OncoSENS: Making cancerous mutations harmless

Identification of the Genetic Basis of ALT

Principal Investigator: Haroldo Silva

Research Team: David Halvorsen, Christine Wu, Manali Aggrawal

The most common way for cancer cells to re-lengthen their telomeres is to hijack the enzyme telomerase. However, other cancers — some of which are notoriously difficult to treat — rely on another, less commonly-exploited (and less well understood) mechanism to extend their telomeres: a system known as alternative lengthening of telomeres (ALT). The SENS Research Foundation Research Center (SRF-RC) ALT team is making progress along a number of paths toward demystifying ALT and enabling progress toward potentially revolutionary cancer treatments. They are rapidly developing faster, simpler, and less expensive assays to measure hallmarks of ALT activity such as APB (ALT-associated Promyelocytic-leukemia nuclear Bodies) and the linear and circular repeats of telomeric DNA called “C-circles”. The SRF-RC ALT team has, for instance, developed a fast (8 hour versus 2-4 days), high-throughput version of the assay that will enable researchers to quantitatively measure C-circles in human ALT cells.
 
The team also submitted a patent application on their C-circle assay technology, which has recently been upgraded into a full patent application. They have received very favorable feedback for their presentations at the EMBO conference on “Telomeres, Telomerase, and Disease” and the Cold Spring Harbor Laboratories Telomeres & Telomerase conference. A collaboration with the inventor of the original C-Circle assay, Dr. Jeremy Henson of the University of New South Wales’s Cancer Cell Immortality Group is ongoing: this collaboration has been awarded a $200,000 grant for ALT research by Tour de Cure, an Australian cancer research charity. A separate collaboration with Dr. Denis Mottet of the Université de Liège in Belgium has also been initiated to study the possible involvement of a protein called HDAC5 in ALT. This year, the team was also awarded a $25,000 grant from the Life Extension Foundation to advance the development of the APB assay; this work is now being extended with testing of a synthetic polymer drug whose structure is similar to peptides that was sent to the team by Dr. Robert Shmookler-Reis at the University of Arkansas.
 
As part of validating their assays, the SRF-RC ALT team has replicated the effects of “silencing” (negating the expression of) specific proteins on APB levels in ALT-exploiting cancer lines as reported using the earlier and more cumbersome assay, and also of two chemicals (telomestatin and hydroxyurea). In collaboration with Capital Biosciences, the SRF-RC ALT team is now initiating the testing of more than 70 reference cell lines from the private, nonprofit biological resource center ATCC for the presence of ALT activity. This important line of investigation may identify new ALT-dependent cell lines in the collection which can be put to use as reference standards.