Crucial new molecular mechanisms and biomarkers in ovarian cancer

Date:
July 30, 2021
Source:
UT Southwestern Medical Center
Summary:
Medical researchers have discovered what appears to be an Achilles'
heel in ovarian cancers, as well as new biomarkers that could
point to which patients are the best candidates for possible
new treatments.



FULL STORY ==========================================================================
UT Southwestern faculty have discovered what appears to be an Achilles'
heel in ovarian cancers, as well as new biomarkers that could point to
which patients are the best candidates for possible new treatments.


==========================================================================
The finding, published in the journal Cell, was made in part using a
research tool invented in a UT Southwestern lab in the Cecil H. and Ida
Green Center for Reproductive Biology Sciences.

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 are trying to find dependencies in cancers by asking
why a cancer cell amplifies a gene, increases the levels of a protein,
or upregulates a critical cellular pathway. These changes give that cancer
a selective advantage, but at the same time they can become an Achilles'
heel -- something that, if the alteration was blocked, would kill the
cancer or stop its growth," he said.

Dr. Kraus and his team, including lead author Sridevi Challa, Ph.D., a postdoctoral researcher in the lab, found that ovarian cancers massively amplify an enzyme, NMNAT-2, that makes NAD+. NAD+ is the substrate for
a family of enzymes called PARPs, which chemically modify proteins with ADP-ribose from NAD+. In this study, the team found that one PARP family member, PARP-16, uses NAD+ to modify ribosomes, the protein synthesizing machines of the cell.

A challenge for this work was that a single ADP-ribose group attached to
a protein is difficult to detect. Dr. Kraus and his team overcame this
problem by developing a synthetic mono(ADP-ribose) detection reagent
made up of natural protein domains fused together, which can be used to
detect ADP-ribosylated proteins in cells and patient samples.



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In collaboration with UT Southwestern clinicians, led by Jayanthi Lea,
M.D., Professor of Obstetrics and Gynecology and member of the Simmons
Cancer Center, Dr. Kraus and his team screened human ovarian cancer
patient samples using the mono(ADP-ribose) detection reagent to identify
those with low or high levels of mono(ADP-ribose).

"We were able to show that when ribosomes are mono(ADP-ribosyl)ated in
ovarian cancer cells, the modification changes the way they translate
mRNAs into proteins," Dr. Kraus said. "The ovarian cancers amplify
NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a selective advantage by
allowing them to fine-tune the levels of translation and prevent toxic
protein aggregation. But that selective advantage also becomes their
Achilles' heel. They're addicted to NMNAT-2, so inhibition or reduction of NMNAT-2 inhibits the growth of the cancer cells." This study identified mono(ADP-ribose) and NMNAT-2 as potential biomarkers for ovarian cancers,
which may allow clinicians to determine which ovarian cancer patients
may respond well and which will not. Even more ovarian cancer patients
might do well if an inhibitor is developed for PARP-16, which blocks
ribosome mono(ADP-ribosyl)ation.

Dr. Kraus, an expert in PARPs, said medical science has had great
success in developing FDA-approved PARP-1 inhibitors, and an inhibitor
for PARP-16 is likely.

"No PARP-16 inhibitors are currently in clinical trials, but labs
in academia and the pharmaceutical industry are developing specific
and potent inhibitors of PARP-16. Such a drug could be an effective
therapeutic for treating ovarian cancers," he said.



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Dr. Kraus is a founder and consultant for Ribon Therapeutics Inc., and
ARase Therapeutics Inc. He is also co-holder of U.S. patent 9,599,606
covering the mono(ADP-ribose) detection reagent, which has been licensed
to and is sold by EMD Millipore.

"Dr. Kraus' research is not just a great advance in basic science. It has
real promise for clinician investigators and cancer care practitioners
because it shows a biomarker and a pathway a future drug could target. The
fact that technology developed in his laboratory helped make these
findings shows how our faculty builds on their findings to break new
ground," said Carlos L. Arteaga, M.D., Director of the Simmons Cancer
Center.

Other researchers who contributed to this study include Beman
R. Khulpateea, Tulip Nandu, Cristel V. Camacho, Keun W. Ryu, Hao Chen,
and Yan Peng.

The research work 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 the Ovarian Cancer Research Alliance (GAA202103-0003)
to Challa.

Dr. Arteaga holds the 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 holds the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sridevi Challa, Beman R. Khulpateea, Tulip Nandu, Cristel
V. Camacho,
Keun W. Ryu, Hao Chen, Yan Peng, Jayanthi S. Lea, W. Lee
Kraus. Ribosome ADP-ribosylation inhibits translation and maintains
proteostasis in cancers. Cell, 2021; DOI: 10.1016/j.cell.2021.07.005 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210730121427.htm

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