{"entity":{"id":"idea-bio1-arv7-degrader","kind":"idea","name":"Destroy the truncated androgen receptor that hormone drugs cannot touch","aka":[],"tldr":"In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.","summary":"AR-V7 lacks the ligand-binding domain, so enzalutamide and abiraterone cannot act on it, and its presence predicts resistance. Degraders and N-terminal-domain binders that engage full-length AR and its splice variants could restore control. Full-length AR degraders have reached the clinic; variant-competent agents are the unmet need, and AR-V7 status is already measurable in circulating tumour cells.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":["prostate-roadmap","idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine"],"cancers":["prostate"],"sections":[],"technologies":["protac-degrader"],"targets":["androgen-receptor"],"drugs":[],"companies":["arvinas"],"institutions":[],"pathways":["ar-signaling"],"terms":[],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":["paper-dang-nat-rev-cancer","paper-androgen-receptor-prostate-endocr-rev-2004","paper-androgen-receptor-prostate-nat-rev-cancer-2015","paper-androgen-receptor-prostate-acta-pharmacol-sin-2015"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"An AR degrader or N-terminal-domain agent active against AR-V7 produces PSA responses in AR-V7-positive castration-resistant prostate cancer, where the response rate to further AR-pathway inhibition is near zero.","rationale":"AR-V7 is a well-defined, biomarker-selectable population with a mechanistically obvious unmet need; the degrader modality directly bypasses the missing ligand pocket.","test":"Phase 1b enriched for AR-V7-positive patients by circulating tumour cell assay, with PSA response rate and paired biopsy AR degradation as endpoints.","maturity":"preclinical-evidence","actor":"industry","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-arv7-degrader/","neighbours":{"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"idea":[{"id":"idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine","kind":"idea","name":"Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it","route":"/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/"}],"cancer":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"company":[{"id":"arvinas","kind":"company","name":"Arvinas","route":"/companies/arvinas/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-androgen-receptor-prostate-endocr-rev-2004","kind":"paper","name":"Androgen receptor in prostate cancer","route":"/key-papers/paper-androgen-receptor-prostate-endocr-rev-2004/"},{"id":"paper-androgen-receptor-prostate-acta-pharmacol-sin-2015","kind":"paper","name":"Androgen receptor: structure, role in prostate cancer and drug discovery","route":"/key-papers/paper-androgen-receptor-prostate-acta-pharmacol-sin-2015/"},{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/"},{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"},{"id":"paper-androgen-receptor-prostate-nat-rev-cancer-2015","kind":"paper","name":"Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer","route":"/key-papers/paper-androgen-receptor-prostate-nat-rev-cancer-2015/"}]}}