Glioblastoma multiforme is the 17th leading cause of cancer and the second leading cause of cancer in children. Owing to its aggressive nature, a diagnosis with glioblastoma multiforme results in severe reduction in quality of life and the disease rapidly causes death. Glioblastoma multiforme is a leading cause of death in children, second only to road injuries in Western Europe and the third leading cause of child death in the USA. Gliomas constitute 60% of all brain tumors and 50% of these are considered aggressive malignant tumors. Among aggressive gliomas, glioblastoma multiforme is the deadliest. Patients with glioblastoma multiforme, which is the most frequent and malignant form of glioma, present a median overall survival of approximately 15 months after diagnosis. The current front line treatment for glioblastoma multiforme, Temozolomide, improves patient survival by a mere 2.5 months. New treatments for glioblastoma multiforme are urgently need to improve and extend patients’ lives.
A hallmark of human cancers is the depletion of the highly modified DNA base, 5-hydroxymethylcytosine. Subsequent modifications of this DNA base result in the activation of the DNA damage response. 5-hydroxymethylcytosine is synthesised by the TET2 enzyme. Restoration of normal TET2 activity in cancer cells results in the establishment of normal 5-hydroxymethylcytosine levels. As normal human cells have saturating levels of 5-hydroxymethylcytosine, the TET2 enzyme does not reestablish 5-hydroxymethlycytosine levels in normal cells. This sharp and sudden increase of 5-hydroxymethylcytosine in cancer cells, invokes the DNA damage response, resulting in cancer cell death. Hemispherian has developed a suite of promising compounds that are highly efficient at enhancing the activity of the TET2 enzyme. These GLIX molecules are highly selective anti-cancer agents. Owing to this novel mechanism and the demonstrated improvements in efficacy and safety, our compounds represent ‘first-in-class’ therapeutics. Our data suggests that high doses of our drugs are minimally cytotoxic to normal cells, highly specific and toxic to many cancers including glioblastoma multiforme and are more effective than the current standard of care.
The modified DNA base, 5-hydroxymethylcytosine, is universally depleted in cancers. The TET2 enzyme synthesizes genomic 5-hydroxymethylcytosine. Rapid reestablishment of 5-hydroxymethylcytosine invokes the DNA damage response, leading to cancer cell death. Hemispherian’s proprietary GLIX molecules act on TET2 to increase genomic 5-hydroxymethylcytosine levels. The GLIX molecules are cancer cytotoxic in vitro and in vivo animal models
The modified DNA base, 5-hydroxymethylcytosine, is universally depleted in cancers
The TET2 enzyme synthesizes genomic 5-hydroxymethylcytosine
Rapid reestablishment of 5-hydroxymethylcytosine invokes the DNA damage response, leading to cancer cell death
Hemispherian’s proprietary GLIX molecules act on TET2 to increase genomic 5-hydroxymethylcytosine levels
The GLIX molecules are cancer cytotoxic in vitro and in vivo animal models
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