revolutionary approach towards cancer therapeutics.

Indication

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.

Scientific Rationale

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.

Mechanism of Action

The modified DNA base, 5-hydroxymethylcytosine, is universally depleted in cancersThe TET2 enzyme synthesizes genomic 5-hydroxymethylcytosineRapid reestablishment of 5-hydroxymethylcytosine invokes the DNA damage response, leading to cancer cell deathHemispherian’s proprietary GLIX molecules act on TET2 to increase genomic 5-hydroxymethylcytosine levelsThe 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

Key Publications

Prikrylova, Terezia, Julia Robertson, Francesca Ferrucci, Dorota Konorska, Havard Aanes, Adeel Manaf, Beibei Zhang, Adam B. Robertson, et al. “5-Hydroxymethylcytosine Marks Mammalian Origins Acting as a Barrier to Replication.” Scientific Reports 9 (July 30, 2019): 11065.

https://doi.org/10.1038/s41598-019-47528-3.

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Klungland, Arne, and Adam B. Robertson. “Oxidized C5-Methyl Cytosine Bases in DNA: 5-Hydroxymethylcytosine; 5-Formylcytosine; and 5-Carboxycytosine.” Free Radical Biology and Medicine 107 (June 2017): 62–68.

https://doi.org/10.1016/j.freeradbiomed.2016.11.038.

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Weber, Alain R., Claudia Krawczyk, Adam B. Robertson, Anna Kusnierczyk, Cathrine B. Vagbo, David Schuermann, Arne Klungland, and Primo Schaer. “Biochemical Reconstitution of TET1-TDG-BER-Dependent Active DNA Demethylation Reveals a Highly Coordinated Mechanism.” Nature Communications 7 (March 2016): 10806.

https://doi.org/10.1038/ncomms10806.

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Robertson, Adam B., John Arne Dahl, Rune Ougland, and Arne Klungland. “Pull-down of 5-Hydroxymethylcytosine DNA Using JBP1-Coated Magnetic Beads.” Nature Protocols 7, no. 2 (February 2012): 340–50.

https://doi.org/10.1038/nprot.2011.443.

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Robertson, Julia, Adam B. Robertson, and Arne Klungland. “The Presence of 5-Hydroxymethylcytosine at the Gene Promoter and Not in the Gene Body Negatively Regulates Gene Expression.” Biochemical and Biophysical Research Communications 411, no. 1 (July 22, 2011): 40–43.

https://doi.org/10.1016/j.bbrc.2011.06.077.

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Robertson, Adam B., John A. Dahl, Cathrine B. Vagbo, Pankaj Tripathi, Hans E. Krokan, and Arne Klungland. “A Novel Method for the Efficient and Selective Identification of 5-Hydroxymethylcytosine in Genomic DNA.” Nucleic Acids Research 39, no. 8 (April 2011): e55.

https://doi.org/10.1093/nar/gkr051.

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Robertson, Adam B., John Arne Dahl, and Arne Klungland. “Bases of DNA Repair and Regulation (Vol 10, Pg 487, 2014).” Nature Chemical Biology 10, no. 12 (December 2014): 1074–1074.

https://doi.org/10.1038/nchembio1214-1074a.

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