DALLAS – July 30, 2021 – The faculty at UT Southwestern has discovered what appears to be an Achilles’ heel in ovarian cancer, as well as new biomarkers that could indicate which patients are the best candidates for potential new treatments.
The finding, published in the journal Cell, was made in part with a research tool invented in a UT Southwestern laboratory at the Cecil H. and Ida Green Center for Reproductive Biology Sciences.
W. Lee Kraus, Ph.D.
The research was led by W. Lee Kraus, Ph.D., Professor of Obstetrics and Gynecology and Pharmacology and a member of the Harold C. Simmons Comprehensive Cancer Center.
“Many researchers try to find dependencies in cancer diseases by asking why a cancer cell amplifies a gene, increases the level of a protein or upregulates a critical cellular signaling pathway. These changes give this cancer a selective advantage, but at the same time can become an Achilles’ heel – something that, if the change were blocked, would kill the cancer or stop it from growing, ”he said.
Dr. Kraus and his team, including lead author Sridevi Challa, Ph.D., a postdoctoral fellow in the lab, found that ovarian cancer massively amplifies an enzyme, NMNAT-2, called NAD. manufactures+. NAD + is the substrate for a family of enzymes called PARPs that chemically modify proteins with ADP-ribose from NAD +. In this study, the team found that a member of the PARP family, PARP-16, used NAD + to modify ribosomes, the cell’s protein synthesis engines.
A challenge to this work was that a single ADP-ribose group bound to a protein is difficult to detect. Dr. Kraus and his team have solved this problem by developing a synthetic mono (ADP-ribose) detection reagent made from fused natural protein domains, which can be used to detect ADP-ribosylated proteins in cells and patient samples.
Working with clinicians at UT Southwestern, led by Jayanthi Lea, MD, Professor of Obstetrics and Gynecology and a member of the Simmons Cancer Center, examined Dr. Kraus and his team used human samples from ovarian cancer patients with the mono (ADP-ribose) detection reagent to identify those with low or high mono (ADP-ribose) levels.
“We were able to show that when ribosomes are mono (ADP-ribosyl) ation in ovarian cancer cells, the modification changes the way in which they translate mRNAs into proteins,” said Dr. Kraus. “The ovarian cancers amplify NMNAT-2 to increase the NAD + level available for PARP-16 to mono (ADP-ribosyl) ate ribosomes, which gives them a selective advantage by allowing them to fine-tune the degrees of translation and prevent the aggregation of toxic proteins. But that selective advantage also becomes their Achilles heel. You are addicted to NMNAT-2, so inhibiting or reducing NMNAT-2 inhibits the growth of cancer cells. “
This study identified mono (ADP-ribose) and NMNAT-2 as potential ovarian cancer biomarkers that could allow clinicians to determine which ovarian cancer patients are responding well and which are not. Even more ovarian cancer patients could be successful if an inhibitor for PARP-16 that blocks ribosome mono (ADP-ribosyl) ation is developed.
Dr. Kraus, an expert on PARPs, said medical science has had great success developing FDA-approved PARP-1 inhibitors and an inhibitor for PARP-16 is likely.
“There are currently no PARP-16 inhibitors in clinical trials, but laboratories in universities and the pharmaceutical industry are developing specific and effective inhibitors of PARP-16. Such a drug could be an effective therapeutic for treating ovarian cancer, ”he said.
Dr. Kraus is the founder and advisor to Ribon Therapeutics Inc. and ARase Therapeutics Inc. He is also co-owner of US Patent 9,599,606 for the mono (ADP-ribose) detection reagent, which is sold to EMD. has been licensed and is distributed by Millipore.
“DR. Kraus’ research is not just a huge advance in basic research. It really holds great promise for clinical researchers and cancer therapists as it shows a biomarker and a pathway that a future drug could target. The fact that those in his Laboratory developed technology that helped achieve these results shows how our faculty is building on their results to break new ground, ”said Carlos L. Arteaga, MD, director of the Simmons Cancer Center.
Other researchers who contributed to this study include: Bemann R. Khulpatea, Tulip Nandu, Cristel V. Camacho, Keun W. Ryu, Hao Chen and Yan Bang.
The research was supported by a grant from the National Institutes of Health / National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK069710) as well as funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to Kraus, and a postdoctoral fellowship from Ovarian Cancer Research Alliance (GAA202103-0003) for Challah.
Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. Kraus holds the Cecil H. and Ida Green Distinguished Chair in Reproductive Biology Sciences. Dr. Lea is the holder of the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology.
Via the UT Southwestern Medical Center
UT Southwestern, one of the leading academic medical centers in the country, combines groundbreaking biomedical research with exceptional clinical care and education. The institution’s faculty has won six Nobel Prizes and includes 25 members from the National Academy of Sciences, 16 members from the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty, with more than 2,800 employees, is responsible for breakthrough medical advances and is committed to quickly translating science-based research into new clinical treatments. UT Southwestern doctors care for more than 117,000 hospital patients, more than 360,000 emergency rooms in approximately 80 specialties, and oversee nearly 3 million outpatient visits annually.