Imatinib – eine mögliche Therapieoption beim Zervixkarzinom: Ergebnisse einer präklinischen Phase-I-Studie

Kümmel, Sherko; Heidecke, Harald; Brock, Brenda; Denkert, Carsten; Hecktor, J.; Köninger, Angela; Becker, Ina; Sehouli, Jalid; Thomas, Anke; Blohmer, Jens U.; Lichtenegger, W.

doi:10.1159/000119032

Cited by 7 publications

(4 citation statements)

References 67 publications

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“…Our results are in agreement with the described absence of activating mutations in 17 cervical carcinomas [38]. Nevertheless, recent preclinical studies in mouse model and human cervical carcinomas tumour samples, showed significant therapeutic benefits of Imatinib-based therapy [40,41]. …”

Section: Discussionsupporting

confidence: 92%

Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma

et al. 2009

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BackgroundAdenosquamous carcinoma of the uterine cervix is an infrequent but aggressive subtype of cervical cancer. A better understanding of its biological behaviour is warranted to define more accurate prognosis and therapeutic targets. Currently, the blockage of receptor tyrosine kinase (RTKs) activity is an efficient therapeutic strategy for many different cancers. The objective of this study was to investigate EGFR, PDGFRA and VEGFR2 RTKs overexpression and activating gene mutations in a cohort of 30 adenosquamous carcinomas of the uterine cervix.MethodsEGFR, PDGFRA and VEGFR2 immunohistochemistry was performed in all samples, followed by DNA isolation from the gross macroscopically dissection of the neoplastic area. Screening for EGFR (exons 18–21) and PDGFRA (exons 12, 14 and 18) mutations was done by PCR – single-strand conformational polymorphism (PCR-SSCP).ResultsDespite the presence of EGFR immunohistochemical positive reactions in 43% (13/30) of the samples, no EGFR activating mutations in the hotspot region (exons 18–21) were identified. A silent base substitution (CAG>CAA) in EGFR exon 20 at codon 787 (Q787Q) was found in 17 cases (56%). All PDGFRA immunohistochemical reactions were positive and consistently observed in the stromal component, staining fibroblasts and endothelial cells, as well as in the cytoplasm of malignant cells. No activating PDGFRA mutations were found, yet, several silent mutations were observed, such as a base substitution in exon 12 (CCA>CCG) at codon 567 (P567P) in 9 cases and in exon 18 (GTC>GTT) at codon 824 (V824V) in 4 cases. We also observed the presence of base substitutions in intron 14 (IVS14+3G>A and IVS14+49G>A) in two different cases, and in intron 18 (IVS18-50insA) in 4 cases. VEGFR2 positivity was observed in 22 of 30 cases (73.3%), and was significantly associated with lack of metastasis (p = 0.038).ConclusionThis is the most extensive analysis of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinomas. Despite the absence of EGFR and PDGFRA activating mutations, the presence of overexpression of these three important therapeutic targets in a subset of cases may be important in predicting the sensitivity of adenosquamous carcinoma to specific anti-RTKs drugs.

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Section: Discussionsupporting

confidence: 92%

Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma

et al. 2009

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“…For example, the first tyrosine kinase inhibitor, imatinib, was reported to prevent the activation of platelet-derived growth factor receptor (PDGFR), which is often overexpressed in cervical cancer [4], thus inhibiting cervical cancer cell proliferation. In a study which screened carbo- and cisplatin, topotecan, paclitaxel, imatinib, gefitinib, cetuximab, and trastuzumab on freshly isolated tumor cells of 16 patients, 66% of tumor samples were sensitive to imatinib [5]. When administered orally, it worked effectively in the clinic, possibly due to its high plasma protein binding and insufficient drug delivery to the vaginal mucosal epithelium.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer

Huang

et al. 2019

Pharmaceutics

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The present study was carried out to investigate the potential of cationic functionalization on imatinib nanocrystals to improve the mucoadhesiveness and, thus, delivery to the lesion of cervicovaginal tumors. Amino-group-functionalized imatinib nanocrystals (NC@PDA-NH2) were prepared with near-spheroid shape, nanoscale size distribution, positive zeta potential, and relatively high drug content with the aid of the polydopamine-coating technique. Efficient interaction between NC@PDA-NH2 and mucin was proven by mucin adsorption which was related to the positive zeta-potential value of NC@PDA-NH2 and the change in the size distribution on mixing of NC@PDA-NH2 and mucin. Cellular uptake, growth inhibition, and apoptosis induction in cervicovaginal cancer-related cells demonstrated the superiority of NC@PDA-NH2 over unmodified nanocrystals. For practical intravaginal administration, NC@PDA-NH2 was dispersed in Pluronic F127-based thermosensitive in situ hydrogel, which showed suitable gelation temperature and sustained-release profiles. In comparison with unmodified nanocrystals, NC@PDA-NH2 exhibited extended residence on ex vivo murine vaginal mucosa, prolonged in vivo intravaginal residence, and enhanced inhibition on the growth of murine orthotopic cervicovaginal model tumors indicated by smaller tumor size, longer median survival time, and more intratumor apoptosis with negligible mucosal toxicity. In conclusion, cationic functionalization endowed NC@PDA-NH2 significant mucoadhesiveness and, thus, good potential against cervicovaginal cancer via intravaginal administration.

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“…Additionally, many studies have indicated that patients with increased iCAFs-related genes do not respond to antiangiogenic drugs in diverse types of cancers, including pancreatic ductal adenocarcinoma and TNBC (55,56). Indeed, imatinib, a well-known anticancer drug for chronic myeloid leukemia, has also been shown to inhibit the iCAFs marker PDGFRA to suppress angiogenesis in cervical carcinoma (57). This indicates that the iCAFs signature could be a useful biomarker in TNBC BRCA1 MT patients for enhance the e cacy of anti-angiogenic therapy (58, 59).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 mutation promotes sprouting angiogenesis in inflammatory cancer-associated fibroblast of triple-negative breast cancer

Fang,

Lee,

Hwang

et al. 2023

Preprint

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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with inferior outcomes owing to its low treatment response and high invasiveness. Based on abundant cancer-associated fibroblasts (CAFs) and frequent mutation of breast cancer-associated 1 (BRCA1) in TNBC, the characteristics of CAFs in TNBC patients with BRCA1 mutation compared to wild-type BRCA1 were investigated using single-cell analysis. Intriguingly, we observed a dominant presence of inflammatory CAFs (iCAFs) in BRCA1 mutation compared to the wild-type BRCA1 TNBC patients. iCAFs in patients with BRCA1 mutation exhibited strong signaling to endothelial cells (ECs) clusters, including chemokine (C-X-C motif) ligand 1 (CXCL) and vascular endothelial growth factor (VEGF). During CXCL signaling, the atypical chemokine receptor 1 (ACKR1) mainly interacts with CXCL family members in tumor endothelial cells (TECs). ACKR1-high TECs also showed high expression levels of angiogenesis related genes, such as ANGPT2, MMP1 and SELE, which might lead to EC migration. Furthermore, iCAFs showed VEGF signals for FLT1 and KDR in TECs, which showed high co-expression with tip cell marker genes, including ZEB1 and MAFF, involved in sprouting angiogenesis. Moreover, BRCA1 mutation patient with relatively abundant iCAFs and tip cell gene expression, exhibited a limited response to neoadjuvant chemotherapy, including cisplatin and bevacizumab. Importantly, our study observed the intricate link between iCAFs-mediated angiogenesis and chemoresistance in TNBC with BRCA1 mutation.

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Imatinib – eine mögliche Therapieoption beim Zervixkarzinom: Ergebnisse einer präklinischen Phase-I-Studie

Cited by 7 publications

References 67 publications

Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma

Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma

Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer

BRCA1 mutation promotes sprouting angiogenesis in inflammatory cancer-associated fibroblast of triple-negative breast cancer

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