New 5-FU Derivative EB-18 Shows Potency Against Resistant Cancers

For more than six decades, 5-fluorouracil, better known as 5-FU, has been a cornerstone of cancer chemotherapy, quietly doing its work in operating rooms and oncology wards around the world. The drug, first synthesized in 1957, sabotages the ability of cancer cells to manufacture DNA, forcing rapidly dividing tumors into catastrophic replication errors. Yet for all its staying power, 5-FU has always carried a frustrating set of limitations: cancer cells frequently develop resistance, healthy tissue suffers collateral damage, and the drug’s effectiveness varies dramatically depending on where in the body a tumor resides. Now, a team of researchers based largely at Aix-Marseille University in France reports that they have re-engineered this venerable molecule into something far more formidable. In a study published in the Journal of Experimental & Clinical Cancer Research, the scientists describe EB-18, a phosphonium-substituted derivative of 5-FU that they say outperforms not only the parent compound but also several clinically deployed chemotherapies across a battery of preclinical models, including tumors that have already learned to shrug off standard treatment.

The chemistry behind the new agent is as intriguing as its biological performance. Rather than simply tweaking the fluorouracil scaffold, the team constructed a library of fourteen compounds in which the 5-FU core was conjugated to phosphonium groups, positively charged chemical motifs that are drawn to the negative electrical potential that exists across the inner membrane of mitochondria, the energy factories of cells. This design strategy, sometimes exploited in mitochondrial-targeting drugs, was intended to ferry the cytotoxic payload more effectively into the cellular compartments where pro-survival signaling is orchestrated. When the researchers screened their library against prostate cancer cells, one candidate separated decisively from the pack. EB-18 displayed sub-micromolar cytotoxicity against both PC-3 cells, which lack the androgen receptor, and C4-2 cells, a model of castration-resistant prostate cancer in which the androgen receptor remains active. That dual potency matters, because castration-resistant prostate cancer that no longer responds to androgen-deprivation therapy represents one of the most stubborn clinical challenges in urologic oncology.

Prostate cancer was only the beginning. The investigators extended their testing across a panel of malignant solid-tumor cell lines from other organs, and EB-18 retained its killing power, supporting the team’s description of the compound as a candidate for pan-cancer application. In laboratory assays designed to mimic key stages of tumor aggression, the molecule inhibited cell proliferation, impaired cell migration, and suppressed the growth of three-dimensional tumor spheroids, which are considered more faithful stand-ins for real tumors than flat layers of cells. When the researchers peered into the treated cells, they found the hallmarks of a coordinated self-destruction program: perturbation of the cell cycle, the tightly regulated sequence of events by which cells duplicate their DNA and divide, followed by apoptosis, the programmed cell death that cancer cells so often evade.

The mechanistic story that emerged from these studies is layered and, in several respects, unexpected for a 5-FU descendant. Classic 5-FU works largely by masquerading as a normal DNA and RNA building block, poisoning nucleotide synthesis. EB-18, by contrast, appears to attack cancer cells on multiple fronts simultaneously. The compound disrupted survival signaling associated with HSP27, a heat shock protein that tumor cells rely on to buffer stress and resist chemotherapy-induced death. HSP27 has long interested oncologists precisely because elevated levels of the protein correlate with poor treatment outcomes in several cancers; indeed, a corresponding author of the new study holds patents on an antisense inhibitor of HSP27 previously developed for clinical use. EB-18’s ability to interfere with this protective machinery at the small-molecule level rather than through genetic silencing represents a different route to the same therapeutic vulnerability.

The compound’s second major target proved equally consequential. EB-18 promoted the ubiquitination of DDX5, a DNA helicase protein involved in transcription and cell proliferation, tagging it for destruction by the proteasome, the cellular waste-disposal system that shreds proteins marked with ubiquitin chains. Loss of DDX5 crippled downstream AKT/mTOR signaling, a central growth pathway that tumors co-opt to sustain unrelenting proliferation. In parallel, the researchers observed that EB-18 increased levels of γ-H2AX, a molecular beacon that flags double-strand breaks in DNA, while reducing expression of Ku70 and Ku80, proteins that help repair precisely those breaks. In other words, the drug appears to inflict severe DNA damage while simultaneously dismantling the repair crews that would normally rescue the cell, a one-two combination that pushes malignant cells past the point of no return. In androgen receptor-positive C4-2 cells, EB-18 additionally drove down expression of the androgen receptor itself, striking at the engine of castration-resistant disease.

What elevates the study beyond conventional cell-culture pharmacology is the rigor of its disease models. The team tested EB-18 in patient-derived organoids, miniature tumors grown from tissue donated by people with prostate cancer, which preserve much of the cellular heterogeneity and drug responsiveness of the original malignancies. The compound retained its activity in these organoids and, critically, in multidrug-resistant castration-resistant prostate cancer cells, the kind of refractory disease that clinicians most dread encountering. Patient tissue for this work was obtained through the Biological Resource Centre of the Marseille Public Hospital System with written informed consent, under protocols certified to international biobanking standards, lending the findings a translational credibility that laboratory models alone cannot provide.

The final preclinical proof came from living animals. In mouse xenografts bearing PC-3 prostate tumors, treatment with EB-18 significantly inhibited tumor growth, confirming that the compound’s cellular effects translate into tangible anti-tumor activity in vivo. According to the authors, EB-18 demonstrated superior anticancer activity compared with 5-FU itself and with clinically used chemotherapies including docetaxel, cabazitaxel, and mitoxantrone across the preclinical models examined. That comparison is striking, because docetaxel and cabazitaxel are the current workhorses of chemotherapy for metastatic castration-resistant prostate cancer, and both eventually fail as resistance develops. A single small molecule capable of matching or exceeding the performance of these agents, while retaining efficacy in multidrug-resistant cells, would represent a meaningful expansion of the therapeutic arsenal.

The research was carried out by a multidisciplinary team spanning several French institutions, including CNRS and INSERM research units in Marseille and the Institut Pasteur in Paris, and was supported by INSERM, the Ligue Nationale Contre Le Cancer, ITMO Cancer, and the Amidex Foundation, with additional funding under the France 2030 investment plan. The work emerges from a laboratory with a long-standing interest in HSP27 biology and its exploitation in cancer therapy, and the authors note commercial interests, including co-founding of a biotechnology company focused on precision medicine and nucleic acid therapeutics, alongside patent filings related to HSP27 inhibition. Such entanglements are common in translational oncology and underscore how close the scientists consider this molecule to be to real-world relevance, though they also signal the need for independent validation.

Considerable distance remains between a promising preclinical candidate and an approved medicine. EB-18 has not yet been tested in humans, and the authors themselves frame their findings as a rationale for further pharmacological, mechanistic, and translational evaluation rather than as a treatment ready for the clinic. Toxicology, pharmacokinetics, dosing, formulation, and safety profiling all lie ahead, along with the unpredictable attrition that claims most experimental drugs. Nevertheless, the study offers a compelling proof of concept: that a sixty-year-old chemotherapy scaffold, creatively re-engineered with mitochondrial-targeting chemistry and aimed at resistance-driving pathways such as HSP27 signaling, DDX5 degradation, and the DNA damage response, can be reborn as a broader, harder-to-defeat weapon. If subsequent development sustains the momentum reported here, EB-18 could eventually give oncologists a genuinely new option against tumors that have exhausted every currently available line of defense.

Subject of Research: A novel phosphonium-substituted 5-fluorouracil derivative, EB-18, developed as a pan-cancer chemotherapy candidate that improves antitumor efficacy and overcomes therapy resistance.

Article Title: A novel 5-FU derivative chemotherapy: a promising pan-cancer treatment to improve antitumor efficacy and overcome therapy resistance

Article References: Duong, Q. H., Khusnutdinova, E., Le, T. K., Hu, Y., Tran, T. T., Nail, V., Balasse, L., Dinh, T. D., Phan, T. T. U., Borie-Guichot, M., Baboudjian, M., Garzino, F., Guillet, B., Taïeb, D., Camplo, M., & Rocchi, P. (2026). A novel 5-FU derivative chemotherapy: a promising pan-cancer treatment to improve antitumor efficacy and overcome therapy resistance. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03826-z

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03826-z

Keywords: 5-fluorouracil, EB-18, chemotherapy, castration-resistant prostate cancer, drug resistance, HSP27, DDX5, AKT/mTOR signaling, DNA damage response, apoptosis, patient-derived organoids, xenograft models