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Could starving ovarian cancer cells be the answer to blocking spread?
BY TIHA M. LONG, PHD
Ovarian cancer can be a devastating disease because it is often not detected until it has spread to other tissues. Understanding the biology of ovarian tumors that have spread, or metastasized, is critical to finding new therapeutic targets and discovering novel treatments to keep patients alive and improve their quality of life. Physicians and researchers from the UChicago Medicine Comprehensive Cancer Center are dedicated to unraveling the complex biology of ovarian cancer in order to improve the treatment of metastatic disease.
Ernst Lengyel, MD, PhD, Arthur L. and Lee G. Herbst Professor of Obstetrics and Gynecology, is a preeminent oncologist specializing in the treatment of ovarian and other gynecological cancers, and a leading translational researcher working toward discovery of novel targets and treatments for ovarian cancer. Lengyel, along
Ernst Lengyel, MD, PhD, is a leading translational researcher working toward discovery of novel targets and treatments for ovarian cancer.
with Iris Romero, MD, professor of obstetrics and gynecology, lead teams of researchers in highimpact translational studies to improve therapy options for advanced ovarian cancer. Lengyel and Romero are evaluating an area ripe for therapeutic inquiry: cancer metabolism.
When normal cells transform into cancer, their metabolism is reprogrammed to allow these cells to take advantage of their environment and use all available sources of energy to support rapid growth. In recent years, the altered metabolism of cancer cells has emerged as a salient area of investigation toward developing novel mechanisms for attacking and starving these cells. The spread and progression of ovarian cancer is critically linked to metabolic reprogramming.
The main site of metastatic tumor growth for ovarian cancer is the omentum, the fatty tissue of the abdomen that forms a protective layer in front of the large and small intestines. Metastatic cancer cells break away from the primary tumor of the ovary and colonize the energy-rich tissue of the omentum, where new tumors can rapidly grow. The secret to blocking ovarian cancer progression may lie in controlling the altered metabolism of these cells to inhibit nutrient uptake and starve the cancer cells.
Exploring approaches designed to starve ovarian cancer
Comprehensive Cancer Center physician-scientists Lengyel and Romero have catapulted the field of cancer metabolism forward. Together, they discovered that ovarian cancer cells interact with other types of cells in the metastatic environment to alter the metabolism of cancer cells. That experimental discovery led to the realization that drugs already approved to modulate metabolism in people, in diseases like diabetes, might be able to regulate cancer cell metabolism to block cancer progression.
In 2019, they showed that metastasis can be interrupted by a diabetes drug called metformin,1 opening the door to investigations of disrupting metabolic interactions between metastatic cells and their nutrient-rich environments.
Along a similar line of research, Lengyel showed that ovarian cancer cells interact with fat cells, or
Iris Romero, MD, focuses her research on developing new agents for gynecologic cancer prevention and treatment.
adipocytes, in a symbiotic relationship that benefits the cancer cells.2 In this relationship, fat cells are programmed to release fatty acids and the cancer cells benefit by absorbing these energy-rich molecules, which they utilize for tumor growth. Lengyel determined that when ovarian cancer cells come into close contact with adipose tissue, they up-regulate a surface channel protein, called CD36, that allows for efficient absorption of fatty acids from the adipose tissue into the cancer cells. That study provided a clear picture of how ovarian cancer cells feed off of the high-fat tissue of the omentum and revealed a potential mechanism to interfere with nutrient uptake and growth of the metastasized cancer cells by blocking a route of fat absorption.
A new study by Lengyel and Romero, with staff scientist Abir Mukherjee, PhD, confirmed the upregulation and activity of CD36 and revealed the primary regulator of fatty acid distribution in metastasized ovarian cancer cells: fatty acid-binding protein-4 (FABP4), a regulator of metabolism linked to metabolic syndrome, glucose regulation and insulin resistance.3 They discovered that the up-regulation of FABP4 allows cancer cells to effectively utilize the fatty acids that are in the environment to rapidly multiply and grow. They next asked if blocking FABP4 could be an effective therapeutic strategy to starve metastatic ovarian cancer.
New research shows that FABP4, a regulator of cell metabolism, could potentially be blocked to starve metastatic ovarian cancer.
To evaluate the potential of FABP4 targeting to treat ovarian cancer, they performed extensive preclinical experiments. In laboratory models, they were able to slow down ovarian cancer growth using a small molecule inhibitor that attaches to FABP4 and prevents binding to fatty acids. The drug showed promising results in animal models, as the loss of FABP4 function led to decreased metastasis and lower cancer burden. The FABP4 inhibitor was also tested in animals in combination with the chemotherapy that is currently the standard of care for ovarian cancer. In this case, the addition of FABP4 inhibition reduced both the number and size of metastatic tumors more than using chemotherapy alone. Although the compound used in this study is not approved for use in people, additional FABP4 inhibitors that could potentially work in humans are currently under development.
The increase in fatty acid metabolism by ovarian cancer cells not only helps cells grow rapidly, but it may also improve the ability of cancer cells to migrate beyond the abdominal cavity to new metastatic sites. Lengyel and Romero found that within the metastatic ovarian tumor cells, there are higher levels of reactive oxygen species, or ROS, that can further damage the DNA, causing genetic instability which allows the cancer cells to diverge and possibly colonize additional sites in the body. The fatty acid metabolites produced by the cancer cells also contribute to inflammation, another factor that aggravates ovarian cancer progression.
The thorough investigations of Lengyel and Romero have provided direction for improved treatment of ovarian cancer. Therapies that block metabolic reprogramming of ovarian cancer cells may limit the ability of these cells to metastasize to the omentum and to other sites in the body. This clinically relevant work has great potential benefit for ovarian cancer patients in the future.
1 Hart et al., Cell Reports 29:4086-98, 2019 2 Ladanyi et al., Oncogene 37(17):2285-301, 2018 3 Mukherjee et al., Cancer Res 80(8):1748-61, 2020
