Integrated computational modeling and biology experiments suggest a ready-made Rx

Researchers at the Houston Methodist Research Institute and The University of Texas MD Anderson Cancer Center have found new potential for treating high-grade serous ovarian cancer, the most common and difficult form of the disease. Their study in The Journal of the National Cancer Institute in May 2018 pinpointed a molecular pathway between malignant cells and supportive cells that are associated with poor prognoses for patients with the disease. A multi-cellular crosstalk modeling tool called Cell-Cell Communication Explorer (CCCExplorer), pioneered by Stephen Wong, PhD, Houston Methodist's chair of Systems Medicine and Bioengineering and the study’s co-senior author, helped map the complex ecosystem of interactions among tumor cells and between various supporting cells.

To map this pathway, the team knew they had to look beyond cancer cells as the only target for treating cancer, so they focused on fibroblasts, which provide connective tissue as a scaffolding for organs. Using laser microdissection, the team at MD Anderson precisely carved out fibroblasts from tumor samples—and found two distinct gene expressions: CAF-C and CAF-N. A survival analysis in 46 ovarian cancer patients showed a poor prognosis for those with CAF-C fibroblasts, with median overall survival of 16 months compared to 33 months for those with CAF-N fibroblasts.

To reveal what makes the CAF-C group promote aggressive disease, CCCExplorer was used to identify a signaling pathway, called Smad. More experiments by the MD Anderson team confirmed that patients with high expression of Smad-regulated genes had median overall survival of 15 months compared to 26 months for those with low expression.

Next, the CCCExplorer tool was used to search known drugs that could target Smad signaling. It found a prescription drug, Calcitriol, which stops communication between cancer cells and fibroblasts by inhibiting the binding of Smad proteins to their target genes. This was confirmed when Calcitriol showed reduced cancer cell proliferation and tumor volume in mice, with overall survival increasing from 36 to 48 weeks.

Already approved by the Food and Drug Administration for treating calcium deficiency and kidney diseases, Calcitriol is on the fast track for testing in human clinical trials, and may be a major milestone on the path to treating ovarian cancer.

“We identified a signaling pathway, called Smad, as the culprit of poor ovarian cancer outcomes. Reprogramming these cells by targeting their communication networks presents an opportunity for the development of new cancer treatment strategies. Targeting these supportive cells in the tumor microenvironment instead of the tumor itself could lead to less toxic, more effective treatments.”  – Stephen T. Wong, PhD, John S. Dunn, Sr. Presidential Distinguished Chair in Biomedical Engineering Professor of Systems Medicine and Bioengineering Houston Methodist.

Yeung T-L, Sheng J, Leung CS, Li F, Samuel JK, Ho Y, Matzuk MM, Lu KH, Wong STC, Mok SC. Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer. JNCI: Journal of the National Cancer Institute, May 31, 2018; djy097.

The study was funded by grants from the National Cancer Institute of the National Institutes of Health (R01CA133057, R01CA142832, RC4CA156551, U01188388, U54CA151668, U54CA149196, and UH2 TR000943) MD Anderson’s Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50CA083639), MD Anderson’s Uterine SPORE grant (P50CA098258) and by MD Anderson’s Cancer Center Support Grant (P30CA016672 ) from the National Institutes of Health; by the U.S. Department of Health and Human Services; the Ovarian Cancer Research Program, U.S. Department of Defense; the Gilder Foundation; the Cancer Prevention and Research Institute of Texas (CPRIT) and a CPRIT Core Facility Support Award: funding from Mr. Carl L. Norton, the Anna and John J. Sie Foundation, The Mary K. Chapman Foundation, the Ovarian Cancer Research Fund, the Ting Tsung and Wei Fong Chao Center for Bioinformatics Research and Imaging for Neurosciences (BRAIN), Cancer Fighters of Houston, Inc., and the John S. Dunn Foundation.