Ovarian cancer: Potential therapeutic target identified

Date:
August 5, 2021
Source:
University of Alabama at Birmingham
Summary:
A gene called DOT1L appears to play a role in progression and
severity of ovarian cancer, and inhibitors of the DOT1L enzyme
may offer a new therapeutic approach for the disease, researchers
say in a new study. The need is clear -- despite decades of work
to develop new treatment modalities, the five-year survival of
patients with advanced ovarian cancer is between 10 and 30 percent.



FULL STORY ==========================================================================
A gene called DOT1L appears to play a role in progression and severity
of ovarian cancer, and inhibitors of the DOT1L enzyme may offer a new therapeutic approach for the disease, University of Alabama at Birmingham researchers say in a study published in the journal Oncogenesis.


==========================================================================
The need is clear -- despite decades of work to develop new treatment modalities, the five-year survival of patients with advanced ovarian
cancer is between 10 and 30 percent.

Others have found that DOT1L is overexpressed in several cancer types,
and recent clinical work has shown synergistic antiproliferative activity
for a DOT1L inhibitor against MLL-rearranged leukemia.

The UAB researchers, led by Romi Gupta, Ph.D., assistant professor
of biochemistry and molecular genetics, now show that DOT1L promotes
ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic
pathways and blocking the programmed cell death called apoptosis.

Gupta and colleagues first looked at data sets from patients. They found
that DOT1L expression was significantly higher in tissues from ovarian
cancer patients compared with tissues from healthy patients. Furthermore, patients with ovarian tumors that had high DOT1L expression showed
shorter progression- free survival and shorter overall survival rates
compared with patients whose ovarian tumors had lower DOT1L expression.

DOT1L is a histone methyltransferase that epigenetically methylates
the histone H3 lysine 79 in chromatin, and this alters gene expression
in cells. The UAB researchers found that EPZ-5676 -- a DOT1L inhibitor
that has been used in several clinical trials to treat MLL-rearranged
leukemia -- was able to block the growth of ovarian cancer cells in
culture. EPZ-5676 also significantly blocked subcutaneous ovarian cancer
tumor growth in a mouse xenograft model.

Mechanistically, DOT1L inhibition downregulated the expression of various
genes that are required for biosynthetic pathways and reduced the levels
of essential biosynthetic metabolites in the ovarian cancer cells. DOT1L inhibition also upregulated genes involved in programmed cell death, which increased apoptotic cell death for ovarian cancer cells in culture. The pharmacologic inhibition of DOT1L also upregulated expression of ligands
for natural killer cells in some of the ovarian cancer cell lines tested.

These gene expression changes seen in DOT1L inhibitor-treated cells thus suggest that DOT1L overexpression in ovarian cancer leads to plentiful
supplies of the metabolites needed for rapid tumor growth and also
protects against tumor cell death caused by apoptosis or natural killer
cell attack.

"Our results suggest that DOT1L might be a pharmacologically tractable
drug target for ovarian cancer therapy," Gupta said. "It will also be
useful in combination with other immunotherapeutic agents to further
enhance their effectiveness in treating ovarian cancer." Co-authors with
Gupta for the study, "Disruptor of telomeric silencing 1-like promotes
ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic
pathways and blocking apoptosis," are Suresh Chava, Suresh Bugide
and Yvonne J.K. Edwards, UAB Department of Biochemistry and Molecular
Genetics.

Support came from National Institutes of Health grants CA230815-02
and CA248913-01.

========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Suresh Chava, Suresh Bugide, Yvonne J. K. Edwards, Romi
Gupta. Disruptor
of telomeric silencing 1-like promotes ovarian cancer tumor growth
by stimulating pro-tumorigenic metabolic pathways and blocking
apoptosis.

Oncogenesis, 2021; 10 (7) DOI: 10.1038/s41389-021-00339-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210805154731.htm

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