Cancer: a new molecule to combat metastases.

Despite significant advances in oncology, some cancers remain difficult to control. These include secondary cancers, also known as metastases. They occur when cancer cells leave their site of origin to colonise other tissues. Today, metastatic cells are the principal cause of cancer-related death. Their biological plasticity, ability to evade the immune system, and adaptability to foreign environments make them resistant to treatment.

Added to this category are refractory tumours: cancers that do not respond or no longer respond to standard treatments such as chemotherapy, radiotherapy or immunotherapy. This phenomenon affects various tumour types, including glioblastomas, pancreatic cancer, breast cancer, certain sarcomas, or advanced forms of melanoma or liver cancer. Resistance can be present from the outset–known as primary resistance–or emerge after several lines of treatment, known as acquired resistance.

A common feature of these specific cancer forms is their ability to evade apoptosis, a cell death programme, and to bypass growth arrest induced by senescence. These therapy-resistant and metastatic cells alter their metabolism. They increase glucose uptake (the Warburg effect) and show increased iron dependence, an element essential to their proliferation. This dependence now opens the way to an innovative therapeutic approach, ferroptosis, which underpins a recent discovery by researchers at the Institut Curie.

Ferroptosis is a form of programmed cell death that depends on iron and is characterised by oxidation of plasma membrane lipids.

Today, a significant proportion of cancers remains resistant to standard treatments. Chemotherapies, radiotherapies, and targeted therapies can reduce primary tumours but fail to eliminate residual tumour cells. These cells drive recurrence and metastases, the leading cause of cancer mortality. Research by Raphaël Rodriguez’s team at the Institut Curie in partnership with CNRS and Inserm has revealed an increased dependence on iron. This represents a potential vulnerability. Iron catalyses the production of free radicals that can damage cell membranes, leading to a specific type of cell death called ferroptosis. The team discovered this reaction begins in lysosomes, intracellular organelles responsible for degrading cellular components.

To exploit this vulnerability, scientists have 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 process by which molecules are transported into the cell, and activate iron within these compartments. This activation triggers a cascade of oxidative reactions that damage cellular membranes, inducing ferroptosis. Iron reacts with hydrogen peroxide to generate oxygen radicals. These radicals attack membrane phospholipids, leading to cell death if the membrane integrity cannot be restored.

Among phospholipid degraders, fentomycin (Fento-1) was developed with a fluorescent property, enabling researchers to track its cellular localisation by fluorescence microscopy. Fluorescence is a technique used in cell biology to confirm that molecules reach their target. Experiments used human cell lines of metastatic breast cancer. After incubation with Fento-1, cells were fixed and labelled with a lysosome-specific dye, LysoTracker, to allow signal colocalisation. Images showed a near-complete overlap between the Fento-1 signal and the lysosomes, confirming the molecule’s preferential accumulation in these organelles.

The initial tests with the compound Fento-1 were conducted both in vitro on human cells and in vivo in mouse models of cancer. In vitro, Fento-1 showed a selective cytotoxic activity on human tumour cells, on patient-derived pancreatic cancer and sarcoma biopsies. Tumour cells were exposed to Fento-1 at concentrations of 1 µM to 20 µM for 24 hours, with a negative control lacking Fento-1. After 16 hours of incubation, cell viability was 20%. At 24 hours it was close to 0%. The test included healthy cells that were not affected by Fento-1. The team observed selective lysosomal disruption leading to tumour cell death. These effects result from intense lipid peroxidation and intracellular iron accumulation. They 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 reduced tumour growth rate. After ten days, tumour volume was approximately 0.2 cm3 in treated mice versus 0.7 cm3 in control mice, a 70% reduction. However, euthanasia took place early, limiting long-term observations, including potential tumour recurrence.

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

Although the work from Raphaël Rodriguez’s team focused on breast cancer, pancreatic cancer, and sarcomas, the targeted biological mechanisms—iron dependence and sensitivity to ferroptosis—could also apply to certain skin cancer types. In dermatological oncology, metastatic malignant melanoma remains among the most severe cancers. Despite advances in immunotherapy and targeted therapies, some patients develop refractory forms that evade conventional cell death pathways. These cancer cells may, as in the study, exhibit increased iron dependence and vulnerability to ferroptosis.

Moreover, the skin can serve as a site of cutaneous metastases, in breast, lung, colon or pancreatic cancer. These cutaneous metastases, difficult to eradicate, may share biological profiles with primary cells. Phospholipid degraders such as Fento-1 may target these secondary lesions and offer an option for patients with refractory skin cancer, pending clinical validation.