Tailoring chemotherapy to specific cancer cells

As part of the Australian Society for Medical Research's (ASMR) Medical Research Week, the Amgen Medical Researcher Award was presented today to Dr Ricky Johnstone from Melbourne's Peter MacCallum Cancer Centre.

Johnstone's work focuses on better understanding how chemotherapy drugs kill cancer cells, how certain cancer cells evade these agents, and developing a more targeted approach to chemotherapy.

"The concept is this," said Johnstone.

"There is this stack of chemotherapeutic drugs out there and still no one really knows how most of them kill a cancer cell. We sort of know that they might target DNA, or they might target microtubules and then 'magic happens' and the cell undergoes apoptosis.

"The key is to understand the exact molecular pathways that are being targeted because then we might know how best to use that drug because we could pre-screen patients and ask 'are the genes essential for those apoptosis pathways intact?' And if they're not intact then we use another drug."

One class of drugs Johnstone is concentratingonis the histone deacetylase (HDac) inhibitors --anew class of drugs just entering preclinical trials.HDac inhibitors have a remarkable selectivity for cancer cells and a very low toxicity against normal cells. They target histones, regulating transcription and altering chromatin structure to induce apoptosis in cancer cells.

Johnstone is focusing on two HDac inhibitors: Depsi peptide, made by Fugisawa in Japan, and SAHA (suberoylanilide hydroxamic acid), made by Aton Pharmaceuticals in the US (a company basically built on the back of this drug that came out of the Memorial Sloan Kettering Cancer Centre in New York).

Not only does Johnstone work on HDac inhibitors and how they kill, he is also working on understanding what defects can occur in tumour cells that give them resistance to these drugs. For example he has found that if a tumour cell overexpresses BCL2 -- a classic anti-apoptotic protein -- HDac inhibitors will no longer kill the cell.

"Putting it simplistically, if you could pre-screen patients those patients that didn't have BCL2 or related genes overexpressed then they would be very good candidates for using these drugs. Whereas if you had a patients who did have overexpressed BCL2 what you would do, in an ideal world, is go to the next shelf and pick a drug that you know can work when BCL2 is over expressed," explained Johnstone.

Because it is an inherent property of cancer cells to become drug resistant -- especially since chemotherapy drugs themselves alter DNA -- it is important to kill the cells with the first treatment. Thus using a more targeted approach,as Johnstone envisions, would increase the chances of killing the cancer cell and reduce the likelihood of drug resistance occurring.

Johnstone recently had a paper accepted into Cancer Research that compares three different HDac inhibitors and shows they have similarities and differences -- so even though they are all meant to do the same thing they don't.

"This will revolutionise chemotherapy, I'm convinced of that," said Johnstone. Johnstone said he will most likely use the award money to attend an apoptosis conference to be held in New York in September.