Research in mice at the Mayo Clinic in Rochester, Minnesota, has shown that rapamycin boosts the therapeutic effect of radiation by delaying the regrowth of brain tumours after treatment.
Their findings are being presented at the EORTC-NCI-AACR[3] Symposium on Molecular Targets and Cancer Therapeutics, in Frankfurt, Germany.
Lead investigator Dr Jann Sarkaria, assistant professor and consultant in the clinic's Department of Oncology, told a news briefing today (Thursday 21 November) that combined rapamycin and radiation treatment delayed regrowth of glioblastoma multiforme (GBM)[4] human tumours in mice for an average 19 days compared to treatment with rapamycin alone. In contrast, radiation treatment alone or rapamycin alone had no effect on tumour growth compared to control treatment.
Rapamycin inhibits the activity of a protein, mTOR, which functions in a signalling pathway to promote tumour growth. Rapamycin binds to a receptor protein (FKBP12) and the rapamycin/FKB12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signalling pathway.
"It's already known that rapamycin specifically inhibits mTOR and that mTOR is important in regulating cell growth and proliferation. Many GBM tumours have genetic changes that hyperactivate mTOR signalling, and these are the tumours most likely to respond to rapamycin therapy," said Dr Sarkaria.
"But, the exciting finding from our study is that this is the first evidence that mTOR is involved in the cellular response to radiation. It's not clear yet how it works but we think rapamycin slows tumour proliferation during radiation treatment. Similar to its effects with radiation, rapamycin may also enhance the effectiveness of chemotherapies. We already have preliminary data in mice to suggest that rapamycin can enhance the efficacy of one chemotherapy agent in GBM tumours. Moreover, it's possible that the combination of rapamycin with either radiation or chemotherapy might enhance the effectiveness of treatment in other types of cancers, in particular lung and prostate cancer."
The research team is now planning clinical trials looking at the combination of radiation and a rapamycin analogue in GBM and in lung cancer, and other researchers at the Mayo Clinic are evaluating rapamycin in phase I and II trials as a single agent for recurrent GBM.
Dr Sarkaria said that the doses of rapamycin and radiation in the animal studies were realistic approximations of what is used clinically. "Rapamycin is a highly targeted drug that we think inhibits only mTOR. Rapamycin analogues are well tolerated in patients and, unlike the standard chemotherapy agents commonly combined with radiation, we think it is less likely that they will significantly increase the toxicity of radiation."
He concluded: "It is too early to say how significant this finding is. Although the majority of patients presumably will not benefit from this specific combination, it is possible a small subset will. In the long term, the goal of molecular medicine is to custom-tailor treatments to the genetic make-up of individual patients and their tumours. So, if we can identify which patients are likely to respond to this specific combination, then we can treat just those patients who are most likely to benefit from the combination treatment and use alternative treatments for other patients."
Notes:
[1] Rapamycin: Rapamycin (Sirolimus) is an antibiotic that was isolated over 25 years ago from a strain of fungus found in a soil sample in the Easter Islands. It is used clinically as an immunosuppressant to prevent organ rejection in kidney patients in combination with other drugs e.g. corticosteroids.
[2] Rapamycin use in cardiovascular stents: the drug is used to prevent coronary arteries re-narrowing after angioplasty – a method of treating blockage or narrowing of blood vessels by inserting a balloon into the constriction to reopen it.
[3] EORTC [European Organisation for Research and Treatment of Cancer]; NCI [National Cancer Institute]; AACR [American Association for Cancer Research].
[4] Glioblastoma Multiforme (GBM): The most common and aggressive of the primary brain tumours. It is highly malignant and infiltrates the brain extensively. Surgical resection followed by radiation is the standard of care. However, this aggressive tumour is incurable and the overall prognosis has changed little in the past two decades despite major improvements in neuroimaging, neurosurgery and radiotherapy.
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