High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas

Kurnit, Katherine C.; Steiner, M.; Lastra, Ricardo R.; Weroha, S. John; Cursio, John F.; Lengyel, Ernst; Fleming, Gini F.; Conzen, Suzanne D.

doi:10.1016/j.gore.2022.100987

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…In contrast to UroCa, the relevance of GR and its associated pathway had not been addressed in the context of histological variants of bladder cancer, such as SARC so far. Noteworthily, other sarcomatoid tumor entities have been suggested to display high GR levels, suggesting that our findings may have relevance beyond the bladder context (17).…”

Section: Discussionmentioning

confidence: 68%

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Garioni

Blukacz

Nuciforo

et al. 2023

Preprint

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Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53, RB1, and KRAS. High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

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Section: Discussionmentioning

confidence: 68%

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Garioni

Blukacz

Nuciforo

et al. 2023

Preprint

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“…Although patients treated with paclitaxel–carboplatin had a longer overall survival (30 months versus 25 months) and PFS (15 months versus 10 months) when compared to paclitaxel–ifosfamide, these differences were not statistically significant. 101 A high glucocorticoid receptor (GR) expression can identify patients who are less likely to derive benefit from nab-paclitaxel 102 and given the high expression of GR in OCS, 103 it may have a role as a biomarker for this patient population. These high GR levels may also mean that the GR modulator relacorilant could be beneficial in the treatment of OSC patients with recurrent disease.…”

Section: Ovarian Carcinosarcomamentioning

confidence: 99%

Disparity in the era of personalized medicine for epithelial ovarian cancer

Devlin

Miller

2023

Ther Adv Med Oncol

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The treatment of high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer has seen significant improvements in recent years, with BRCA1/2 and homologous recombination status guiding a personalized approach which has resulted in improved patient outcomes. However, for other epithelial ovarian cancer subtypes, first-line treatment remains unchanged from the platinum–paclitaxel trials of the early 2000s. In this review, we explore novel therapeutic approaches being adopted in the treatment of clear cell, mucinous, carcinosarcoma and low-grade serous ovarian cancer and the biological rational behind them. We discuss why such disparities exist, the challenges faced in conducting dedicated trials in these rarer histologies and look towards new approaches being adopted to overcome them.

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Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Garioni,

Tschan,

Blukacz

et al. 2023

npj Precis. Onc.

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Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of a long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological, phenotypical, and transcriptional features of SARC and harbors somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 (p53) and RB1 (pRB). High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and conventional urothelial carcinoma (UroCa) organoids, identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, including agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts and in organoid models, GR and its encoding gene NR3C1 were found to be significantly more expressed in SARC as compared to UroCa, suggesting that high GR expression is a hallmark of SARC tumors. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

show abstract

High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas

Cited by 3 publications

References 17 publications

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Disparity in the era of personalized medicine for epithelial ovarian cancer

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

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