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Wistar Science Highlights: Novel Targets for Cancer and Metastasis Therapy Show Potential in Preclinical Models 

Mitochondria, the organelles that supply energy to our cells, also control multiple cell death mechanisms. Their role in cancer is intricate and a field of intense research.

The lab of Dario C. Altieri, M.D., Wistar president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor, described the role of a protein called mitochondrial fission factor (MFF) in controlling survival of cancer cells, suggesting the protein could represent a promising therapeutic target.

In a study published online in the journal EBioMedicine, the team showed that, in cancer, MFF interacts with VDAC1, a mitochondrial regulator of cell death, shutting down its function to keep tumor cells alive. Disruption of the MFF-VDAC1 complex activated multiple mechanisms of mitochondrial cell death and reduced tumor growth in mouse models. 

Based on these findings, the lab designed a molecule that mimics MFF and binds to VDAC1, disrupting the MFF-VDAC1 interaction and inducing cell death as a consequence. This peptidomimetic inhibitor was tested in different preclinical settings and effectively delivered anticancer activity while being well tolerated in mice, with no overt signs of toxicity. This study was published in Cancer Research.

“We are hopeful that this compound will be translated into a novel anticancer therapy with potential to be effective in multiple cancer types and less prone to drug resistance,” said Altieri.  

Brain metastasis is an important contributor to overall cancer mortality in patients with advanced-stage disease, especially lung, breast, colon, and kidney carcinoma, and melanoma. Current therapeutic strategies have shown limited efficacy, underscoring the need to expand our knowledge of brain metastasis mechanisms to identify novel therapeutic targets.

The laboratory of Qing Chen, M.D., Ph.D., assistant professor in the Immunology, Microenvironment & Metastasis Program, focused on clinically relevant mouse models of melanoma brain metastasis and showed that cancer cells growth and metastasis development in the brain are favored by astrocytes, the most abundant supporting cells in the brain. 

According to the study, published in Cancer Discovery, polyunsaturated fatty acids released by astrocytes activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) signaling pathway in cancer cells, which in turn results in enhanced proliferation.

Importantly, treatment of mouse models of melanoma and breast cancer brain metastasis with a PPAR-gamma inhibitor decreased the metastatic burden and was well tolerated in mice.

“Previous studies have indicated a tumor-suppressive function for PPAR-gamma in primary tumors,” said Chen. “Our work suggests that this pathway may play an opposite role in metastatic cells, particularly in the lipid-rich brain environment, and highlights PPAR-gamma as a viable therapeutic target to control brain metastasis.”