow.

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.
3.
Figure 2

Figure 2. Imetelstat inhibits telomerase activity in GBM tumor-initiating cells in a dose-dependent manner which is reversed upon drug removal. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

A. TRAP gel of the GBM neurospheres treated with various doses of imetelstat; B. IC50 of telomerase activity inhibition is 0.45μM for this specific GBM tumor-initiating line; C. TRAP activity recovers to normal levels after imetelstat removal from the media. The cells were treated with imetelstat for 72 hours then cultured in drug-free media and samples were collected for TRAP every three days. Equal numbers of cells were used for the TRAP assay. HeLa cells lysate was used as a positive control; the bars represent average data from three independent TRAP assays. The internal telomerase amplification starndard (ITAS) used for quantitation is indicated by an arrow.

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.
4.
Figure 1

Figure 1. Isolation and characterization of primary GBM tumor-initiating cells. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

Fresh primary GBM samples were dissociated and propagated as non-adherent neurospheres in serum-free defined media. Orthotopic injection with dissociated neurosphere cells (5 × 104/mouse) produced a neurologically symptomatic, T1-contrast enhancing tumor mass following a latency of 8-10 weeks. Histopathological features of the tumor were consistent with high-grade glioma, including GFAP positivity, diffuse infiltration, high MiB-1 index (Ki67 positive), and areas of neovascularization. Immunohistochemistry analysis confirmed EGFR over-expression. Chromagen-based in-situ hybridization (CISH) indicated increased EGFR copy number in the orthotopic tumors. Orthotopic tumors also showed a heterogeneous mix of nestin-positive tumor cells (neural stem/progenitor marker) intermingled with clusterin-positive cells (astrocyte marker).

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.
5.
Figure 3

Figure 3. Long-term treatment with imetelstat in vitro leads to decrease clonogenic capacity, telomere shortening and cell death. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

A. Clonogenic neurosphere formation assay of GBM tumor-initiating cells exposed to imetelstat. A total of 500 cells were plated on 10cm dishes, fresh media was exchanged after 5 days and the neurospheres were counted after 10-14 days; B. Live/dead assay on the long term-treated cells versus the untreated controls. Green cells - Calcein AM (live cells), red cells - ethidium homodimer (necrotic cells); C. TRF gel shows that GBM tumor cells have short telomeres (average about 6kb) compared to normal brain (∼10-12kb); D. TRF analysis of another primary glioma that has even shorter initial average telomere length (∼3.5-4kb) indicates progressive telomere shortening in GBM tumor-initiating cells treated in vitro 2×/week with 2μM imetelstat.

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.
6.
Figure 4

Figure 4. Radiation therapy and temozolomide are more efficient on GBM tumor-initiating cells when used in combination with imetelstat. From: The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth.

A. Cell survival assay (MTT) performed on cells treated with the telomerase inhibitor drug (16 weeks), TMZ and irradiation (5Gy). The data was normalized to the control, oligonucleotide mismatch-treated cells; B. Addition of TMZ to tumor cells pretreated with imetelstat for 72 hours produced a marked impact on tumor cell viability (P<0.001), as indicated by the MTT assay. Treatment with TMZ alone or in combination with 5Gy irradiation produced only a small decrease in tumor cell proliferation. C. Western blot of GBM tumor-initiating cells pre-treated with imetelstat (72hrs) followed by IR (5Gy) indicated a effect on DNA double strand breaks as measured by increased γH2AX (Ser139) and 53BP1 phosphorylation; D. Western blot of GBM tumor-initiating cells treated with a combination of imetelstat and TMZ (5, 10 and 20μM) showed increased activation of γH2AX and 53BP1 phosphorylation compared to the mismatch controls.

Calin O. Marian, et al. Clin Cancer Res. ;16(1):154-163.

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