2 Studies Probe Ways to Attack Ovarian Cancer

A subset of ovarian cancer patients could potentially benefit from an experimental therapy that targets a key amino acid, according to a study led by Sandra Orsulic, PhD, a research scientist at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and professor of Obstetrics and Gynecology.

The study, recently published in The Journal of Pathology: Clinical Research, found that two subtypes of ovarian epithelial cancer may be vulnerable to treatment with a novel therapeutic agent known as ADI-PEG 20.

The current standard of care for patients with ovarian epithelial cancer, in which malignant cells form in the tissue covering the ovary and fallopian tubes, does not discriminate among subtypes of the disease with different microscopic structures, or histologies, according to the study. Given that these subtypes do not respond uniformly to conventional chemotherapy, Orsulic and her colleagues at the Women's Cancer Program sought to explore the opportunity to develop individualized therapies.

The researchers found that two histological subtypes of ovarian epithelial cancer — endometrioid and mucinous — expressed low levels of the enzyme argininosuccinate synthetase, which they need to produce the amino acid arginine, essential for cell survival. When these cancer subtype cell lines were exposed to ADI-PEG 20 in vitro, they showed extreme sensitivity to it. ADI-PEG 20 works by systemically depleting the external supply of arginine in the blood, which causes arginine-dependent cancer cells to die while leaving the normal cells unharmed.

"This study has practical implications because it identifies a subset of patients with ovarian cancer as potential candidates for arginine depletion therapy with ADI-PEG 20," said Orsulic. "The current options for chemotherapy-resistant tumors are extremely limited, making this possibility highly relevant."

Orsulic's collaborators on the study included:

  • Beth Y. Karlan, MD, director of the Women's Cancer Program at the Cancer Institute and professor of Obstetrics and Gynecology
  • W. Ruprecht Wiedemeyer, PhD, research scientist in the Women's Cancer Program and assistant professor of Obstetrics and Gynecology
  • Christine S. Walsh, MD, assistant professor and research scientist in the department of Obstetrics and Gynecology
  • Jenny Lester, MPH, research manager at the Women's Cancer Program
  • Jessica Beach, graduate student the Orsulic laboratory
  • Ann E. Walts, MD, research pathologist
  • Dong-Joo (Ellen) Cheon, PhD, a postdoctoral fellow in the Women's Cancer Program
  • John S. Bomalaski, MD, from Polaris Group, a biopharmaceutical company that provided the drug ADI-PEG 20

A second study, led by Orsulic and recently published in the journal Cancer & Metabolism, found that succinate dehydrogenase, a metabolic enzyme, can function as a tumor suppressor in ovarian cancer. By analyzing the enzyme in ovarian cancer cell lines in mouse models, Orsulic and her colleagues found a metabolic weak point that potentially can be exploited for therapeutic purposes, they said.

"This study provides support for the emerging hypothesis that one of the defining features of cancer cells is their distinct metabolism. Though this is still a developing field, this study provides better understanding, which may potentially be adapted for anticancer strategies in the future," said Orsulic.

Orsulic's collaborators on this article included Karlan; Wiedemeyer; Beach; Maricel Gozo, PhD, a former graduate student in the Orsulic laboratory; and postdoctoral research fellow Paul-Joseph Aspuria, PhD. The study also included collaborators from Michigan State University, Massachusetts Institute of Technology, Chalmers University of Technology in Sweden and UCLA.

Staff of the Women's Cancer Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute: (front row, left to right) Steven Stokes; Christine Walsh, MD, MS; Tony Braswell, MBA, MHA; Bowen Gao, PhD; Jenny Lester, MPH; Director Beth Y. Karlan, MD; Yael Bogler, MD; Jeffrey Johnson, MD; Xiaojiang Cui, PhD; Marie Holzapfel, MD; Sandra Orsulic, PhD; W. Ruprecht Wiedemeyer, PhD; Meredith Axtell, and (back row, l. to r.) John Lee, MS, LCGC; BJ Rimel, MD; Jessica Beach; Phyllis Lopez; Ying Qu, PhD; Yi Yu, PhD; Hang Tran; Justyna Kanska, PhD; Nur Yucer, PhD; Xiao Yang; Paula Anastasia, RN, MN; Paul-Joseph Aspuria, PhD; and Bingchen Han, PhD.