New class of drug compounds puts cancer in a sleeper hold
Cancer isn't some foreign illness invading your body – it's essentially just regular cells dividing out of control. Current cancer treatments like chemotherapy and radiotherapy are designed to kill tumors, but they often take down healthy cells as well. An emerging technique could provide a more targeted approach, stopping tumorous cells from proliferating and effectively putting the cancer to sleep.
Cells seem to have a natural limit to the amount of times they can divide, before their DNA starts getting too damaged to function. At a certain point, the body shuts down these damaged cells through a biological process called senescence, which prevents them from dividing any further. In a perfect world, the immune system can then take out the trash.
But of course, we don't live in a perfect world, and some cells refuse to follow the rules. Cancer has a nasty knack for hijacking this mechanism and continuing to divide unchecked. Figuring out a way to turn senescence back on could be a crucial new weapon in the fight against cancer – and now researchers in Australia have developed new compounds that could do just that.
"This new class of compounds stop cancer cells dividing and proliferating by switching off their ability to continue the cell cycle," says Anne Voss, co-lead researcher on the study. "The technical term is cell senescence, but essentially the cells are put to sleep. The cancer cells aren't dead, but they are effectively stopped in their tracks."
In 2012, the researchers discovered that removing KAT6A, a gene that controls cell proliferation, helped mice with fatal lymphoma live four times longer than otherwise. The team began focusing on this gene and the related KAT6B, to investigate whether blocking their function could help treat cancers.
After screening around 250,000 molecules that may be able to inhibit these genes, the researchers found two promising candidates, known as WM-8014 and WM-1119. In animal tests, the team found that these molecules were able to induce senescence in cancer cells without causing DNA damage or affecting healthy cells. WM-8014 was tested on zebrafish with liver cancer, while WM-1119 halted the progression of lymphoma in mice.
"The compound was well tolerated in our preclinical animal models and is very potent against tumour cells, while appearing not to adversely affect healthy cells," says Tim Thomas, co-lead researcher on the study.
While the study hasn't yet looked into what happens to the "sleeping" cells afterwards, the researchers believe that the immune system will eventually recognize them and clear them out. Future work will examine that, as the molecules are prepared for eventual human clinical trials.
"We think these compounds will be effective in treating those cancers where the proliferation of cancer cells through the cell cycle is driven by these KAT6A and KAT6B genes, and if we inhibit these genes it should have a therapeutic effect," says Thomas. "For example, we think it will be effective in some blood cancers that block cells from differentiating normally into different cell types. In the case of leukaemia, the cancer causes the excessive proliferation of white blood cells, diluting oxygen-carrying red blood cells. Eventually a patient starts to lose their ability to circulate oxygen. We'd hope to be able to stop that from happening."
The research was published in the journal Nature.
Source: University of Melbourne