Scientists at King’s College London have described a new, orally available drug candidate that in laboratory models appears to make tumours more responsive to chemotherapy by disarming an immune‑based defence mechanism. The molecule, described as KCL‑HO‑1i, was reported to improve responses in mouse models of breast cancer when given as a tablet between chemotherapy cycles, and the researchers say the compound converts immunologically “cold” tumours into “hot” ones that attract CD8+ T‑cells. According to the original report, the work was supported by Cancer Research UK and the Medical Research Council.

The science rests on a protein, haem oxygenase‑1 (HO‑1), produced by certain tumour‑associated macrophages that sit close to blood vessels. HO‑1 has antioxidant and anti‑apoptotic functions that can protect malignant cells and blunt the immune activation chemotherapy would otherwise trigger. Review literature on HO‑1 describes multiple mechanisms by which its expression in tumour and stromal cells can suppress anti‑tumour immunity and promote resistance to therapy, a rationale the KCL team used to target the pathway.

In the preclinical studies the investigators either genetically inactivated HO‑1 or inhibited it pharmacologically and reported increased infiltration of cytotoxic CD8+ T‑cells into tumours, and improved efficacy of several standard chemotherapies. Abstracts and data accompanying the work report oral bioavailability in mice with a roughly three‑hour serum half‑life and describe durable tumour control in established murine models when KCL‑HO‑1i was combined with chemotherapy. The submitted transcriptomic dataset for the programme is publicly available, which the authors say supports reproducibility of the immune changes they observed.

The laboratory programme has moved beyond the university: Aethox Therapeutics, described as a King’s College spin‑out, identifies KCL‑HO‑1i as its lead preclinical candidate and states it is preparing a first‑in‑human Phase I study (programme ATX101) in solid tumours. The company says the goal is to develop an oral companion medicine that can be given between chemotherapy sessions to reprogram the tumour microenvironment; those corporate descriptions should be read as the company’s claims pending independent clinical data.

Investigators and funders expressed guarded optimism about the clinical potential. Tanya Hollands of Cancer Research UK said the findings illustrate how combining established treatments with new agents can make better use of existing medicines and potentially boost chemotherapy’s effectiveness. The university team similarly suggested the approach could help more patients benefit from available therapies while reducing the need for more aggressive interventions. These comments were made in the original reporting and university statements accompanying the research.

Those statements come with important caveats. Experts who have reviewed the field stress that HO‑1 is a multifunctional enzyme whose inhibition may carry safety and delivery challenges, and that many promising preclinical immunomodulators fail or require dose refinement in human trials. Earlier work from the same group used a repurposed metalloporphyrin HO‑1 inhibitor as a proof of principle and underlined the need for careful phase‑I safety studies before effectiveness in people can be established.

The KCL team has suggested human trials could begin within a relatively short timeframe, but translating a mouse‑model result into a safe, effective human medicine typically involves additional pharmacology, toxicology and regulatory steps. The company and university are seeking collaboration and investment to accelerate clinical testing, while the public deposition of transcriptomic data provides a resource for independent validation of the mechanism.

If the approach proves safe and effective in people, an orally dosed HO‑1 inhibitor would be an attractive companion strategy because it could be prescribed between chemotherapy sessions without requiring hospital infusions. For now, however, the evidence is preclinical and the next crucial milestones are formal toxicity studies, regulatory approval to start first‑in‑human trials, and early clinical data that confirm both safety and the immunological effects seen in mice.

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Source: Noah Wire Services