{"entity":{"id":"b-preclinical-models","kind":"bottleneck","name":"Lab models that fail to predict what happens in patients","aka":[],"tldr":"Nine in ten cancer drugs that work in mice fail in humans. Our models are the reason.","summary":"Oncology has the lowest probability of success of any therapeutic area: only a few percent of agents entering phase 1 reach approval, and most failures are for lack of efficacy that the preclinical package did not anticipate. Immortalised cell lines have drifted for decades and lack a microenvironment; subcutaneous xenografts grow in immunodeficient mice with no human immune system, stroma or metastatic pattern; genetically engineered mouse tumours evolve with far less heterogeneity than human disease; and patient-derived organoids capture epithelial biology but not vessels, immune cells or drug pharmacokinetics. Preclinical studies are also small, unblinded and rarely replicated. The result is a pipeline that spends billions in humans to learn what the models could not tell it. Better-validated models, functional testing on fresh patient tissue, and systematic benchmarking of model predictions against clinical outcomes are the fixes.","asOf":"2026-09-08","links":[{"label":"Wong, Siah & Lo, Estimation of clinical trial success rates (Biostatistics 2019)","url":"https://doi.org/10.1093/biostatistics/kxx069"},{"label":"Begley & Ellis, Raise standards for preclinical cancer research (Nature 2012)","url":"https://doi.org/10.1038/483531a"},{"label":"Cancer Models / PDCM Finder","url":"https://www.cancermodels.org/"}],"tags":[],"related":["cancer-models","depmap","idea-organoid-guided-adc","idea-bio1-immune-matched-humanised-mice","idea-bio1-co-clinical-avatar-trials","idea-bio1-organoid-immune-coculture","idea-bio1-tumour-on-chip-penetration","idea-bio1-in-silico-trials-dose","idea-bio1-preclinical-preregistration","idea-bio1-multicentre-mouse-trials","idea-bio1-model-predictivity-benchmark","idea-bio1-negative-preclinical-repository","idea-bio1-tumour-slice-cultures","idea-bio1-metastatic-niche-models","idea-bio1-aged-comorbid-models","idea-bio1-comparative-oncology-dogs","idea-bio1-zebrafish-avatars","idea-bio1-multi-organ-chip-tox","idea-bio1-rare-cancer-organoid-bank","idea-bio1-organoid-assay-clinical-validation","idea-bio1-organoid-cell-therapy-potency","idea-bio1-somatic-crispr-gemms","idea-bio1-ctc-derived-explants","idea-bio1-model-authentication-mandate","idea-bio1-reverse-translation-resistance-models","idea-bio1-ex-vivo-perfused-tumour","idea-bio1-model-patient-matching","idea-bio1-virtual-cell-perturbation","idea-moon-self-driving-cancer-labs"],"cancers":["pancreatic","glioblastoma","colorectal"],"sections":["drug-discovery"],"technologies":["organoids","pdx-models","functional-drug-testing","pdac-organoid-pharmacotyping","crispr-screens","bh3-profiling"],"targets":[],"drugs":[],"companies":["champions-oncology","xilis","curesponse","sengine","recursion"],"institutions":["broad-institute","nci","cold-spring-harbor","francis-crick"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-wong-biostatistics","paper-begley-nature"],"journals":[],"dependsOn":[],"notes":[],"stage":"biology","severity":"critical","metrics":[{"label":"Probability that an oncology drug entering phase 1 is eventually approved","value":"3.4%","source":"Wong, Siah & Lo, Biostatistics 2019","url":"https://doi.org/10.1093/biostatistics/kxx069"},{"label":"Oncology likelihood of approval from phase 1 (industry data 2003-2011), lowest of all disease areas","value":"6.7%","source":"Hay et al., Nature Biotechnology 2014","url":"https://doi.org/10.1038/nbt.2786"},{"label":"Landmark preclinical cancer papers whose findings Amgen scientists could reproduce","value":"6 of 53 (11%)","source":"Begley & Ellis, Nature 2012","url":"https://doi.org/10.1038/483531a"}],"causes":["Cell lines have adapted to plastic for decades and no longer resemble the tumours they came from.","Xenografts require immunodeficient hosts, so anything involving the immune system is invisible.","Mouse tumours are clonally simpler and are treated when small, which overstates drug effect.","Organoids lack stroma, vasculature and immune cells, and organoid drug exposure is not human pharmacokinetics.","Preclinical efficacy studies are small, unblinded, unregistered and rarely include controls that match clinical practice.","There is no systematic scoring of which models predicted which clinical results, so the field cannot learn which models to trust."],"currentEfforts":["The Human Cancer Models Initiative (NCI, Cancer Research UK, Wellcome Sanger, Hubrecht) and the PDCM Finder catalogue next-generation organoid and PDX models with clinical annotation.","DepMap (Broad Institute) systematically maps genetic dependencies across more than a thousand cell lines to separate robust from model-specific findings.","Champions Oncology, Xilis and cureSponse run functional drug testing on patient-derived xenografts, micro-organospheres and ex vivo tumour explants, with prospective studies comparing model prediction to patient response.","The NCI Patient-Derived Models Repository distributes clinically annotated PDX and organoid models.","Humanised-mouse and immune-competent organoid co-culture systems are being developed to test immunotherapies preclinically.","The FDA Modernization Act 2.0 (2022) removed the statutory requirement for animal testing, opening the door for validated human-cell and computational models."],"successLooksLike":"A drug that clears a defined preclinical panel has a documented, prospectively measured probability of clinical efficacy well above today's few percent, and functional testing on a patient's own tumour cells is validated to predict that patient's response."},"route":"/bottlenecks/b-preclinical-models/","neighbours":{"collection":[{"id":"cancer-models","kind":"collection","name":"Cancer Models (PDCM Finder) & HCMI","route":"/collections/cancer-models/"},{"id":"depmap","kind":"collection","name":"DepMap (Cancer Dependency Map)","route":"/collections/depmap/"}],"idea":[{"id":"idea-bio2-marrow-niche-on-chip","kind":"idea","name":"A bone marrow niche on a chip to study human dormancy","route":"/ideas/idea-bio2-marrow-niche-on-chip/"},{"id":"idea-tr2-cell-line-passport","kind":"idea","name":"A digital passport for every cell culture: identity, contamination status, passage number","route":"/ideas/idea-tr2-cell-line-passport/"},{"id":"idea-bio2-dormancy-selective-screen","kind":"idea","name":"A drug screen that only rewards killing sleeping cancer cells","route":"/ideas/idea-bio2-dormancy-selective-screen/"},{"id":"idea-fund-organoid-translation-gate","kind":"idea","name":"A funded organoid and PDX panel as the go/no-go gate before IND-enabling money","route":"/ideas/idea-fund-organoid-translation-gate/"},{"id":"idea-bio2-rapid-autopsy-commons","kind":"idea","name":"A global rapid tissue donation network for metastatic disease","route":"/ideas/idea-bio2-rapid-autopsy-commons/"},{"id":"idea-bio1-negative-preclinical-repository","kind":"idea","name":"A home for the animal and organoid experiments that failed","route":"/ideas/idea-bio1-negative-preclinical-repository/"},{"id":"idea-fund-phase-zero-fund","kind":"idea","name":"A phase 0 fund to test academic compounds in humans with microdoses and imaging","route":"/ideas/idea-fund-phase-zero-fund/"},{"id":"idea-tr2-organoid-matrix-atlas","kind":"idea","name":"A public atlas of drug-pair responses across a thousand patient-derived organoids","route":"/ideas/idea-tr2-organoid-matrix-atlas/"},{"id":"idea-bio1-virtual-cell-perturbation","kind":"idea","name":"A virtual cancer cell that predicts what a drug will do before you test it","route":"/ideas/idea-bio1-virtual-cell-perturbation/"},{"id":"idea-tr2-synergy-ranking-engine","kind":"idea","name":"An open engine that ranks every drug pair by predicted synergy before anyone runs a trial","route":"/ideas/idea-tr2-synergy-ranking-engine/"},{"id":"idea-data-open-cell-foundation-model","kind":"idea","name":"An open foundation model of the cancer cell trained on perturbation data","route":"/ideas/idea-data-open-cell-foundation-model/"},{"id":"idea-bio2-rare-tumour-model-bank","kind":"idea","name":"An open model bank for the rare tumours nobody has models for","route":"/ideas/idea-bio2-rare-tumour-model-bank/"},{"id":"idea-moon-open-cancer-cell-state-model","kind":"idea","name":"An open model of every cancer cell state, built from perturbation atlases","route":"/ideas/idea-moon-open-cancer-cell-state-model/"},{"id":"idea-bio1-rare-cancer-organoid-bank","kind":"idea","name":"An open organoid bank for cancers too rare to have models","route":"/ideas/idea-bio1-rare-cancer-organoid-bank/"},{"id":"idea-tr2-arrive-audit","kind":"idea","name":"Audit animal studies for randomisation and blinding, published by institution","route":"/ideas/idea-tr2-arrive-audit/"},{"id":"idea-moon-automated-combination-discovery","kind":"idea","name":"Automated combination discovery: patient-sample screens feeding Bayesian platform trials","route":"/ideas/idea-moon-automated-combination-discovery/"},{"id":"idea-bio1-barcoded-avatars-clonal-fitness","kind":"idea","name":"Barcode patient-derived tumours to watch which clones win under each drug","route":"/ideas/idea-bio1-barcoded-avatars-clonal-fitness/"},{"id":"idea-bio2-blood-csf-barrier-model","kind":"idea","name":"Build a human model of the barrier that guards the brain fluid","route":"/ideas/idea-bio2-blood-csf-barrier-model/"},{"id":"idea-bio1-metastatic-niche-models","kind":"idea","name":"Build laboratory models of the organs cancer spreads to","route":"/ideas/idea-bio1-metastatic-niche-models/"},{"id":"idea-tr2-reference-compound-panels","kind":"idea","name":"Every drug screen includes standard reference compounds whose performance is published","route":"/ideas/idea-tr2-reference-compound-panels/"},{"id":"idea-bio1-reverse-translation-resistance-models","kind":"idea","name":"Every resistance mechanism found in a patient must be rebuilt in the laboratory","route":"/ideas/idea-bio1-reverse-translation-resistance-models/"},{"id":"idea-bio2-ctc-culture-functional-testing","kind":"idea","name":"Grow blood-borne tumour cells to test drugs on the cells that actually spread","route":"/ideas/idea-bio2-ctc-culture-functional-testing/"},{"id":"idea-tr2-organoid-coclinical-arms","kind":"idea","name":"Grow each trial patient's tumour as organoids to decide which platform arm opens next","route":"/ideas/idea-tr2-organoid-coclinical-arms/"},{"id":"idea-bio1-ctc-derived-explants","kind":"idea","name":"Grow models from tumour cells in the blood when a biopsy is impossible","route":"/ideas/idea-bio1-ctc-derived-explants/"},{"id":"idea-bio1-organoid-immune-coculture","kind":"idea","name":"Grow tumour organoids together with the patient's own immune cells","route":"/ideas/idea-bio1-organoid-immune-coculture/"},{"id":"idea-bio1-organoid-assay-clinical-validation","kind":"idea","name":"Hold organoid drug tests to the same standard as a diagnostic test","route":"/ideas/idea-bio1-organoid-assay-clinical-validation/"},{"id":"idea-bio1-immune-matched-humanised-mice","kind":"idea","name":"Humanised mice with an immune system matched to the tumour donor","route":"/ideas/idea-bio1-immune-matched-humanised-mice/"},{"id":"idea-bio2-implantable-microdevice-screen","kind":"idea","name":"Implant a tiny device that tests twenty drugs inside the patient's own tumour","route":"/ideas/idea-bio2-implantable-microdevice-screen/"},{"id":"idea-bio1-in-silico-trials-dose","kind":"idea","name":"In silico trials to choose the dose before the first patient","route":"/ideas/idea-bio1-in-silico-trials-dose/"},{"id":"idea-bio1-ex-vivo-perfused-tumour","kind":"idea","name":"Keep a freshly removed tumour alive on a pump and test drugs in it","route":"/ideas/idea-bio1-ex-vivo-perfused-tumour/"},{"id":"idea-bio1-multi-organ-chip-tox","kind":"idea","name":"Linked human organ chips to predict side effects before people are dosed","route":"/ideas/idea-bio1-multi-organ-chip-tox/"},{"id":"idea-bio1-somatic-crispr-gemms","kind":"idea","name":"Make bespoke mouse cancer models in weeks with in vivo gene editing","route":"/ideas/idea-bio1-somatic-crispr-gemms/"},{"id":"idea-bio2-metastasis-screen-standard","kind":"idea","name":"Make in vivo metastasis screens a required step in drug discovery","route":"/ideas/idea-bio2-metastasis-screen-standard/"},{"id":"idea-bio1-multicentre-mouse-trials","kind":"idea","name":"Multi-centre randomised animal trials before committing to a human trial","route":"/ideas/idea-bio1-multicentre-mouse-trials/"},{"id":"idea-tr2-multilab-preclinical","kind":"idea","name":"Multi-laboratory preclinical trials as the standard for go/no-go decisions","route":"/ideas/idea-tr2-multilab-preclinical/"},{"id":"idea-organoid-guided-adc","kind":"idea","name":"Patient-derived organoids to pick ADC payloads","route":"/ideas/idea-organoid-guided-adc/"},{"id":"idea-bio1-comparative-oncology-dogs","kind":"idea","name":"Pet dogs with spontaneous cancer as a bridge before human trials","route":"/ideas/idea-bio1-comparative-oncology-dogs/"},{"id":"idea-bio1-model-patient-matching","kind":"idea","name":"Pick the laboratory model that matches the patient, not the one to hand","route":"/ideas/idea-bio1-model-patient-matching/"},{"id":"idea-bio1-preclinical-preregistration","kind":"idea","name":"Pre-register animal efficacy studies like clinical trials","route":"/ideas/idea-bio1-preclinical-preregistration/"},{"id":"idea-tr2-animal-power-mandate","kind":"idea","name":"Pre-specified sample sizes for animal studies; no more 'representative' experiments","route":"/ideas/idea-tr2-animal-power-mandate/"},{"id":"idea-bio1-model-authentication-mandate","kind":"idea","name":"Prove the cell line is what you say it is, or the paper does not run","route":"/ideas/idea-bio1-model-authentication-mandate/"},{"id":"idea-tr2-cell-line-authentication-mandate","kind":"idea","name":"Prove your cell lines are what you say they are, or the paper is not published","route":"/ideas/idea-tr2-cell-line-authentication-mandate/"},{"id":"idea-pdac-stromal-reprogramming-not-depletion","kind":"idea","name":"Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint","route":"/ideas/idea-pdac-stromal-reprogramming-not-depletion/"},{"id":"idea-bio1-co-clinical-avatar-trials","kind":"idea","name":"Run the mouse or organoid trial at the same time as the human trial","route":"/ideas/idea-bio1-co-clinical-avatar-trials/"},{"id":"idea-bio1-model-predictivity-benchmark","kind":"idea","name":"Score every model system on how well it predicted real trial results","route":"/ideas/idea-bio1-model-predictivity-benchmark/"},{"id":"idea-tr2-model-report-cards","kind":"idea","name":"Score every preclinical model by how often it predicted the clinical result","route":"/ideas/idea-tr2-model-report-cards/"},{"id":"idea-moon-self-driving-cancer-labs","kind":"idea","name":"Self-driving laboratories that run the cancer biology hypothesis loop autonomously","route":"/ideas/idea-moon-self-driving-cancer-labs/"},{"id":"idea-tr2-reference-model-panels","kind":"idea","name":"Shared reference organoid and PDX panels that every lab can test against","route":"/ideas/idea-tr2-reference-model-panels/"},{"id":"idea-bio1-aged-comorbid-models","kind":"idea","name":"Test cancer drugs in old and unhealthy animals, not just young fit ones","route":"/ideas/idea-bio1-aged-comorbid-models/"},{"id":"idea-bio1-tumour-slice-cultures","kind":"idea","name":"Test drugs on freshly cut slices of the patient's own tumour","route":"/ideas/idea-bio1-tumour-slice-cultures/"},{"id":"idea-bio2-functional-precision-rare","kind":"idea","name":"Test drugs on the patient's own cancer cells when there is no trial to join","route":"/ideas/idea-bio2-functional-precision-rare/"},{"id":"idea-bio1-tumour-on-chip-penetration","kind":"idea","name":"Tumour-on-a-chip with blood flow to test whether big drugs actually get in","route":"/ideas/idea-bio1-tumour-on-chip-penetration/"},{"id":"idea-tr2-window-of-opportunity-triplets","kind":"idea","name":"Two-week pre-operative windows to compare combination biology head to head","route":"/ideas/idea-tr2-window-of-opportunity-triplets/"},{"id":"idea-bio1-organoid-cell-therapy-potency","kind":"idea","name":"Use patient organoids to check a cell therapy will work before infusing it","route":"/ideas/idea-bio1-organoid-cell-therapy-potency/"},{"id":"idea-moon-validated-digital-twins","kind":"idea","name":"Whole-patient digital twins validated in prospective randomised trials","route":"/ideas/idea-moon-validated-digital-twins/"},{"id":"idea-bio1-zebrafish-avatars","kind":"idea","name":"Zebrafish avatars for a drug answer within a week","route":"/ideas/idea-bio1-zebrafish-avatars/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"}],"technology":[{"id":"bh3-profiling","kind":"technology","name":"BH3 profiling (functional apoptosis testing)","route":"/technologies/bh3-profiling/"},{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"functional-drug-testing","kind":"technology","name":"Functional (ex vivo) drug testing","route":"/technologies/functional-drug-testing/"},{"id":"organoids","kind":"technology","name":"Patient-derived organoids","route":"/technologies/organoids/"},{"id":"pdx-models","kind":"technology","name":"Patient-derived xenografts","route":"/technologies/pdx-models/"},{"id":"pdac-organoid-pharmacotyping","kind":"technology","name":"PDAC organoid pharmacotyping","route":"/technologies/pdac-organoid-pharmacotyping/"}],"company":[{"id":"champions-oncology","kind":"company","name":"Champions Oncology","route":"/companies/champions-oncology/"},{"id":"curesponse","kind":"company","name":"Curesponse","route":"/companies/curesponse/"},{"id":"recursion","kind":"company","name":"Recursion Pharmaceuticals","route":"/companies/recursion/"},{"id":"sengine","kind":"company","name":"SEngine Precision Medicine","route":"/companies/sengine/"},{"id":"xilis","kind":"company","name":"Xilis","route":"/companies/xilis/"}],"institution":[{"id":"wake-forest-cancer","kind":"institution","name":"Atrium Health Wake Forest Baptist Comprehensive Cancer Center","route":"/institutions/wake-forest-cancer/"},{"id":"karmanos","kind":"institution","name":"Barbara Ann Karmanos Cancer Institute","route":"/institutions/karmanos/"},{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"cancer-center-at-illinois","kind":"institution","name":"Cancer Center at Illinois","route":"/institutions/cancer-center-at-illinois/"},{"id":"cz-biohub","kind":"institution","name":"Chan Zuckerberg Biohub","route":"/institutions/cz-biohub/"},{"id":"cold-spring-harbor","kind":"institution","name":"Cold Spring Harbor Laboratory","route":"/institutions/cold-spring-harbor/"},{"id":"mit-koch","kind":"institution","name":"David H. Koch Institute for Integrative Cancer Research at MIT","route":"/institutions/mit-koch/"},{"id":"candiolo","kind":"institution","name":"Istituto di Candiolo IRCCS (FPO)","route":"/institutions/candiolo/"},{"id":"nci","kind":"institution","name":"National Cancer Institute (NIH)","route":"/institutions/nci/"},{"id":"mcgill-goodman","kind":"institution","name":"Rosalind and Morris Goodman Cancer Institute, McGill University","route":"/institutions/mcgill-goodman/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"},{"id":"jackson-laboratory","kind":"institution","name":"The Jackson Laboratory Cancer Center","route":"/institutions/jackson-laboratory/"},{"id":"wistar","kind":"institution","name":"The Wistar Institute","route":"/institutions/wistar/"},{"id":"uc-davis-cancer","kind":"institution","name":"UC Davis Comprehensive Cancer Center","route":"/institutions/uc-davis-cancer/"},{"id":"umc-utrecht","kind":"institution","name":"UMC Utrecht Cancer Center","route":"/institutions/umc-utrecht/"}],"paper":[{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-depmap-tsherniak-cell-2017","kind":"paper","name":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without","route":"/key-papers/paper-depmap-tsherniak-cell-2017/"},{"id":"paper-begley-nature","kind":"paper","name":"Drug development: Raise standards for preclinical cancer research","route":"/key-papers/paper-begley-nature/"},{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","kind":"paper","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/"},{"id":"paper-wong-biostatistics","kind":"paper","name":"Estimation of clinical trial success rates and related parameters","route":"/key-papers/paper-wong-biostatistics/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/"},{"id":"paper-reproducibility-project-cancer-biology-elife-2021","kind":"paper","name":"Reproducibility Project: Cancer Biology found that landmark preclinical results mostly shrank or vanished on replication","route":"/key-papers/paper-reproducibility-project-cancer-biology-elife-2021/"}],"roadmap":[{"id":"drug-discovery-roadmap","kind":"roadmap","name":"Drug discovery roadmap: screening in mice → maps of dependency → designing in silico","route":"/roadmaps/drug-discovery-roadmap/"}]}}