Glioblastomas (GBM) are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis. The drug letrozole was approved by the U.S. FDA as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow by allowing the synthesis of estradiol. In 2012 scientists wondered: Does aromatase play a similar role in glioblastomas, and if so, will letrozole work as an effective treatment? Early research at the University of Cincinnati found the enzyme was present in brain tumor cell lines, and further testing found a very high amount of aromatase at protein and mRNA levels in brain tumor samples from UC’s tumor bank.
The hypothesis that either rat and human brain cancers express aromatase was originally confirmed in 2004 (Jague et al.). Under physiological conditions, the expression of aromatase in the mammalian brain is restricted to neurons. However, following studies have shown that reactive astrocytes express aromatase after brain injury and the most common lines of glioblasoma cells grown in lab mat express both aromatase and estrogen receptor alpha. By analogy to the implication of aromatase into the growth of other forms of estrogen-sensitive tumors, such as breast or uterine cancers, researchers in time became aware that the expression of aromatase may play a role in the growth of glioblastoma sas well. However, that did not guarantee that letrozole would be similarly effective in brain tumors like it is in breast cancer tumors. However, compared to other drugs with the same purpose, letrozole has a good possibility to cross the blood-brain barrier and eventually reach the malignant tissue.
Studies in animal models showed that letrozole was effective, and the research team moved to test the compound in cells derived from human brain tumor tissues. In this phase of work, the researchers noticed that in the patient-derived cells letrozole is very effective in killing the tumor cells in cell culture models. With funding support from the Cancer Center and the University fo Cincinnaty Brain Tumor Center, the team launched a phase 0/1 clinical trial testing what dosage of letrozole is appropriate to treat glioblastomas. This trial was led by Trisha Wise-Draper, MD, PhD, an expert in phase 1 oncology trials with contributions from several other neuro-oncologists and neurosurgeons. The trial is set to be completed soon, but preliminary data have shown the drug is “unequivocally” reaching its target of the brain tumor tissue safely. The same data sets also show that doses of letrozole higher than those needed for breast cancer treatment can be safely achieved in patients with brain cancers.
As promising as letrozole is, it is still unlikely that the drug will be a singular cure for the disease: scientists deem that i twill be combined to other therapied to hit another signaling pathway inside the cancer cells, hopoing that this will be synergistic. Supported by a new NIH/NINDS funding, the team will research the preclinical effectiveness of combining letrozole with other chemotherapy compounds. A just published research, that will appear next month in the journal Cancer Chemotherapy and Pharmacolgy, already demonstrated that letrozoloe potentiates the activity of temozolomide, the standard therapy for this type of cancer. The lab that conducted the research and started this clinical trial, has focused on tumors deficient in a cellular protein called PTEN, a cellular phosphatate that work as a tumor suppressor. Only when mutated this protein gains oncogenic potential. The team hopes that the new research may reveal how letrozole in combination with other therapies may lead to a suitable treatment for PTEN-deficient glioblastomas.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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