The brain barrier

If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.

Fluid taken from the lower back contains DNA from brain tumours. Testing it can diagnose, monitor and detect resistance without brain surgery.

Pumping drugs slowly through fine tubes into a brain tumour can bypass the barrier, but the fluid often leaks away. Robotic placement and live scans would show where it actually goes.

Giving a targeted drug in pulses rather than continuously might slow the emergence of resistant cells and reduce side effects. Early results are mixed, so this needs careful trials with clear rules for when to try it.

Brain tumours release little DNA into blood because of the blood-brain barrier. Sonobiopsy briefly opens the barrier with focused ultrasound and microbubbles, raising circulating tumour DNA severalfold so a blood sample can replace repeat surgical biopsy for diagnosis and resistance monitoring in glioma and brain metastases.

Aggressive glioblastomas, sarcomas and gastric cancers keep amplified cancer genes such as EGFR, MYC, MDM2 and CDK4 on free-floating DNA circles (ecDNA) whose copy number rises and falls quickly, letting the tumour dial resistance up and down. Cells carrying ecDNA depend on CHK1, giving a first drug target.

The nerves at the top of the nose lead directly into the brain, bypassing the barrier. Nasal delivery of drugs, and even immune cells, has worked in animals.

The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves.

Resistance mutations often exist in a tiny fraction of cells before treatment starts. Error-corrected sequencing that detects variants below 0.01 percent allele fraction could find them at diagnosis and prompt a mechanism-matched combination from day one.

When a resistance mutation first appears in the blood, the current drug is often still controlling most of the tumour. Adding a second drug rather than swapping may keep both under control.

Pack-year rules miss people who get lung cancer without heavy smoking, including East Asian women who never smoked, as Taiwan's TALENT study showed. Eligibility by a validated risk model with a set threshold, plus a never-smoker arm where family history matters, would find more cancers per scan.

A small ultrasound device implanted in the skull can be switched on at each chemotherapy visit to briefly open the brain barrier, letting drugs in every cycle.

Most cancer drugs cannot cross into the brain. Combine ultrasound that briefly opens the barrier with drugs engineered to be carried across, and make this a standard platform for every brain tumour and brain metastasis.

Stomach cancer now has three add-on biomarkers (HER2, PD-L1, Claudin 18.2) that often overlap. Test whether combining two add-ons beats picking one.

Up to a fifth of people with advanced solid tumours have cancer in the brain and are usually barred from trials. Letting in those whose brain disease is treated, stable or symptom-free would widen trials and tell us whether drugs work in the brain.

Cancer spreading along the linings of the brain is almost untreatable. Injecting engineered immune cells directly into the brain fluid, through a small reservoir, reaches it.

Serous endometrial cancers often overproduce HER2. Enhertu already works in them; testing HER2 in every p53-abnormal tumour and using the ADC earlier could change outcomes for the worst subtype.

Interleukin-12 is an immune-stimulating cytokine that caused severe toxicity when injected into the bloodstream in the 1990s and was abandoned. An oncolytic herpes or adenovirus carrying the interleukin-12 gene under a drug-inducible promoter makes it only inside the tumour, keeping exposure local; trials include recurrent glioblastoma.

With Enhertu and tucatinib controlling brain metastases in most patients, radiation could be reserved for those who do not respond, sparing cognitive side effects.

Drugs that grab T cells and drag them onto tumours work well in blood cancers. The same trick aimed at tumour-eating cells might work where T cells are absent.