Nav: Home

Murine study finds potential boost for ovarian cancer drug Olaparib

January 25, 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 metabolic pathways 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 cancer cells 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 breast cancer cells injected into mice. Olaparib had no effect on tumors formed by breast cancer cells containing functional BRCA1 and BRCA2 genes. But by combining the drug with a PGAM1 inhibitor to impair both homologous recombination 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.
-end-
Qu et al., 2017. J. Cell Biol.http://jcb.rupress.org/cgi/doi/10.1083/jcb.201607008?PR

About The Journal of Cell Biology

The Journal of Cell Biology (JCB) features peer-reviewed research on all aspects of cellular structure and function. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JCB provides free online access to many article types from the date of publication and to all archival content. Established in 1955, JCB is published by The Rockefeller University Press. For more information, visit jcb.org.

Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

Follow JCB on Twitter at @JCellBiol and @RockUPress.

Rockefeller University Press

Related Cancer Cells Articles:

Scientists have identified the presence of cancer-suppressing cells in pancreatic cancer
Researchers have identified cells containing a protein called Meflin that has a role in restraining the progression of pancreatic cancer.
Changes in the metabolism of normal cells promotes the metastasis of ovarian cancer cells
A systematic examination of the tumor and the tissue surrounding it -- particularly normal cells in that tissue, called fibroblasts -- has revealed a new treatment target that could potentially prevent the rapid dissemination and poor prognosis associated with high-grade serous carcinoma (HGSC), a tumor type that primarily originates in the fallopian tubes or ovaries and spreads throughout the abdominal cavity.
The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.
White blood cells related to allergies may also be harnessed to destroy cancer cells
A new Tel Aviv University study finds that white blood cells which are responsible for chronic asthma and modern allergies may be used to eliminate malignant colon cancer cells.
Conversion of breast cancer cells into fat cells impedes the formation of metastases
An innovative combination therapy can force malignant breast cancer cells to turn into fat cells.
Breast cancer cells in mice tricked into turning into fat cells
As cancer cells respond to cues in their microenvironment, they can enter a highly plastic state in which they are susceptible to transdifferentiation into a different type of cell.
Brain cancer: Typical mutation in cancer cells stifles immune response
The exchange of a single amino acid building block in a metabolic enzyme can lead to cancer.
Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.
Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant
A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.
An index measures similarity between cancer cells and pluripotent stem cells
The new methodology measures tumor aggressiveness and the risk of relapse, helping doctors plan treatment, according to Brazilian scientists authors of a paper published in a special issue of the journal Cell.
More Cancer Cells News and Cancer Cells Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab