Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Liu, Shilei; Liang, Haibin; Yang, Ziyi; Cai, Chen; Wu, Zhihua; Wu, Xiangsong; Dong, Ping; Li, Maolan; Zheng, Lei; Gong, Weiwei

doi:10.7150/ijms.68404

Cited by 8 publications

(6 citation statements)

References 36 publications

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“…Accordingly, in vivo experiments with H295R xenografts confirmed that pharmacological inhibition of ERRα strongly inhibited ACC cell growth without exerting any marked toxic effect. Our results are supported by additional in vivo studies performed with breast [ 34 ], endometrial [ 35 ] and pancreatic [ 36 ] cancer cells, which altogether point to ERRα as a specific target for the treatment of high energy demanding cells such as tumor cells.…”

Section: Discussionsupporting

confidence: 75%

Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression

Avena

Luca

Chimento

et al. 2022

Cancers

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The aim of this study was to investigate the metabolic changes that occur in adrenocortical cancer (ACC) cells in response to the modulation of Estrogen Related Receptor (ERR)α expression and the impact on ACC progression. Proteomics analysis and metabolic profiling highlighted an important role for ERRα in the regulation of ACC metabolism. Stable ERRα overexpression in H295R cells promoted a better mitochondrial fitness and prompted toward a more aggressive phenotype characterized by higher Vimentin expression, enhanced cell migration and spheroids formation. By contrast, a decrease in ERRα protein levels, by molecular (short hairpin RNA) and pharmacological (inverse agonist XCT790) approaches modified the energetic status toward a low energy profile and reduced Vimentin expression and ability to form spheroids. XCT790 produced similar effects on two additional ACC cell lines, SW13 and mitotane-resistant MUC-1 cells. Our findings show that ERRα is able to modulate the metabolic profile of ACC cells, and its inhibition can strongly prevent the growth of mitotane-resistant ACC cells and the progression of ACC cell models to a highly migratory phenotype. Consequently, ERRα can be considered an important target for the design of new therapeutic strategies to fight ACC progression.

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Section: Discussionsupporting

confidence: 75%

Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression

Avena

Luca

Chimento

et al. 2022

Cancers

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“…For example, in another case reported by Zhao et al [ 40 ], personalized treatment based on MiniPDX and whole-exome sequencing was used to rapidly assess drug sensitivity and reveal significant genetic changes in patients with metastatic duodenal adenocarcinoma. Moreover, Liu et al [ 41 ] found that gemcitabine and XCT790 have synergistic antitumor effects on pancreatic cancer by the MiniPDX model. By establishing the MiniPDX model, Xu et al [ 42 ] found that the combined application of AKT inhibitors and PARP inhibitors might be a feasible method for clinical trials in patients with recurrent ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study

Zhang

Zhu

et al. 2023

Discov Onc

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Background Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. Methods In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). Results A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2–34) months. The median PFS time was 14.1 (2–34) months, the median OS time was 16.9 (2–34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3–4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. Conclusion Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.

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“…So far, this model has been applied to a variety of solid tumours: gastric cancer, 8,9 ovarian cancer, 10,11 gallbladder cancer, 12 pancreatic cancer, 13 etc.…”

Section: Introductionmentioning

confidence: 99%

“…Compared with traditional PDX models, is a time‐saving model with a higher success rate and strong clinical feasibility. So far, this model has been applied to a variety of solid tumours: gastric cancer, 8 , 9 ovarian cancer, 10 , 11 gallbladder cancer, 12 pancreatic cancer, 13 etc.…”

Section: Introductionmentioning

confidence: 99%

The combination of breast cancer PDO and mini‐PDX platform for drug screening and individualized treatment

Cui,

Ran,

et al. 2024

J Cellular Molecular Medi

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The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient‐derived organoids (PDOs) with mini‐patient‐derived xenografts (Mini‐PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high‐fidelity three‐dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug‐resistant breast cancer, we combined PDO and Mini‐PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini‐PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

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Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Cited by 8 publications

References 36 publications

Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression

Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression

OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study

The combination of breast cancer PDO and mini‐PDX platform for drug screening and individualized treatment

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