PARP inhibitors are effective to other cancer types except for breast cancer

Posted by beauty33 on November 14th, 2019

In July 2019, a new molecular mechanism discovered by researchers at the University of Texas Southwestern Medical Center (UT Southwestern) suggests that some PARP inhibitors currently used to treat less than 10% of breast cancer actually can be used for a wider range of treatments, including ovarian cancer and prostate cancer. The new study also found a potential biomarker that would guide the use of PARP inhibitors to fight cancer. The study was published online on the Moleular Cell.

PARP inhibitors are anticancer drugs developed using the principle of "synthesis to death". By inhibiting the PARP-mediated DNA damage repair mechanism, accumulation of excessive DNA damage is caused in tumors carrying BRCA gene mutations, thereby triggering cell death. PARP inhibitors are effective in the treatment of breast and ovarian cancer, but their use is currently limited to a small number of patients carrying BRCA mutations. But recent research suggests that its range of applications may not be limited to patients with mutations in the BRCA gene. In addition to disrupting the repair of DNA, PARP inhibitors also block the formation of ribosomes. This is an organelle that relies on them for explosive growth.

The new study found that in addition to its ability to repair DNA damage, PARP1 can help maintain the presence and function of a protein called DDX21 in the nucleus of the nucleus. If PARP1 is deleted, DDX21 will leak from the nucleolus into the nucleus, blocking the transcription of ribosomal RNA. If PARP1 is inhibited, DDX21 in the nucleolus will also leak into the nucleus, blocking the transcription of ribosomal RNA. High levels of DDX21 in the nucleolus indicate that the cancer may be sensitive to PARP inhibitors.
"If there is no ribosomal RNA, a complete ribosome can't be assembled. Without ribosomes, the level of protein translation in cells is reduced, and the rapid proliferation of cancer cells depends on rapid protein synthesis." Dr. W. Lee Kraus of the University of Texas Southwestern Medical Center said.
PARP inhibitors can act similarly to PARP1 deletions by inhibiting protein synthesis to achieve anticancer effects. High levels of expression of DDX21 in the nucleolus may indicate which cancers may be most sensitive to PARP inhibitors.

"DDX21 can also help determine which patients may respond to PARP inhibitors. We believe that the location in the DDX21 nucleus may be an important indicator of whether cells respond to PARP inhibitors," Dr. Kraus added. "If DDX21 has left the nucleolus , distributed throughout the nucleus, then PARP inhibitors may have limited efficacy."
Next, the researchers plan to conduct clinical trials to test whether the study can be validated in human patients. "What we want to do is group patients - do their cancers have DDX21 in the nucleolus? Or is it more dispersed in the nucleus? We will study the therapeutic effects of PARP inhibitors in both populations." Dr. Kraus said.

Reference
1. New discovery could open up PARP inhibitors to more cancer patients. Retrieved July 24, 2019, from https://www.fiercebiotech.com/research/new-pathway-could-open-up-parp-inhibitors-to-more-patients
2. UT Southwestern Researchers find evidence a cancer drug may be extended to many more patients. Retrieved July 24, 2019, from https://www.prnewswire.com/news-releases/ut-southwestern-researchers-find-evidence-a-cancer-drug-may-be-extended-to-many-more-patients-300889949.html
3. Kim et al., (2019). Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. Molecular Cell, https://doi.org/10.1016/j.molcel.2019.06.020