Three new drugs tackle cancer's resistance problem — from lab bench to first human trials

Cancer's most dangerous trick is not growing — it's surviving. Tumours that shrug off chemotherapy, hide from immunotherapy, or mutate around targeted drugs kill far more patients than cancers caught early and treated successfully. Now three separate research teams, working on different continents and through entirely different biological routes, have published or presented results on experimental drugs each designed to break that resistance — and one has already shown tumour shrinkage in a human trial.

The furthest along is GRWD5769, a tablet developed by Oxford-based Greywolf Therapeutics. In a phase 1 trial spanning the UK, France, Spain and Australia, 83 patients with cervical, bladder, liver, bowel, lung or head and neck cancers — all of whom had already failed previous treatment, most with no options remaining — were given GRWD5769 alongside the immunotherapy drug cemiplimab. Tumours shrank in 26 of those patients; 15 saw reductions of at least 30%, according to results presented at the American Society of Clinical Oncology's annual meeting in Chicago.

The drug works by blocking an enzyme called ERAP1, which cancer cells manipulate to hide from the immune system's T-cells. By inhibiting ERAP1, GRWD5769 effectively removes what researchers describe as an 'invisibility cloak' from tumour cells, making them visible to T-cells that could not previously find them — and allowing cemiplimab to do its job.

Immunotherapy has been a gamechanger in the way we treat cancer, but the number of people that can benefit is still relatively low. What excites me about this trial is the combination of what we're seeing – strong signals of efficacy across six tumour types that have shown great resistance to immunotherapy, with very few side-effects. That's unusual at such an early stage, when we're usually just looking at how safe it is.— Prof Fiona Thistlethwaite, consultant medical oncologist and medical director, Christie clinical research facility

The drug halted disease progression for at least six months in 18% of cervical cancer patients, 32% of liver cancer patients, 36% of bladder cancer patients, 38% of head and neck cancer patients, 51% of bowel cancer patients and 55% of lung cancer patients, according to The Guardian. The trial is ongoing, with a larger study planned.

It is unusual to see such outcomes in patients whose cancers have already stopped responding to treatment, particularly across several hard‑to‑treat cancer types, so these results are encouraging. However, this is still an early‑stage study, and larger trials will be needed to determine whether this approach can deliver lasting benefits for patients.— Dr Samuel Godfrey, research information lead, Cancer Research UK

The second drug, KCL-HO-1i, targets a different layer of cancer's defences: not the tumour cell itself, but the immune cells that protect it. Researchers at King's College London, funded by Cancer Research UK and the Medical Research Council, spent nearly 13 years tracing why macrophages — white blood cells normally tasked with fighting infection — end up acting as bodyguards for tumours instead.

We discovered that macrophages guard the tumour and can block effects of chemotherapy. They're acting as gatekeepers stopping cancer-fighting immune cells from coming in and supporting the treatment, but, by targeting the right pathway, we can open the door.— Professor James Arnold, head of the Tumour Immunology Group, King's College London

The KCL team found that tumour-associated macrophages produce unusually high levels of an enzyme called heme oxygenase-1 (HO-1), which shields tumours from T-cells and blunts chemotherapy's effectiveness. Their drug, KCL-HO-1i, blocks HO-1 and is designed to be taken as a daily pill at home between chemotherapy sessions — a deliberate design choice to avoid adding hospital visits for patients already undergoing treatment. In mouse models of breast cancer, the drug made chemotherapy-resistant tumours responsive to a range of commonly used chemotherapy drugs, according to KCL.

The mechanism exploits an evolutionary mismatch: macrophages evolved to distinguish between wounds that need healing and infections that need fighting, but cancer — our own cells dividing uncontrollably — falls into neither category. A fast-growing tumour can look to a macrophage like a wound trying to heal, prompting it to wall off the area from T-cells that might otherwise attack the cancer.

The immune system is basically not understanding the site it's in, and it ends up doing something catastrophically inappropriate. Our therapeutic basically rewires that microenvironment to now allow these T cells in. It's taking away the tumour's defences.— Professor James Arnold, head of the Tumour Immunology Group, King's College London

The KCL team has launched a spinout company, Aethox Therapeutics, to take KCL-HO-1i into clinical trials. The researchers say that with funding, human trials in breast and other cancers could begin within two years, according to KCL.

The third drug, CS18, is the earliest in development but takes perhaps the most ambitious approach. Researchers at Baylor College of Medicine set out to disrupt not one cancer pathway but a central control point that governs several at once. Their target is a protein called TopBP1, which they describe as a 'biological switchboard' regulating multiple processes involved in cancer growth and survival. The study was published in Science Advances.

Therapeutic resistance is a main obstacle to achieve effective and durable cancer treatments. While some therapies are effective at the beginning, many patients eventually relapse because cancer cells can activate compensatory and convergent biological pathways that allow them to overcome the toxic effects of therapy, promoting survival.— Dr Weei-Chin Lin, professor of medicine and molecular and cellular biology, Baylor College of Medicine

After screening thousands of chemical compounds using computer modelling and laboratory experiments, the Baylor team identified a candidate compound and refined it into CS18. When CS18 binds to a specific region of TopBP1 called BRCT7/8, it simultaneously reduces the cancer-promoting activities of proteins MYC and mutant p53, makes DNA repair proteins less active, and increases the activity of genes that suppress uncontrolled growth — in effect dismantling several of the defences cancer cells use to survive therapy at once, according to ScienceDaily.

The effects were observed across triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukemia cells. CS18 was also less toxic to non-cancerous cells than to cancer cells. When combined with existing drugs — including PARP inhibitors and osimertinib, a lung cancer treatment — CS18 outperformed either drug used alone. In lung cancer cells already resistant to osimertinib, adding CS18 restored their sensitivity to the drug. Animal models showed significant tumour growth reduction with no major weight loss or other signs of toxicity, according to ScienceDaily.

In the case of lung cancer cells that were already resistant to osimertinib, adding CS18 restored the cells' sensitivity to osimertinib, increasing cancer cell death. We observed a significant reduction of tumor growth in animal models with no major weight loss or other signs of toxicity.— Dr Weei-Chin Lin, professor of medicine and molecular and cellular biology, Baylor College of Medicine

All three drugs are designed as combination treatments — to be used alongside existing therapies rather than to replace them. That approach matters practically: if one component of a combination has already been tested and approved, the path to the clinic for the new drug can be faster and less costly. None of the three is yet approved for use in patients. CS18 and KCL-HO-1i remain in preclinical stages; GRWD5769 is in a phase 1 trial, the first stage of human testing, which primarily assesses safety.

Why it matters — Treatment resistance — not initial diagnosis — is the reason most cancer patients die from the disease, and these three drugs each attack that problem through a different mechanism, raising the prospect that combinations of such approaches could eventually keep resistant cancers in check.

Reported by sciencedaily.com, news.cancerresearchuk.org, kcl.ac.uk, openaccessgovernment.org, nytimes.com, theguardian.com