open-question

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.

MYC drives half of all cancers but has no pocket for a drug and is needed by normal cells too. The first direct MYC blockers are in trials; the question is whether there is a therapeutic window.

Nerves feed pancreatic, prostate, and other tumours. Beta-blockers and botulinum toxin are cheap, safe, and already in trials to see if severing that link slows cancer.

Several studies found patients infused with checkpoint inhibitors earlier in the day lived longer. If a randomised trial confirms it, it is a free improvement available everywhere tomorrow.

Whole regions of tissue carry cancer mutations long before a tumour exists. Detecting and treating the field, not the tumour, could prevent cancers rather than cure them.

Most cancers have the wrong number of chromosomes; normal cells do not. If that difference creates a specific weakness, a drug against it would spare normal tissue by definition.

Instead of trying to kill every hidden cancer cell after surgery, keep them dormant for life with low-toxicity drugs, the way extended hormone therapy already does in breast cancer.

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.

Metabolic drugs keep failing because tumours switch fuels. Measuring what a patient's tumour actually eats, with tracers and PET, could pick the right metabolic drug for the right tumour.

Stool transplants from immunotherapy responders have rescued some non-responders in melanoma. If defined bacterial cocktails work as well, every immunotherapy patient could get one.

Chemotherapy leaves behind senescent cells that inflame tissues and help tumours relapse. A short course of senolytic drugs afterwards might reduce relapse and long-term side effects at once.

Mutations in the RNA splicing genes SF3B1, SRSF2 and U2AF1 produce the same mis-spliced proteins in patient after patient with MDS, CLL or uveal melanoma. If fragments of those proteins are displayed on common HLA molecules and seen by T cells, one off-the-shelf vaccine or TCR-T therapy could serve every SF3B1-mutant patient instead of being built per person.

Cachexia, the muscle wasting driven partly by the hormone GDF-15, kills cancer patients and stops chemotherapy being completed, and late muscle loss is largely irreversible. Ponsegromab, an anti-GDF-15 antibody, reversed weight loss in established cachexia in 2024; the next test is a phase 3 giving it from first-line chemotherapy in pancreatic cancer to prevent wasting rather than treat it.

In immune-excluded tumours T cells reach the border but cannot get in, held back by fibroblasts, matrix, abnormal vessels, CXCL12 gradients or myeloid cells, and TGF-β drugs on their own have failed. If single-cell and spatial profiling can show which stromal programme dominates in each tumour, matching the drug (TGF-β, FAP, CXCR4 or VEGF) to it could let immunotherapy work.

Most cancer cells that spread die or sleep forever; a few grow into lethal metastases. Nobody can yet tell them apart, and doing so would show whom to treat after surgery.

Vaccines can now encode dozens of a tumour's mutations, but only a minority provoke useful T cells. Learning the rules would make vaccines smaller, cheaper, and stronger.

PARP inhibitors, platinum, and radioligand drugs can push pre-existing blood-cell clones toward leukaemia in a few patients. Predicting who could let us choose therapies more safely.