Developing therapeutic strategies to selectively kill ATRX-deficient cancer cells
Cancer cells are characterised by indefinite proliferation, which represents a clear target for anti-cancer therapies. Continuous cellular replication requires maintenance of telomeres, which are terminal regions of each genomic DNA molecules and normally eroded as the cell divides. To maintain telomeres, cancer cells typically make use of the enzyme telomerase, which is normally expressed in self-renewing stem cells to elongate telomeres. Therefore, inhibition of telomerase has been widely attempted, but in many cases cancer cells activated a mechanism that maintains telomeres without telomerase activity. This mechanism, called ALT (alternative lengthening of telomeres), is also found in naturally occurring cancers, being particularly prevalent in certain cancer types such as osteosarcoma and glioblastoma. Since ALT is only found in cancer cells, therapeutic targeting of ALT is currently a subject of active investigations in the field.
Notably, ALT cancers often lose expression of ATRX gene, which thus provides a genetic biomarker that could be used as a surrogate target for therapies. In normal cells, ATRX protein is required for efficient replication of genomic DNA and the repair of DNA damage (detailed scientific writing is provided in the right wing). Therefore, cells that do not have ATRX are intrinsically vulnerable to synthetic modulations in the intracellular systems for DNA replication and repair. In this light, it is widely attempted to develop therapeutic interventions that can specifically kill ATRX-deficient cancer cells.
My research focuses on identifying pharmacological agents that can selectively eliminate ALT, or ATRX-deficient, cancer cells. Candidate reagents are selected based on previous reports on their mechanism of action or pilot screening conducted on model organisms. In order to assess its selective lethal effect, the drug is applied to cultured human cancer cell lines of various tissue origins, and their short-term proliferation and long-term viability are evaluated. Identified leads are then further studied for mechanistic details of its selectivity. Also, synergistic effect with doxorubicin, which is currently used in clinical settings to treat multiple ALT-prevalent cancers, is also examined, with the aim of contributing to complete treatment and preventing recurrence of cancer.
Function of ATRX
Full-length ATRX is a SWI/SNF2-type protein that has chromatin remodelling activity, with a size of 280 kDa. One major function of ATRX is to facilitate the deposition of histone variant H3.3 into chromatin. ATRX forms complex with histone chaperone DAXX and supports its activity, thus promoting the incorporation of (H3.3-H4)2 tetramer into the chromatin.
H3.3 deposition by ATRX/DAXX is essential for maintaining genome stability, as it is required for homologous recombination (HR) during DNA replication and repair. In S phase, when replication fork stalls, its restart is mediated by the reversal of the fork and recombination of the nascent DNA end with the duplex region ahead of the fork. The ensuing DNA synthesis requires H3.3, ATRX and DAXX. When two-ended DNA double strand break (DSB) occurs in G2 phase, it can be repaired via HR, where one end is elongated using the sister chromatid as a template. This repair synthesis can be either short- (about 100 kb) or long-tract (longer than 1 kb), where the latter requires concurrent loading of H3.3 by ATRX/DAXX.