Fresh look at cancer’s secret of eternal youth
August 18, 2016
Recent advances in drug discovery technology and molecular studies could yield a suite of potential drugs that target cancer’s secret of eternal youth, argue Australian researchers in a Nature Reviews Cancer paper this month.
In their invited paper, the Children’s Cancer Institute researchers advocate new tools for a fresh look at an old problem – inhibiting the enzyme that helps cancer cells divide without stopping.
Dr Greg Arndt and Dr Karen MacKenzie say cancer researchers worldwide are searching for safe, effective anti-cancer drugs that kill rapidly growing cancer cells but leave normal cells alone. MacKenzie, Senior Scientist in Personalised Medicine, says this is especially challenging for childhood cancer as children are themselves rapidly growing.
“We’ve known for more than 20 years that the enzyme telomerase helps cancer cells achieve immortality, but we still don’t have a safe, effective drug on the market that inhibits it.
“The most promising telomerase inhibitor drug candidate has proved disappointing in recent clinical trials for adult cancer.
“With new technologies at our disposal, it’s time for a fresh look”, she said.
Telomerase, which in normal cells controls the number of times a cell divides before stopping, is disrupted in cancer and makes cancer cells divide out of control. It is located at the ends of chromosomes, in the telomeres, which shorten with each cell division. To date, however, targeting it has failed to yield a new treatment.
In the review paper, Drs Arndt and MacKenzie distil current knowledge about telomerase and argue that, with the increased rapidity and sensitivity of today’s molecular analysis technologies, researchers should explore new approaches. They say that targeting telomerase beyond its usual role in the telomere could be the key to finding the next generation of small-molecule telomerase inhibitors.
They suggest strategies for targeting molecules and events central to telomerase’s biogenesis, regulation, transport and function, and identifies which technologies could be used to investigate them.
Dr Greg Arndt, Manager of the ACRF Drug Discovery Centre at Children’s Cancer Institute, says automation of drug testing means it takes days rather than years to test thousands of chemical compounds against normal and cancer cells.
“We have technologies now that weren’t available when telomerase was first studied. These allow us to explore it in more detail than ever.
“We can bring new knowledge in cell biology and drug discovery together and speed up the search for new therapeutics”, he said.
Looking beyond the telomere is an approach Arndt and MacKenzie have some success with.
In April the researchers published in the journal Cancer Research some exciting findings showing that targeting dyskerin, one of the protein components of telomerase, rapidly kills neuroblastoma cells but in an unexpected way.
MacKenzie said neuroblastoma is the cancer responsible for 15% of Australian childhood cancer deaths.
“We found that, without dyskerin, neuroblastoma cells stopped dividing and died in days, most likely because dyskerin has roles beyond the telomere. Without dyskerin, the protein-building machinery falls apart and the cell dies – an effect that is independent of the telomere” she said.
This intriguing result could have implications in the search for drugs that target dyskerin in other adult and childhood cancers. The next step is to find chemical compounds that target the protein using drug discovery technology for potential use in personalised medicine.
The ACRF Drug Discovery Centre at Children’s Cancer Institute screens many thousands of novel chemicals to identify potential new drugs. The Centre also contains high content imaging software that analyses cell changes, and 3D computer models of molecules.
Research on dyskerin was supported by the Cancer Council NSW.
• New prospects for targeting telomerase beyond the telomere by Greg M. Arndt & Karen L. MacKenzie, Nature Reviews Cancer 16(8):508-524 (doi:10.1038/nrc.2016.55) August 2016
• MYC-driven neuroblastomas are addicted to a telomerase-independent function of dyskerin by O’Brien R, Tran SL, Maritz MF, Liu B, Kong CF, Purgato S, Yang C, Murray J, Russell AJ, Flemming CL, von Jonquieres G, Pickett HA, London WB, Haber M, Gunaratne PH, Norris MD, Perini G, Fletcher JI, MacKenzie KL. Cancer Research 76(12):3604-17 (doi: DOI: 10.1158/0008-5472) Published 15 June 2016 (doi: DOI: 10.1158/0008-5472) Published 15 June 2016
About Children’s Cancer Institute
Originally founded by two fathers of children with cancer in 1976, Children’s Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention and cure of childhood cancer. Forty years on, our vision remains unchanged – to save the lives of all children with cancer and to eliminate their suffering. The Institute has grown to now employ more than 220 researchers, operational staff and students, and has established a national and international reputation for scientific excellence.
Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimise side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life.
We are currently leading the establishment of the Zero Childhood Cancer national child cancer personalised medicine program for children with the most aggressive cancers, in partnership with the Sydney Children’s Hospitals Network. This program will revolutionise the way treatment decisions are made, with the aim of improving survivorship for those children at highest risk of treatment failure from their disease.