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Efficiency of PARP inhibitors beyond BRCA mutations

Posted in Cancer - General, Cancer and Current Therapeutics, tagged biomarkers, cancer cells, DDX21 protein, PARP inhibitors, Pharmaceuticals on July 25, 2019| Leave a Comment »

Efficiency of PARP inhibitors beyond BRCA mutations

Reporter

Irina Robu, PhD

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase, which are developed for multiple indications but most visible is the treatment of cancer. Several forms of cancer are extra dependent on PARP than regular cells, making PARP an striking target for cancer therapy. PARP inhibitors seem to improve progression-free survival in women with recurrent platinum-sensitive cancer. In addition to their use in cancer therapy, PARP inhibitors can be a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction and neurodegenerative diseases.

With this knowledge in hand, Lee Kraus, director of the Green Center for Reproductive Biology Sciences at UT Southwestern his team identified a potential biomarker, DDX21 protein, which is required for the production of ribosomes in nucleoli. Nonetheless, DDX21 in the nucleolus requires PARP-1, which is targeted by existing PARP inhibitors. The use of these drugs, blocks DDX21, hence inhibiting ribosome production which as result means that enhanced DDX21 levels in the nucleolus could regulate cancers that might be the most responsive to PARP inhibitors.

Their data published in the journal Molecular Cell explains why breast cancer patients can be responsive to PARP inhibitors, even though they do not carry BRCA mutation. It is well known that the PARP inhibitors currently on the market such as AstraZeneca’s Lynparza, Clovis’ Rubraca and GSK’s Zejula work by disturbing PARP proteins that help repair damaged DNA in cell, hence steering cancer cells onto a path of annihilation. Since cancer cells are addicted to ribosomes to grow and make proteins to support cell division, inhibiting PARP proteins can slow down the growth of the cell.

Kraus’s group is currently working to design clinical trials with UT Southwestern oncologists to see if their hypothesis works. At the same time, they founded Ribon Therapeutics which is the first industrial biotech program going after PARP7, a protein also similarly activated by stress and cellular response mechanisms.

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