Murine study finds potential boost for ovarian cancer drug Olaparib

January 25, 2017
In tumors formed by human breast cancer cells, DNA damage (brown staining) is increased by simultaneous Olaparib treatment and PGAM1 suppression (right) when compared to either Olaparib treatment (left) or PGAM1 suppression (center) alone. Credit: Qu et al., 2017

Researchers from the Chinese Academy of Sciences have discovered that the metabolic enzyme phosphoglycerate mutase 1 (PGAM1) helps cancer cells repair their DNA and found that inhibiting PGAM1 sensitizes tumors to the cancer drug Olaparib (Lynparza). Their findings in the study "Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells," which has been published in The Journal of Cell Biology, suggest that this FDA-approved ovarian cancer medicine has the potential to treat a wider range of cancer types than currently indicated.

Cancer cells often alter their in order to synthesize the materials they need for rapid growth. By producing the metabolite 2-phosphoglycerate, PGAM1 regulates several different metabolic pathways, and the levels of this enzyme are abnormally elevated in various human cancers, including breast cancer, lung cancer, and prostate cancer.

Min Huang, Jian Ding, and colleagues at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered that inhibiting PGAM1 made more sensitive to drugs that induce breaks in both strands of the cells' DNA. This was because the cells were unable to activate a pathway called homologous recombination that repairs this type of DNA damage. The researchers found that cells synthesized fewer deoxyribonucleotide triphosphates (dNTPs)—the building blocks of DNA—when PGAM1 was inhibited. This, in turn, activated a cellular stress response pathway that culminated in the degradation of a protein called CtIP that is required for homologous recombination repair.

Cancers carrying mutations in the BRCA1 and BRCA2 tumor suppressor genes are unable to undergo homologous recombination and therefore rely on a different pathway to repair their DNA and continue growing. Olaparib blocks this second repair pathway by inhibiting an enzyme called poly ADP ribose polymerase (PARP). Olaparib was approved by the FDA in 2014 to treat ovarian cancers with BRCA mutations.

In this study, the researchers tested the effects of Olaparib on the tumors formed by human cells injected into mice. Olaparib had no effect on tumors formed by containing functional BRCA1 and BRCA2 genes. But by combining the drug with a PGAM1 inhibitor to impair both and PARP-dependent DNA repair, the researchers were able to significantly suppress tumor growth.

"This suggests that PGAM1 inhibitors can sensitize cancers to PARP inhibitors such as Olaparib, thereby expanding the benefits of PARP inhibitors to BRCA1/2-proficient cancers, particularly triple-negative breast cancers that currently lack effective therapies," says author Min Huang.

Explore further: A gene defect as a potential gateway for targeted prostate cancer therapy

More information: Qu et al., 2017. J. Cell Biol. DOI: 10.1083/jcb.201607008

Related Stories

A gene defect as a potential gateway for targeted prostate cancer therapy

September 5, 2016
The loss of CHD1, one of the most frequently mutated genes in prostate tumors, sensitizes human prostate cancer cells to different drugs, including PARP inhibitors. This suggests CHD1 as a potential biomarker for targeted ...

Study identifies promising drug target in certain breast and ovarian cancers

February 16, 2015
The Food and Drug Administration's recent approval of the drug olaparib for ovarian cancer patients with inherited mutations in the genes BRCA1 or BRCA2 came as welcome news to the thousands of women now eligible to receive ...

New findings may enhance PARP inhibitors therapy in breast cancer

January 18, 2016
Findings from a new study reveal that PARP inhibitors, an emerging class of drugs being studied in cancer clinical trials, may be enhanced by combining them with inhibitors targeting an oncogene known as c-MET which is overexpressed ...

Heat helps cancer drugs battle cancer

May 10, 2011
(PhysOrg.com) -- Localized hyperthermia has been used occasionally with cancer drugs for some time, but until now, the reason it helps has been a mystery. In a report in the Proceedings of the National Academy of Sciences, ...

Enzyme that regulates DNA repair may offer new precision treatments for breast and ovarian cancer

December 12, 2016
Researchers at Mayo Clinic have identified an enzyme called UCHL3 that regulates the BRCA2 pathway, which is important for DNA repair. Results of this research are published online in Genes & Development.

First of new generation of cancer drugs granted European approval

December 18, 2014
A new drug for ovarian cancer, developed by researchers at the University of Cambridge and AstraZeneca, has today become the first of new class of drugs, known as PARP-inhibitors, to be granted approval anywhere in the world. ...

Recommended for you

New bowel cancer drug target discovered

October 17, 2017
Researchers at the Francis Crick Institute have discovered a new drug target for bowel cancer that is specific to tumour cells and therefore less toxic than conventional therapies.

Using artificial intelligence to improve early breast cancer detection

October 17, 2017
Every year 40,000 women die from breast cancer in the U.S. alone. When cancers are found early, they can often be cured. Mammograms are the best test available, but they're still imperfect and often result in false positive ...

Many pelvic tumors in women may have common origin—fallopian tubes

October 17, 2017
Most—and possibly all—ovarian cancers start, not in ovaries, but instead in the fallopian tubes attached to them.

Researchers find novel mechanism of resistance to anti-cancer drugs

October 17, 2017
The targeted anti-cancer therapies cetuximab and panitumumab are mainstays of treatment for advanced colorectal cancer, the second leading cause of cancer-related deaths in the United States. However, many patients have tumors ...

New assay may boost targeted treatment of non-Hodgkin lymphoma

October 17, 2017
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer and the most frequently diagnosed non-Hodgkin lymphoma worldwide (nearly 40% of cases). Recent advancements indicate that both the prognosis and choice of treatment ...

Biology of childhood brain tumor subtypes offers clues to precision treatments

October 17, 2017
Researchers investigating pediatric low-grade gliomas (PLGG), the most common type of brain tumor in children, have discovered key biological differences in how mutated genes combine with other genes to drive this childhood ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.