Shortening end caps on chromosomes in human cervical cancer cells disrupts DNA repair signaling, increases the cells'sensitivity to radiation treatment and kills them more quickly,according to a study in Cancer Prevention Research. Researchers would to like see their laboratory findings - publishedin the journal's Dec. 5 print edition - lead to safer, moreeffective combination therapies for hard-to-treat pediatric braincancers like medulloblastoma and high-grade gliomas. To this end,they are starting laboratory tests on brain cancer cells. |
"Children with pediatric brain cancers don't have very many optionsbecause progress to find new treatments has been limited the last30 years," said Rachid Drissi, PhD, principal investigator on thestudy and a researcher in the Division of Oncology at CincinnatiChildren's. "The ability to make cancer cells more sensitive toradiation could allow physicians to use lower radiation doses tolessen side effects. Too many children with brain cancer candevelop disabilities or die from treatment." Before treating cells with ionizing radiation, the researchersblocked an enzyme called telomerase, found in over 90 percent ofcancer cells but barely detectable in most normal human cells. Incancer cells, telomerase helps maintain the length of caps on theends of chromosomes called telomeres.
This helps cancer cellsreplicate indefinitely, grow and spread, Drissi said. Unraveling DNA stability Found on chromosomes in both cancerous and normal cells, telomeresare analogous to plastic caps that keep shoestring ends fromunraveling. Telomeres help preserve DNA stability in cells bycontaining genetic miscues. This helps explain why cells withmaintained or long telomeres appear to be more resistant toradiation.
In normal cells lacking the telomerase enzyme, telomeres getshorter each time cells divide. They continue doing so until normalcells stop dividing, reaching a condition called senescence. Ifthis first cell-cycle "stop sign" is bypassed, cells continuedividing until telomeres become critically short and reach a secondstopping point, when most cells die. In rare instances, cellsbypass this second "stop sign" and survive. This survival is oftenassociated with telomerase activation and the onset of cancer.
This was the basis for experiments Drissi and his colleaguesconducted to compare the radiation sensitivity and survivability ofcells based on telomere length. They also monitored DNA repairresponses in the cells by looking for specific biochemical signsthat indicate whether the repair systems are working. The tests involved normal human foreskin cells - called fibroblasts- and human cervical carcinoma cells. They exposed the cells toionizing radiation and analyzed DNA repair responses as telomeresbecame progressively shorter. In the cervical cancer cells,researchers blocked the telomerase enzyme before radiationtreatment to induce progressively shorter telomeres.
Both late-stage noncancerous cells with shorter telomeres, andcancer cells with induced shorter telomeres, were moreradiosensitive and died more quickly, according to the study. Among cancer cells with maintained telomere length, close to 10percent receiving the maximum dose of ionizing radiation used inthe study (8 Gy, or Gray Units) survived the treatment. None of thecancer cells with the shortest telomeres survived that exposure. Researchers said the cancer cells became more radiosensitivebecause material inside the chromosomes - called chromatin -compacted as telomeres became shorter. Compacted chromatin thendisrupted the biochemical signaling of a protein called ATM(ataxiatelangeietasia mutated).
ATM is a master regulator of DNA repair and cell division. It sendssignals to activate other biochemical targets (H2AX, SMC1, NBS1 andp53) that help direct DNA repair and preserve genetic stability. Intelomere-shortened cancer cells, the compacted chromatin inhibitedATM signaling to all of the chromatin-bound targets tested in thestudy. This disrupted DNA repair responses and increased radiationsensitivity.
Testing brain cancer cells The researchers are now testing their findings in cells fromhard-to-treat pediatric brain tumors. These tests begin as Drissi'slaboratory also leads correlative cancer biology studies of tumorsamples from a current clinical trial. The trial is evaluatingtelomere shortening as a stand-alone therapy for pediatric cancer. Managed through the National Institutes of Health's Children'sOncology Group (COG), the multi-institutional Phase 1 trial istesting the safety and tumor response capabilities of the drugImetelstat, which blocks telomerase in cancer cells.
Drissi serveson the clinical trial committee along with Maryam Fouladi, MD, MSc,and medical director of Neuro-Oncology at Cincinnati Children's.She leads the medical center's clinical participation in the trial. Drissi and Fouladi are starting preparatory work to develop, andseek approvals for, a possible clinical trial to test telomereshortening and radiation treatment as a safer, more effectivetreatment for pediatric brain tumors. Funding support for the current study in Cancer Prevention Research- published by the American Society for Cancer Research - came fromthe National Institutes of Health, the American Lebanese SyrianAssociated Charities of St. Jude Children's Research Hospital andCincinnati Children's Hospital Medical Center.
Also collaboratingwere researchers from Children's National Medical Center inWashington, D.C., and from St. Jude. Funding support for the Drissilab's correlative studies on the COG clinical trial comes fromCancerFree Kids Pediatric Cancer Research Alliance and fromChildren's Cancer Research Fund. Additional References Citations.
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