PARP inhibitors sometimes work beyond BRCA-mutations, researchers may finally know why
A class of potent cancer treatments could shine brighter than previously thought in a broader array of patients, new research suggests.
PARP inhibitors, including AstraZeneca’s $AZN pioneering Lynparza, Clovis’ $CLVS Rubraca and GSK’s $GSK Zejula — work by thwarting PARP proteins that help repair damaged DNA in cell — thereby steering cancer cells onto a path of annihilation. So far, their use has primarily been in ovarian cancers containing BRCA mutations, rare genetic mutations that disable a DNA repair pathway in cancer cells, as well as BRCA-mutated breast cancer. (Although last month, Zejula was granted priority review to expand its use in late-stage ovarian cancer patients with or without BRCA mutations).
While the assault on DNA repair is being waged, these drugs are also attacking ribosomes — the machinery that makes proteins, said Lee Kraus, director of the Green Center for Reproductive Biology Sciences at UT Southwestern. “These findings could increase the patient population benefiting from these drugs by two, three, or four-fold. Up to 70 percent of breast cancer patients could now be good candidates.”
The data, published in the journal Molecular Cell on Wednesday, could explain why breast cancer patients can be responsive to PARP inhibitors, despite not carrying BRCA mutations.
Kraus and his team identified a potential biomarker — a protein called DDX21, which is required for the production of ribosomes in small subcellular compartments called nucleoli. But DDX21 in the nucleolus requires PARP-1, which is targeted by existing PARP inhibitors. The use of these drugs, therefore, blocks DDX21, thereby inhibiting ribosome production. This means enhanced DDX21 levels in the nucleolus could indicate cancers that might be the most responsive to PARP inhibitors, the researchers posited.
“Cancer cells are addicted to ribosomes. Cancer cells grow fast and must make proteins to support cell division and other essential processes going on in the cell. If you can slow down or inhibit the production of ribosomes, then you can slow down the growth of the cancer cell,” Kraus said in a statement.
Kraus et al are now working on designing clinical trials with UT Southwestern oncologists to test their theory.
Kraus is a founder and consultant of Ribon Therapeutics, which earlier this year raised $65 million to target other PARPs in the broad family of 17 enzymes. The Cambridge, Massachusetts-based biotech’s lead program is first going after PARP7, a protein also similarly activated by stress and cellular response mechanisms.