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Inhibiting KDM1 expression slowed glioma growth
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The protein KDM1 was observed to be overexpressed in gliomas and could provide a possible therapeutic treatment option, according to findings presented at the AACR Annual Meeting.
About 20,000 patients a year are diagnosed with gliomas, which represent about 70% of brain tumors, according to the researchers.
“Patients with malignant gliomas have a survival time of approximately 14 months. … Novel therapies are urgently needed,” Gangadhara R. Sareddy, PhD, a postdoctoral fellow in the Vadlamudi Laboratory at the University of Texas Health Science Center, said in a press release. “Evolving evidence suggests that glioma development is a multistep process that results from changes both in genetic and epigenetic mechanisms. Unlike genetic alterations, epigenetic changes are reversible; therefore, targeting epigenetic changes represents a promising therapeutic approach.”
Sareddy and colleagues used immunohistochemical analysis to determine that — in glioma tissue microarrays consisting of different grades of astrocytomas, oligodendrogliomas, ependymomas and normal brain tissues — KDM1 expression was higher in gliomas. Using small interfering RNA, pargyline or NCL-1, the researchers halted or inhibited expression of KDM1 in the tissue samples to observe its functional significance in gliomas.
“We found that KDM1 expression is upregulated in gliomas and have preclinical analysis that suggests pharmaceutical inhibition of the KDM1 axis could have therapeutic implications for the treatment of gliomas,” Sareddy said.
Silencing or inhibiting enzyme function in KDM1 significantly reduced the proliferation and colony formation of glioma cells, results showed.
Additionally, researchers observed that inhibiting KDM1 also reduced the growth of human glioma cells in mice. Inhibiting KDM1 increased levels of H3K4me2 and H3K9ac histone modifications, reduced H3K9me2 modification and promoted expression of p53 target genes, causing apoptosis of glioma xenograft tumors.
“Because KDM1 plays a critical role in glioma biology and because epigenetic modifications are reversible, pharmacological inhibition of KDM1 could be a potential therapy for gliomas” Sareddy said. “Identification of KDM1 as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in patients with glioma.”
For more information:
Sareddy GR. Abstract #674. Presented at: American Association for Cancer Research Annual Meeting; April 6-10, 2013; Washington, D.C.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Daniela A. Bota, MD, PhD
Genetic mutations were extensively researched in GBM, culminating with the complete sequencing of the glioblastoma genome. This has brought a wealth of information about the biology of this very aggressive tumor, but less insight into potential, effective treatments that can change the inevitable lethal prognosis. In this environment, a renewed interest is placed on epigenetic modifications and on how we can harvest the knowledge from this relatively recent avenue of research in order to develop effective treatments.
Sareddy’s work focused on the importance of KDM1 (a lysine-specific demethylase) as a potential therapeutic target in GBM, elegantly demonstrating that this protein levels correlates with glioma malignancy in both cell-based and animal study. This is the first report about KDM1 function in glioma, although it is already well published that KDM1 plays an important role in colon, melanoma and lung cancer, and that KDM1 is involved in both stem cell biology and neuronal differentiation.
Even more significant for the practicing neuro-oncologist is the fact that an old, available hypertension drug — pargyline — can be effectively used as KDM1 inhibitor, which displays impressive activity in reducing the glioma stem cell population and controlling glioma xenograft growth. This is different from the previous published data on azacitidine (Vidaza, Celgene), a non-selective irreversible DNA methyltransferase inhibitor that had little effect on both glioma stem cells and overall tumor growth in animal model, and it raises further hope about the role of this type of therapies in malignant gliomas.
It is questionable if pargyline is ready for prime time. It is an old MAO-B inhibitor, with different and potentially severe side effects. The combination of pargyline with more standard glioblastoma treatments such as radiation, temozolomide and bevacizumab (Avastin, Genentech) merits further research for effectiveness and safety profile. However, we need more options for our patients, and targeting KDM1 might bring us just that.
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