UK Cancer Researcher Fights Disease Using Counterintuitive Approach

UK Cancer Researcher Fights Disease Using Counterintuitive Approach

A researcher at Wellcome Trust/Cancer Research UK Gurdon Institute developed a counterintuitive approach to fighting cancer that led to the development of Lynparza (olaparib) as a prescribed medication for certain types of BRCA-mutated advanced ovarian cancer.

The therapeutic approach is now being considered for other types of cancer that might also derive from BRCA mutations, including prostate and breast cancer.

Common sense tells us that when we’re under attack, we should gather our soldiers to defeat the enemy. But if you’re based at the Wellcome Trust/Cancer Research UK Gurdon Institute in England, this approach might not necessarily be used.

The “counterintuitive” approach was first used by Steve Jackson, a professor who has worked at the institute for more than two decades. Jackson worked on the development of a new class of cancer drugs that work from a different approach to cancer: They switch off a mechanism that exists to repair our DNA and prevent it from mutating.

Many existing chemotherapy drugs encourage apoptosis – programmed cell death. But not only does this damage healthy cells, which is why chemotherapy patients get so sick, apoptosis is also the process that cancer cells use against healthy cells. The seemingly counterintuitive solution suggests that stopping cell death is the answer to save healthy cells.

“If you can somehow inhibit apoptosis, then you can keep the healthy cells alive. And if you keep the healthy cells alive, you stop the cancer cells spreading and the tumor should die away,” Eugenia Piddini, a colleague of Jackson’s at the Wellcome Trust/Cancer Research UK Gurdon Institute, said in a press release.

Jackson developed Lynparza as the result of this approach, and the drug was granted marketing approval from the European Commission and the U.S. Food and Drug Administration (FDA) in 2014.

Lynparza is now available in more than 40 countries as the first oral prescription medicine for women with BRCA-mutated advanced ovarian cancer who have received three or more prior chemotherapy medicines.

The drug was developed after Jackson discovered a DNA repair enzyme known as PARP, and first marketed by his own company, KuDOS, which was later bought by AstraZeneca.

DNA repair is instrumental to our survival – so much so that we have a natural mechanism that jumps into action in case PARP fails, known as homologous recombination.

During homologous recombination, our body exchanges identical DNA pieces to repair the damaged DNA. In some cancers – mainly those associated with BRCA1 or BRCA2 gene mutations – this mechanism also fails because these patients carry two “bad” copies of the gene, which deactivates homologous recombination.

However, patients’ healthy cells also carry one good copy of the gene, meaning that the process can still be carried out.

“This was a Eureka moment,” Jackson said. “We realized that if you block the PARP repair mechanism in these individuals, the healthy cells revert to their backup and survive, but the tumor cells have no backup and so will die.”

It’s estimated that one in three cases of ovarian cancer is caused by the BRCA gene. Recent studies have suggested that the same link might be found for prostate and breast cancer cases. If Lynparza is approved for all these patients, there may be a big difference in survival rates. However, Lynparza is rejected by some patients for unknown reasons, and some people develop a resistance to the drug.

“We all hope to cure cancer, and PARP inhibitors are curing a small proportion of patients,” Jackson added. “But what we’re doing is moving cancer towards becoming a long-term disease that is kept in check through different phases. That’s a good business model for pharmaceutical companies, ensuring that they invest in this area, but most of all, it’s good for the patients.”

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