Dr. Paola Marignani is searching for new treatments. More precisely, the Dalhousie Medical School researcher wants a new combination of drugs to target cancer in a new and different way.
“Many of the drugs we have in the clinic today block oncogenes that were discovered 15 or 20 years ago,” says Dr. Marignani, pictured at right. “We can’t just keep using the same drugs over and over again in different combinations. We need to find new targets and new drugs.”
Her key target is LKB1, a protein that has multiple functions throughout the body, including tumour suppression. LKB1 is often found to be missing or mutated in breast cancer, lung cancer, pancreatic cancer and other forms of the disease. “If you lose LKB1 or its mutated, it sets up protein signalling pathways for disaster,” says Dr. Marignani. “It would be like an intersection that once had stop signs and is now without any. Eventually an accident is going to happen.”
To understand what happens when LKB1 is lost and mutated, her team used re-engineered mice without the ability to express the protein. That led them to finding a combination of compounds that shuts down aggressive, metabolically active HER2-positive breast cancers — a common form of the disease — in the rodents.
Dr. Marignani is using a two-pronged approach by testing the new compounds in combination with Herceptin®, which has become the standard of care for HER2-positive breast cancer. “We know Herceptin® is effective,” says Dr. Marignani. “We can use the discovery we made in mice to strategically attack the cancers from multiple branches using new drugs in combination with the standard treatment of care, and see what happens.”
So far, she is cautiously optimistic. “The animals tolerate the drug combination, which is very important, and early data suggests the tumours are not progressing.”
Beyond shutting down tumour growth, Dr. Marignani and her team want to find ways to stop cancer from recurring by killing off the cancer stem cells that resist the original treatment.
“There is always the possibility that there are some cancer stem cells hiding out, just waiting, that have developed resistance to the treatment that killed off the bulk of the cancer,” she explains. “We have seen that our drug combination reduced the proteins that drive recurrence. We did not anticipate this would happen because there was no evidence in the literature. In our current study, we need to consider whether stem cells play a role in cancer recurrence in our model and look for pathways that are active in those cells. We don’t know yet. We’re working on it.”
With fine tuning of her animal-model preclinical work done, Dr. Marignani hopes to move into a Phase 1 clinical trial, testing the safety of the drug combination in humans. But she emphasizes that the work is in the early stages.
“It is important that we look for new treatment possibilities even though the current treatments are reasonably good. Targeting oncogenes has served us well, however it is time we expand our toolbox. We can do better.”