Latest research gives lipid-targeted cancer therapies a spotlight, and the results are promising

Cancer remains the second leading cause of mortality worldwide and is on track to become the number one cause of deaths globally by 2060.^[] Metastasis, the process responsible for over 90% of all cancer deaths, remains notoriously difficult to treat, primarily due to the metabolic rewiring of the cancerous cells. 

While lipids, glucose, pyruvate, lactate, and glutamine have all been shown to play roles in tumor growth, lipids stand out not just for their role as an energy source but for their impact on tumor signaling, membrane alterations, and immune evasion.

The finer points: Lipid metabolism

This research challenges the previously held assumption that lipids primarily act as fuel and opens up new avenues for therapeutic intervention.

The research team used a genetic screen in order to identify lipid metabolism-related genes essential for cancer survival. By implanting genetically altered cancer cells into immunocompromised mice, they discovered that cancer cells rely heavily on sphingolipids, specifically glycosphingolipids, for survival. Without these lipids, cancer cell proliferation was found to be significantly hindered. More importantly, sphingolipids were found to have a dual role: Not only do they drive tumor growth, but they also enable cancer cells to avoid immune system attacks.

Sphingolipids

Sphingolipids, especially those synthesized de novo, are critical for forming structural domains in the cell membrane—known as lipid nanodomains—that cluster signaling molecules. These nanodomains help regulate tumor cells’ immune evasion signals.^[]

The researchers identified two different sphingolipid thresholds: one promoting cancer cell proliferation and another facilitating their immune escape.

Therapeutic targeting of glycosphingolipids

To explore the therapeutic potential of disrupting glycosphingolipid metabolism, the researchers turned to eliglustat, a drug commonly used to treat Gaucher disease. Eliglustat inhibits glycosphingolipid synthesis, and in multiple cancer models—including pancreatic, lung, and colorectal—treatment with this drug led to significantly impaired tumor growth.^[]

The study demonstrated that cancer cells use glycosphingolipids to form "lipid nanodomains," which cluster signaling molecules at the cell surface. Disrupting these domains enhances the immune system’s ability to recognize and attack cancer cells. 

“Everyone thought of elevated lipid levels as an energy source for cancer cells to consume,” Dr. Soula explained. “We discovered that it’s far more nuanced."

According to a 2023 review in Metabolites, sphingolipids are also central to helping cancer cells evade programmed cell death (PCD).^[] In fact, several other small molecules that interfere with sphingolipid metabolism are also under investigation, including:

• Myriocin: Targets de novo ceramide synthesis and promotes apoptosis with enhanced activity in breast cancer cells.

• FB1: Inhibits C16 (dihydro)ceramide synthesis, triggering caspase activation in lung cancer cells. The drug has also shown promising responses in head and neck cancer cells.

• Fenretinide: Promotes cell cycle arrest and apoptosis by targeting ceramide synthesis in neuroblastoma cells.

• TVB-2640: A fatty acid synthase inhibitor, this drug is already in clinical trials for conditions like colon cancer and Her2+ breast cancer, and could be combined with immune checkpoint inhibitors for a more robust anti-tumor response.^[]

Dietary interventions

While diets rich in fats may fuel lipid-addicted cancers, dietary modifications could also potentially starve cancer cells of the lipids they depend on. According to Kivanç Birsoy, PhD, the corresponding author of the Nature study, “Diets may impact many aspects of cancer biology. We believe modulating dietary lipids may be an interesting avenue to target cancer cells’ ability to evade immune cells.”^[]

A review published in Cellular and Molecular Immunology outlines several dietary strategies:^[]

1. Caloric Restriction (CR): CR has been shown to lower lipid levels in plasma and tumor interstitial fluid, slowing tumor growth in models such as pancreatic ductal adenocarcinoma (PDAC). Lowering caloric intake, especially from fats, reduces lipid availability, thereby starving tumors of the glycosphingolipids they rely on for immune evasion.

2. Avoidance of the Ketogenic Diet (KD): Although low in carbohydrates, the KD is high in fats. For lipid-addicted cancers like PDAC, this high-fat content actually fuels tumor growth. Therefore, patients with cancers dependent on lipid metabolism should be advised to avoid KD.

3. Fatty Acid (FA) Withdrawal: Reducing dietary fatty acids helps restrict the lipid supply to tumors, potentially slowing the growth of melanomas and other lipid-dependent cancers. Limiting dietary fats is believed to enhance the immune system's ability to attack these cancer cells.

Nevertheless, while dietary interventions are a promising area of research, they need to be carefully personalized, as different cancers rely on different lipid metabolic pathways.