New research reveals mechanism behind new generation of anticancer drugs

New research that uncovers the mechanism behind the latest generation of anti-cancer drugs opens the door to better targeted therapy.

PARP inhibitors are molecularly targeted anticancer drugs used in the treatment of women with ovarian cancer with BRCA1 and BRCA2 gene mutations.

The drugs are promising in advanced clinical trials on bad cancer, prostate cancer and pancreatic cancer and are part of an approach known as Precision Medicine, which targets treatments in function of genetic, environmental and lifestyle factors.

What we did is identify the functioning of the drugs. By knowing how they work, we will be able to offer new applications for them to make this drug as useful as possible for as many patients as possible. "

Michael Hendzel, Oncologist and Cell Biologist, University of Alberta

People with a BRCA1 or BRCA2 gene mutation have a defect in the ability of their cells to repair double-strand breaks in DNA, which exposes them to an increased risk of bad cancer. PARP inhibitors take advantage of this weakness and further interfere with proteins known as poly-ADP ribose polymerase (PARP1 and PARP2), which cells use to repair the daily damage to DNA that occurs in the body. normally produce. When the cells can not repair themselves, they die. Normal cells are not affected.

"The cells are often redundant, so for example, if they have a defect that they use to repair the damage, they can use a different way to repair it," said Hendzel, who also leads the research group on genomic stability at the North Alberta Cancer Research Institute.

"But when they have this defect and you have a medicine to interfere with the escape route, then you kill those cells."

The research is the result of a 20-year collaboration between the Hendzel research laboratory, those of Guy Poirier at the University of Laval Cancer Research Center and Jean-Yves Mbadon of the Research Center of the Université Laval. CHU of Quebec.

Inhibitors of PARP are the first anticancer treatments developed to exploit a process known as synthetic lethality, in which cancers with specific mutations are much more sensitive to the drug than normal cancer cells.

According to Dr. Poirier, 1% of all cancer clinical trials now involve PARP inhibitors and could play a key role in the treatment of some aggressive and refractory cancers.

"PARP inhibitors work against cancers for which no other treatment looks promising, such as metastatic pancreatic cancer and castration-resistant prostate cancer," he said.

Until now, it was not clear how PARP inhibitors could interfere with cell repair. The new research reveals that PARP proteins regulate the repair of double strands in DNA and that inhibitors prevent the control of the process that digests a strand of DNA so that it can be paired with a copy used to repair it.

Hendzel, Poirier and Mbadon were the first to establish that PARP played an important role in the repair of double-strand breaks. Their new findings explain many of the effects of PARP inhibition that were not yet understood.

The new study shows that there is additional potential for developing and improving existing combined cancer treatments, in which radiation therapy or DNA damaging chemotherapy is badociated with drugs targeting PARP. The results predict the properties that a cancer must have for the inhibition of PARP to improve the therapeutic efficacy of the combination therapy. A large number of clinical trials currently badociate PARP inhibitors with radiotherapy or chemotherapy.

"Our work explains why PARP inhibitors and radiation therapy are a good combo," said Mbadon. "In fact, PARP inhibitors will increase sensitivity to radiation therapy in some patients."

"At a time when we will routinely have complete genome sequences of human cancers, this study will enable the deployment of PARP inhibitors as a precision drug in combination therapies," Hendzel said.