Drug candidate blocks lung cancer growth without harming healthy cells

A novel small molecule inhibitor – AVJ16 – has blocked the cancer-driving RNA-binding protein IGF2BP1 in preclinical lung cancer models, curbing tumour growth while sparing healthy tissue, in research that may open a route to precision therapies against previously ‘undruggable’ targets

Lung cancer has remained one of the deadliest forms of cancer worldwide, with survival rates stubbornly low despite significant advances in surgery, chemotherapy and immunotherapy. A recent preclinical study has now identified a novel small molecule that may shift how clinicians approach treatment for a subset of aggressive tumours.

In research led by doctoral candidate, Nadav Wallis, in the laboratory of Professor Joel K Yisraeli at the Hebrew University Hadassah Medical School, Jerusalem, Israel, investigators have reported a compound, AVJ16, that interfered with the growth of lung tumours in experimental models.

The work shows how AVJ16 selectively blocked a cancer-driving protein known as insulin-like growth factor 2 messenger ribonucleic acid binding protein 1 (IGF2BP1). This protein appears in many aggressive tumour types yet was essentially absent from healthy adult tissue.

IGF2BP1 functions as what the authors described as a cellular ‘master switch’ inside cancer cells. It binds and stabilises specific messenger ribonucleic acids that encode proteins which promote tumour growth, invasion of surrounding tissue and resistance to existing therapies. By inhibiting IGF2BP1, AVJ16 interrupted several of these processes at once and in effect cut support for multiple cancer-promoting pathways in parallel.

Cell culture experiments showed AVJ16 to reduce the proliferation of lung cancer cells, curtailed their capacity to invade neighbouring tissue and induced programmed cell death. Notably, these effects occurred without detectable damage to non-cancerous lung cells in the same assays. The authors have argued that this selectivity arose from the near absence of IGF2BP1 in normal adult tissue, which created a therapeutic window that traditional cytotoxic chemotherapy often lacks.

The team then tested whether AVJ16 could act beyond simple cell lines. In preclinical models implanted with human lung adenocarcinoma cells, repeated injections of AVJ16 almost completely prevented tumour outgrowth and the formation of metastases in distant organs. Tumours in untreated or control animals progressed as expected, whereas AVJ16-treated animals showed minimal or undetectable tumour burden during the study period.

To move closer to the clinic, the researchers have evaluated the compound in patient-derived tumour organoids. These are miniature three-dimensional cultures grown from individual patients’ lung tumours that preserve much of the complexity and genetic diversity of the original cancer.

In this setting, AVJ16 selectively killed organoids that expressed IGF2BP1 while it left organoids derived from healthy lung tissue largely unaffected. The authors suggested that this pattern supports the concept of a targeted therapy that would apply to patients whose tumours express IGF2BP1, and not to those whose tumours lack the protein.

“What excites us about AVJ16 is its precision.

“Unlike traditional chemotherapy that harms both cancerous and healthy cells, this molecule appears to home in on tumours that express IGF2BP1. That makes it a highly promising candidate for future targeted therapies, especially if we can match the drug to patients with the right tumour profile,” said Prof Yisraeli.

The study has also drawn attention because AVJ16 acts on a class of molecules that many researchers have long regarded as effectively ‘undruggable’. IGF2BP1 belongs to the family of RNA-binding proteins which interact with ribonucleic acid through large, often flat surfaces that small molecules have historically failed to disrupt with high specificity. AVJ16 therefore represents a proof of principle that such proteins can – at least in some circumstances – be modulated by well-designed small molecules.

Although the findings have been compelling at the laboratory and preclinical level, the authors cautioned that AVJ16 remains far from clinical use. The compound has not yet undergone formal safety testing in humans, and the doses and schedules that would prove tolerable in patients remain unknown.

Tumours may also evolve resistance through changes in IGF2BP1 itself or in the broader network of ribonucleic acid regulation. Further work will need to define how durable the effect is, whether combinations with other therapies enhance benefit, and which tumour types beyond lung adenocarcinoma show genuine dependency on IGF2BP1.

If future trials confirm safety and efficacy, AVJ16 could form the basis of a personalised strategy for the subset of patients whose lung cancers express IGF2BP1, and perhaps for other malignancies that use the same protein to support growth and spread. In that scenario, IGF2BP1 expression could serve as a biomarker to select patients, in line with the broader trend towards precision oncology.

For the present, the research has provided a cautious but credible source of optimism in the effort to improve outcomes for lung cancer, a disease that still causes more than a million deaths worldwide each year. By opening a route to target RNA-binding proteins that many had considered out of therapeutic reach, AVJ16 has added a further candidate to the growing armoury of rationally designed cancer agents and has underlined the continuing value of detailed molecular research on the vulnerabilities of tumour cells.

For further reading please visit: 10.1038/s41388-025-03449-2