Cancer: a new molecule to combat metastases.

Despite significant advances in oncology, some cancers remain difficult to control. These include secondary cancers, also called metastases. They occur when cancer cells leave their original site to colonize other tissues. These metastatic cells are the primary cause of cancer-related death. Biological plasticity, immune evasion, and adaptability to foreign environments make them resistant to treatment.

In addition, refractory tumors are cancers that do not respond to or that become unresponsive to standard treatments such as chemotherapy, radiation therapy, or immunotherapy. This phenomenon affects various tumor types, including glioblastoma, pancreatic cancer, breast cancer, certain sarcomas, and advanced forms of melanoma or liver cancer. Resistance may be present from the outset—primary resistance—or may develop after several lines of treatment—acquired resistance.

A common feature of these specific cancer types is their ability to evade apoptosis, a programmed cell death process, and to bypass senescence-induced growth arrest. These refractory and metastatic cells alter their metabolism. They rely more on glucose (Warburg effect) and exhibit increased iron dependence, an element essential for their proliferation. This dependence has led to a therapeutic approach based on ferroptosis, described by researchers at the Institut Curie.

Ferroptosis is an iron-dependent form of programmed cell death characterized by oxidation of plasma membrane lipids.

Today a significant share of cancers remains resistant to conventional treatments. Chemotherapy, radiotherapy, and targeted therapies often reduce primary tumors but fail to eliminate persistent tumor cells. These residual cells drive relapse and the development of metastases, which are now the leading cause of cancer-related mortality. Research by Raphaël Rodriguez’s team at Institut Curie, in collaboration with CNRS and Inserm, has identified a common trait of the most aggressive cancer cells: a heightened dependence on iron, representing a potential vulnerability. Iron catalyzes free radical production, damaging cell membranes and triggering a specific form of cell death known as ferroptosis. The team discovered this reaction begins in lysosomes, the intracellular organelles responsible for degrading cellular components.

To exploit this vulnerability, scientists designed a new class of small molecules called "phospholipid degraders". These compounds are structured to target the plasma membrane of cancer cells, accumulate in lysosomes via endocytosis, the mechanism that transports molecules into the cell, and activate the iron in these compartments. This activation triggers a cascade of oxidative reactions that damage cellular membranes, causing ferroptosis. Iron reacts with hydrogen peroxide to produce oxygen free radicals. These radicals attack membrane phospholipids, leading to cell death if the cell cannot restore its membrane integrity.

Among phospholipid degraders, fentomycin (Fento-1) was developed with a fluorescent property, allowing researchers to track its localization in cells by fluorescence microscopy. Fluorescence is a technique used in biology to verify that molecules reach their target. Experiments were performed on human metastatic breast cancer cell lines. After incubation with Fento-1, cells were fixed and stained with a lysosome-specific dye, LysoTracker, to allow signal colocalization. The resulting images showed a near-complete overlap between the Fento-1 signal and that of lysosomes, confirming preferential accumulation of the molecule in these organelles.

The first tests with the molecule Fento-1 were conducted both in vitro on human cells and in vivo in mouse cancer models. In vitro, Fento-1 showed selective cytotoxic activity against human tumor cells, particularly in pancreatic cancer and sarcoma biopsies from patients. Tumor cells were exposed to Fento-1 at concentrations ranging from 1 μM to 20 μM for 24 hours with a negative control. After 16 hours of incubation, cell viability fell to 20%; after 24 hours it was near 0%. The experiment was also performed on healthy cells, which were not affected by Fento-1. The team observed selective, progressive lysosomal destruction leading to tumor cell death. These effects are linked to intense lipid peroxidation and intracellular iron accumulation and are consistent with a lysosomal ferroptosis mechanism.

In a murine model of metastatic breast cancer, intralymphatic administration of 0.003 mg of Fento-1 every other day slowed tumor growth. After ten days, tumor volume was approximately 0.2 cm3 in treated mice compared with 0.7 cm3 in controls, a 70% reduction. However, mice were euthanized at study end, which limits long-term conclusions about potential tumor recurrence.

The authors note that these results, while promising, remain limited to the preclinical stage. No human toxicity or pharmacokinetic data are available, and clinical trials will be needed to assess actual efficacy and tolerability of these phospholipid degraders.

While Raphael Rodriguez’s team focused on breast, pancreatic cancers, and sarcomas, the biological mechanisms they targeted—iron dependency and sensitivity to ferroptosis—could also apply to certain skin cancers. In oncological dermatology, metastatic malignant melanoma remains one of the most severe cancers. Despite advances in immunotherapy and targeted therapies, some patients develop refractory forms that evade standard cell death pathways. These cancer cells could, like those described in the study, exhibit increased iron dependency and be vulnerable to ferroptosis.

The skin can serve as a site for cutaneous metastases, in breast, lung, colon, or pancreatic cancer. These cutaneous metastases are difficult to eliminate and share biological profiles with the primary tumor cells. Phospholipid degraders such as Fento-1 could target these secondary lesions and offer a treatment option for patients with refractory skin cancers, pending clinical validation.