Geron's Telomerase Inhibitor Drug May Benefit Breast Cancer Patients Receiving Radiation Therapy
Dec 19, 2006 07:30:34 (ET)
MENLO PARK, Calif., Dec 19, 2006 (BUSINESS WIRE) -- Geron Corporation (GERN, Trade ) today reported that its telomerase inhibitor drug, GRN163L, may benefit breast cancer patients receiving radiation therapy, according to the results of a study published online in the International Journal of Radiation Oncology, Biology and Physics ( www.redjournal.org/inpress ).
Written by Dr. Brittney-Shea Herbert, her collaborators at Indiana University and Geron's Dr. Sergei Gryaznov, the paper documents a substantial synergistic effect of GRN163L and radiation on breast cancer cells in vitro and in mice bearing human breast cancer. The study is the first to demonstrate the utility of GRN163L as a radiation sensitizer in cancer therapy.
"The study findings support the potential use of GRN163L in combination with radiation in breast cancer patients," said Calvin Harley, Ph.D., Geron's chief scientific officer. "Similar data have been seen in other animal studies in which telomerase has been knocked out genetically. Lack of telomerase activity is generally associated with increased sensitivity to radiation and other DNA damaging agents, especially when telomeres are short. Our hope is that these observations will translate into improved clinical responses to adjuvant irradiation in breast cancer."
Synergy of GRN163L and Radiation In Vitro
As previously reported by Dr. Herbert's group (Clin Cancer Res. 2006; 12:3184-3198), GRN163L caused near complete inhibition of telomerase in the human breast cancer cells used in this study, while a "mismatch" lipid-conjugated control oligonucleotide with very weak binding to telomerase had no effect. With longer term treatment, GRN163L caused telomere shortening, slowing of tumor cell growth rates, and a dramatic reduction in the ability of the cells to "re-seed" or form colonies of tumor cells in culture dishes.
The new study demonstrated that cells treated for six weeks with GRN163L were more susceptible to radiation-induced cell death, exhibiting a 30% reduction in cell survival compared to radiation alone even after accounting for the stand-alone effect of GRN163L on cell survival (p less than 0.01). These results show that GRN163L can synergize with radiation to trigger greater killing of tumor cells than would be predicted by the additive effects of either treatment alone.
Synergy of GRN163L and Radiation In Vivo
Human breast cancer cells were cultured alone, with mismatched oligonucleotide or GRN163L for seven weeks prior to injection into the flanks of immune-compromised mice. After injection of cells, mice were divided into six in vivo treatment groups: 1) untreated control, 2) mismatched oligonucleotide alone, 3) GRN163L alone, 4) irradiation alone, 5) mismatched oligonucleotide plus irradiation and 6) GRN163L plus irradiation. Fourteen days after tumor cell inoculation, groups 4, 5 and 6 were subjected to 6 Gy irradiation to mimic adjuvant radiation therapy in breast cancer patients. Animals in groups 3 and 6 (those receiving cells pretreated with GRN163L) also received in vivo doses of GRN163L at post-injection days 13 and 31 to ensure continued inhibition of telomerase activity. All animals in group 6 (GRN163L plus irradiation) survived the full 80 days of the trial and exhibited statistically significant reduction in tumor volume compared to all other treatment groups, including mice receiving irradiation alone.
Survival at day 80 in the other groups ranged from 0% to 52% (deaths from sacrifice due to tumor burden), and the average tumor size in the GRN163L plus irradiation group was 25% of the tumor size in the irradiation alone group. GRN163L was well tolerated by the animals, and no health or behavioral abnormalities were observed.
GRN163L is a short, lipid-conjugated oligonucleotide drug capable of potent, specific and durable inhibition of telomerase. Telomerase is expressed in essentially all cancer types and is responsible for the replicative immortality of tumor cells. Unlike antisense oligonucleotides that interfere with a precursor to the target protein, GRN163L acts as a direct enzyme inhibitor by binding to the active site of telomerase. GRN163L is currently in a Phase I trial in solid tumor cancer and a Phase I/II trial in chronic lymphocytic leukemia.
Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and degenerative diseases, including spinal cord injury, heart failure, diabetes and HIV/AIDS. The company is advancing an anticancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials. Geron is also the world leader in the development of human embryonic stem cell-based therapeutics, with a product to treat spinal cord injury expected to enter clinical trials in late 2007. For more information, visit www.geron.com .
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