C13222
UNMET NEED
Cancer is incredibly difficult to treat, due to the confluence of factors that cause and perpetuate the disease and the difficulty of targeting cancer cells without affecting normal cells. As such, the academic and industry space is perpetually engaged in researching new targets and pharmacological strategies.
For the past few decades, targeted cancer therapies have had a largely genetic approach, and have focused on inhibiting oncogenes or onco-proteins or delivering compensatory genes. Epigenetics is emerging as a field with comparable relevance to cancer, as modifications to epigenetic proteins have direct and large-scale control over gene expression. Advances in epigenetics show great potential for new therapeutic strategies.
PROBLEM SOLVED
Epigenetic processes play important roles in regulating stem cell identity and activity. Failure to appropriately regulate epigenetic information may lead to abnormalities in stem cell behaviors, which underlie early progress toward diseases such as cancer and tissue degeneration.
The inventors showed that phosphorylation at threonine 3 of H3 (H3T3P) distinguishes pre-existing versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance. Expression of H3T3A or H3T3D specifically in early stage germline also leads to cellular defects, including germline stem cell (GSC) loss and germline tumors. Finally, compromising the activity of the H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes. These data demonstrate that:
1. H3T3P distinguishes sister chromatids enriched with distinct pools of H3 in order to coordinate asymmetric segregation of ‘‘old’’ H3 into GSCs and,
2. That tight regulation of H3T3 phosphorylation is required for male germline activity.
3. Expression of the H3T3A in fast dividing progenitor non stem cells leads to cell death, indicating that it can be used to restrict tumor cells from dividing and could be applied to cancer treatment.
Finally, inactivation of the kinase that phosphorylates the Thr3 residue of histone H3 was attempted as an anti-tumor strategy. Here we identified a new and effective method to specifically compromise phosphorylation of Thr3 of H3 in fast dividing cells, which could be applied to inhibit cancer cell division and tumor growth.
STAGE OF DEVELOPMENT
- Preclinical data obtained in Drosophila male germ cells.
DISEASE INDICATION
Cancers
ASSOCIATED PUBLICATIONS
- Cell. 2015 Nov 5;163(4):920-33
- Science 02 Nov 2012: Vol. 338, Issue 6107, pp. 679-682
ASSOCIATED REPORTS OF INVENTION (ROIs) AND INTELLECTUAL PROPERTY (IP) FILING NUMBERS
ROI # TITLE
C13222 A H3T3A Mutant Protein Efficiently Reduces H3T3P and Causes Increased Cell Death of Rapidly Dividing Cells
STATUS PRIORITY DATE IP FILING NUMBERS
Pending 4/6/2015 US 62/143,546
TECHNOLOGY CLASSIFICATION
Primary Category: Therapeutics
Primary Subcategory: Epigenetic Therapeutics
