Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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.

SOURCE

PARP inhibitors sometimes work beyond BRCA-mutations, researchers may finally know why

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting PARP

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/19/targeting-parp/