2ⁿᵈ Edition of the Cancer R&D World Conference 2026
Speakers - CRDWC 2026
Roberto Fernandez Acosta
Roberto Fernandez Acosta
- Designation: University of Antwerp
- Country: Belgium
- Title: Reprogramming Ferroptosis Resistance Unlocks Radiotherapy, Flash Rt, And Plasma Therapies in Refractory Cancers
Abstract
High-risk neuroblastoma (NB) represents a paradigm of therapy-refractory pediatric cancer, where aberrant oncogenic signaling and epigenetically enforced resistance to regulated cell death drive treatment failure and relapse. Ferroptosis, an iron-catalyzed, lipid peroxidation- driven form of regulated cell death, has emerged as a compelling therapeutic strategy for refractory tumors that evade apoptosis and other canonical death pathways. Building on our prior identification of epigenetic modulators as ferroptosis sensitizers in NB, we now present a translational, pathway-informed strategy that reprograms ferroptosis resistance to unlock therapeutic vulnerability to radiotherapy, ultra-high dose rate FLASH radiotherapy (FLASH RT), and cold atmospheric plasma (CAP), with demonstrated activity across multiple solid tumor entities.
Using ferroptosis-resistant high-risk NB as the discovery platform, we performed a high- content screen of 1,210 epigenetic compounds and identified three lead sensitizers: S3 and its second-generation analog S3.1 (currently under clinical evaluation in hematologic malignancies), and S2, initially annotated as a Wnt signaling inhibitor. In parallel, T10, an FDA-approved HDAC inhibitor, was identified as a direct ferroptosis-triggering agent. Mechanistically, BRD4 was validated as the functional target of S3/S3.1, while CRISPR/Cas9 analyses excluded canonical Wnt signaling as the mediator of S2 activity. The molecular target of S2 is currently being defined using cellular thermal shift assays (CETSA) and supported by structure-activity relationship (SAR) studies toward patent development.
While S3, S3.1, and S2 alone induced cell-cycle arrest without overt cytotoxicity, combination treatment with FDA-approved ferroptosis triggers, including T10, elicited robust ferroptotic cell death and durable proliferation arrest not only in NB, but also in non- small cell lung cancer (NSCLC), breast, colorectal, pancreatic, melanoma, and head and neck cancer models. In parallel, these chemical combinations further acted as powerful sensitizers to conventional and ultra-high dose rate FLASH radiotherapy, as well as to CAP exposure, permitting substantial radiation dose de-escalation without loss of efficacy, and establishing a clear transition from an NB-centered discovery effort to a pan-cancer therapeutic framework.
Critically, first in vivo studies demonstrated that the S3.1 plus T10 combination induces strong tumor growth inhibition (TGI) in neuroblastoma xenografts while enabling significant dose reduction. A second in vivo study in neuroblastoma, combining epigenetic sensitization with radiotherapy, is currently ongoing and has already shown pronounced tumor regression, highlighting immediate translational relevance. Subsequent in vivo studies are planned to evaluate compound-radiotherapy combinations in non-small cell lung cancer (NSCLC) as a near-term market-entry strategy, while melanoma and head and neck cancer models are designated for CAP-based therapeutic development.
Together, this work establishes a first-in-class, epigenetically driven ferroptosis sensitization platform that integrates chromatin remodeling with biophysical vulnerabilities exploited by radiotherapy, FLASH RT, and plasma-based modalities. This strategy enables scalable, rational combination therapies for resistant cancers.
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