Androgen receptor modulation: A tailored approach for oestrogen receptor-positive metastatic breast cancer
[eng] Breast cancer (BC) is the most diagnosed cancer in women and the second leading cause of cancer-related deaths in this population. Luminal BC accounts for 70% of tumours and is characterised by the expression of hormone receptors: the oestrogen receptor (ER) and the progesterone receptor (PgR)...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/213160 |
| Acceso en línea: | https://hdl.handle.net/2445/213160 http://hdl.handle.net/10803/691442 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer de mama Tractament adjuvant del càncer Andrògens Receptors d'hormones Breast cancer Adjuvant treatment of cancer Androgens Hormone receptors |
| Sumario: | [eng] Breast cancer (BC) is the most diagnosed cancer in women and the second leading cause of cancer-related deaths in this population. Luminal BC accounts for 70% of tumours and is characterised by the expression of hormone receptors: the oestrogen receptor (ER) and the progesterone receptor (PgR). The main treatment strategy for these patients in the metastatic setting is the combination of endocrine therapy (ET) with CDK4/6-inhibitors (CDK4/6i). Despite the significant benefit of these therapies, many patients do not tolerate ET or present mechanisms of intrinsic or acquired resistance, hence novel therapies are needed. The androgen receptor (AR) is co- expressed with ER in 75% of BC tumours and has a tumour suppressor role in luminal B breast cancer. Selective androgen receptor modulators (SARMs) that activate the AR in a tissue-specific manner do not exhibit virilising effects and have been proposed as a therapeutic strategy for ER+ BC. Mechanistically, it has been proposed that agonist activation of AR alters the genomic distribution of ER and essential co- activators, resulting in the repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumour suppressors. Two SARMs are currently being developed and have shown clinical benefit in ET-resistant BC patients with AR expression. The aims of this thesis are to study the activity of the SARM EP0062 in a cohort of ER+/HER2- BC patient-derived xenograft (PDX) models to identify biomarkers of response and to dissect the mechanism whereby AR and ER mediate the antitumor activity of the SARM. The PDX panel is composed of 39 models derived from patients mostly pre-treated with ET and representative of the ER+/HER2- metastatic BC population in terms of nuclear ER, PgR and AR protein levels, molecular alterations and BC intrinsic subtype. We identified a subset of hormone-dependent PDX models that were characterised by high expression of hormone receptor levels, enrichment of oestrogen response signatures and a marked decrease of Ki67-proliferation marker upon hormone deprivation. In a subset of 12 hormone-independent PDX models, the SARM EP0062 exhibited superior antitumor activity than the selective oestrogen receptor degrader (SERD), fulvestrant, and similar antitumor activity than a next generation SERD. EP0062 displayed antitumor activity across tumours harbouring ESR1, PIK3CA or PTEN-alterations and sensitive tumours were enriched in GATA3- frameshift mutations. Of note, AR and ER protein levels did not predict response to EP0062 nor AR nuclear translocation after treatment. In agreement, the SARM equally induced AR-target genes both in resistant and sensitive models. Amongst the genes specifically downmodulated across EP0062-sensitive models, we identified ESR1 and E2F1, consistent with decreased S-phase cyclins upon treatment. The addition of the CDK4/6-inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant, but not in HER2-enriched or PTEN-mutant PDX models, which is consistent with clinical observations of resistance to CDK4/6i. In conclusion, this thesis provides compelling evidence of the activity of SARMs compared to a next generation SERD in clinically relevant PDX models. EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumours that remain ER-driven, the addition of palbociclib displays a potent antitumor effect. Hence, the combination of a SARM plus a CDK4/6i is a potent therapy for AR+/ER+/HER2- metastatic BC patients who do not tolerate ET and/or are resistant to the current standard of care, fulvestrant plus CDK4/6i. |
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