{"slug":"open-question","tag":"open-question","variants":["open-question"],"description":"Ideas framed as open questions the field has not answered.","count":17,"kinds":{"idea":17},"related":[{"slug":"mechanism","tag":"mechanism","shared":17}],"records":[{"id":"idea-dtc-colonisation-determinants","kind":"idea","name":"What decides which disseminated cells ever colonise?","route":"/ideas/idea-dtc-colonisation-determinants/","tldr":"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."},{"id":"idea-immune-exclusion-drivers","kind":"idea","name":"What actually holds T cells at the tumour border?","route":"/ideas/idea-immune-exclusion-drivers/","tldr":"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."},{"id":"idea-drugging-myc","kind":"idea","name":"Can MYC be drugged directly, and will patients tolerate it?","route":"/ideas/idea-drugging-myc/","tldr":"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."},{"id":"idea-targeting-aneuploidy","kind":"idea","name":"Is aneuploidy itself a druggable vulnerability?","route":"/ideas/idea-targeting-aneuploidy/","tldr":"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."},{"id":"idea-neoantigen-immunogenicity-rules","kind":"idea","name":"What makes a neoantigen actually immunogenic?","route":"/ideas/idea-neoantigen-immunogenicity-rules/","tldr":"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."},{"id":"idea-dormancy-maintenance-therapy","kind":"idea","name":"Keep them asleep: dormancy maintenance as adjuvant therapy","route":"/ideas/idea-dormancy-maintenance-therapy/","tldr":"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."},{"id":"idea-metabolic-vulnerability-mapping","kind":"idea","name":"Map metabolic dependencies in the patient, not the dish","route":"/ideas/idea-metabolic-vulnerability-mapping/","tldr":"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."},{"id":"idea-senolytics-after-chemo","kind":"idea","name":"One-two punch: clear senescent cells after chemotherapy","route":"/ideas/idea-senolytics-after-chemo/","tldr":"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."},{"id":"idea-microbiome-io-fmt","kind":"idea","name":"Microbiome transplant as a routine immunotherapy adjunct","route":"/ideas/idea-microbiome-io-fmt/","tldr":"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."},{"id":"idea-nerve-tumour-blockade","kind":"idea","name":"Cut the nerve supply to tumours with old drugs","route":"/ideas/idea-nerve-tumour-blockade/","tldr":"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."},{"id":"idea-cachexia-gdf15-prevention","kind":"idea","name":"Treat cachexia before it starts","route":"/ideas/idea-cachexia-gdf15-prevention/","tldr":"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."},{"id":"idea-chip-risk-modifiers","kind":"idea","name":"Which patients' blood clones will become leukaemia after treatment?","route":"/ideas/idea-chip-risk-modifiers/","tldr":"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."},{"id":"idea-field-interception","kind":"idea","name":"Intercept cancer at the field stage","route":"/ideas/idea-field-interception/","tldr":"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."},{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","route":"/ideas/idea-ferroptosis-persisters/","tldr":"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."},{"id":"idea-splice-neoantigens","kind":"idea","name":"Shared splice-derived neoantigens as off-the-shelf vaccine targets","route":"/ideas/idea-splice-neoantigens/","tldr":"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."},{"id":"idea-chronotherapy-immunotherapy","kind":"idea","name":"Give immunotherapy in the morning","route":"/ideas/idea-chronotherapy-immunotherapy/","tldr":"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."},{"id":"idea-ecdna-targeting","kind":"idea","name":"Attack extrachromosomal DNA, the engine of oncogene amplification","route":"/ideas/idea-ecdna-targeting/","tldr":"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."}]}