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Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment.

ABSTRACT: For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) miR-634 functions as a negative modulator of the cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. In the present study, we found that topical application of an ointment containing miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2, a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo. Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC.

SUBMITTER: Inoue J

PROVIDER: S-EPMC7695908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Improving the efficacy of EGFR inhibitors by topical treatment of cutaneous squamous cell carcinoma with miR-634 ointment

Project description:For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for or refuse surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) miR-634 functions as a negative modulator of cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. Here, we found that topical application of an ointment containing miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a DMBA/TPA-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2, a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo. Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC.

2020-12-15 | GSE159093 | GEO

Improving the efficacy of EGFR inhibitors by topical treatment of cutaneous squamous cell carcinoma with miR-634 ointment

Project description:Improving the efficacy of EGFR inhibitors by topical treatment of cutaneous squamous cell carcinoma with miR-634 ointment

| PRJNA667692 | ENA

Augmentation of lenvatinib efficacy by topical treatment of <i>miR-634</i> ointment in anaplastic thyroid cancer.

Project description:Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin. We previously demonstrated that the topical application of an ointment incorporating tumor suppressive microRNA (TS-miR), miR-634, is a useful strategy as a TS-miR therapeutics. Here, we found that the overexpression of miR-634 synergistically increased lenvatinib-induced cytotoxicity by concurrently downregulating multiple genes related to cytoprotective processes, including ASCT2, a glutamine transporter, in ATC cell lines. Furthermore, the topical application of a miR-634 ointment on subcutaneous tumors effectively augmented the anti-tumor effects of lenvatinib in an ATC xenograft mouse model. Thus, we propose topical treatment of a miR-634 ointment as a rational strategy for improving lenvatinib-based therapy for ATC.

| S-EPMC8131394 | biostudies-literature

Topical kinase inhibitors induce regression of cutaneous squamous cell carcinoma.

Project description:Actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS) are precursor lesions for cutaneous squamous cell carcinoma (cSCC), the second most common form of cancer. Current topical therapies for AKs and SCCIS promote skin inflammation to eradicate lesions and do not directly target the biological mechanisms driving growth. We hypothesized that topical small molecule inhibitors targeting kinases promoting keratinocyte growth in AKs and SCCIS could induce regression of these lesions with less inflammation. To test this hypothesis, we determined the efficacy of topical dasatinib, 5-fluorouracil and BEZ-235 in inducing regression of cSCCs in the K14-Fyn Y528 transgenic mouse model. Topical dasatinib induced regression of cSCC with less inflammation, no ulceration and no mortality compared to 5-fluorouracil. Topical BEZ-235 induced cSCC regression similar to dasatinib without erythema or ulceration. These data indicate that topical small molecule kinase inhibitors targeting drivers of AK/SCCIS/cSCC growth represent a promising therapeutic approach to treat these common skin lesions.

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miR-27a Downregulation Promotes Cutaneous Squamous Cell Carcinoma Progression via Targeting EGFR.

Project description:Cutaneous squamous cell carcinoma (cSCC) is the second common malignant cancer around the worldwide and is etiologically linked to ultraviolet radiation. miRNAs play an important role in the initiation and progression of cancers. However, the functions of miRNAs in cSCC remain to be elucidated. Here, we screened and identified miR-27a as a consistently downregulated miRNA after UVB irradiation in HaCaT cells. It was found that miR-27a expression was significantly decreased in cSCC cells and tissues. in vitro and in vivo experiments showed that miR-27a inhibited cell proliferation and invasion of cSCC cells. Mechanistically, EGFR was identified to be directly targeted by miR-27a and miR-27a suppressed the phosphorylation of EGFR and its downstream NF-?B signaling pathway. Overall, these findings suggest that downregulation of miR-27a promotes tumor growth and metastasis via targeting EGFR and its downstream NF-?B signaling pathway, reminding that miR-27a plays a vital role in the progression of cSCC and could be a new therapeutic target.

| S-EPMC6985147 | biostudies-literature

Potential for reversing <i>miR-634</i>-mediated cytoprotective processes to improve efficacy of chemotherapy against oral squamous cell carcinoma.

Project description:For advanced oral squamous cell carcinoma (OSCC), increasing sensitivity to chemotherapy is a major challenge in improving treatment outcomes, and targeting cytoprotective processes that lead to the chemotherapy resistance of cancer cells may be therapeutically promising. Tumor-suppressive microRNAs (miRNAs) can target multiple cancer-promoting genes concurrently and are thus expected to be useful seeds for cancer therapeutics. We revealed that miR-634-mediated targeting of multiple cytoprotective process-related genes, including cellular inhibitor of apoptosis protein 1 (cIAP1), can effectively increase cisplatin (CDDP)-induced cytotoxicity and overcome CDDP resistance in OSCC cells. The combination of topical treatment with miR-634 ointment and administration of CDDP was synergistically effective against OSCC tumor growth in a xenograft mouse model. Furthermore, the expression of miR-634 target genes is frequently upregulated in primary OSCC tumors. Our study suggests that reversing miR-634-mediated cytoprotective processes activated in cancer cells is a potentially useful strategy to improve CDDP efficacy against advanced OSCC.

| S-EPMC9073396 | biostudies-literature

Therapeutic potential for reversing miR-634-mediated cytoprotective processes to improve the efficacy of chemotherapy against oral squamous cell carcinoma

Project description:For advanced oral squamous cell carcinoma (OSCC), increasing sensitivity to chemotherapy is a major challenge in improving treatment outcomes, and targeting cytoprotective processes that lead to the chemotherapy resistance of cancer cells may be therapeutically promising. Tumor-suppressive microRNAs (miRs) can target multiple cancer-promoting genes concurrently, and are thus expected to be useful seeds for cancer therapeutics. We revealed that miR-634-meditated targeting of multiple cytoprotective process-related genes, including cellular inhibitor of apoptosis proteins 1 (cIAP1), can effectively increase cisplatin (CDDP)-induced cytotoxicity and overcome CDDP resistance in OSCC cells. The combination of topical treatment with miR-634 ointment and administration of CDDP was synergistically effective against OSCC-tumor growth in a xenograft mouse model. Furthermore, the expression of miR-634 target genes is frequently upregulated in primary OSCC tumors. Our study suggests that reversing miR-634-mediated cytoprotective processes activated in cancer cells is a potentially useful strategy to improve CDDP efficacy against advanced OSCC.

2022-05-25 | GSE194269 | GEO

A novel onco-miR-365 induces cutaneous squamous cell carcinoma.

Project description:The expression levels of miR-365 vary in different malignancies. Herein, we found that miR-365 was overexpressed in both cells and clinical specimens of cutaneous squamous cell carcinoma (SCC). We demonstrated that the HaCaT(pre-miR-365-2) cell line, which overexpressed miR-365, could induce subcutaneous tumors in vivo. Antagomir-365, an anti-miR-365 oligonucleotide, inhibited cutaneous tumor formation in vivo, along with G1 phase arrest and apoptosis of cancer cells. These findings suggest that miR-365 may act as an onco-miR in cutaneous SCC both in vitro and in vivo. The present study provides valuable insight into the role of miR-365 in cutaneous SCC formation, which can help develop new drug and miR-365 target-based therapies for cutaneous SCC.

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Treatment of Cutaneous Squamous Cell Carcinoma With the Topical Histone Deacetylase Inhibitor Remetinostat.

Project description: Not available

| S-EPMC8600452 | biostudies-literature

The efficacy of alum sitz baths followed by topical gall ointment in hemorrhoids—a single-arm clinical trial

Project description:Hemorrhoidal disease is one of the most common gastrointestinal ailments affecting life quality of the patients. Unani classical literature is replete with anti-hemorrhoidal drugs, but scientific evidence is lacking. Therefore, Safūf Zāj (powdered alum) and Marham-e-Māzū (gall ointment) having potent anti-hemorrhoidal actions were selected to evaluate their efficacy in hemorrhoids. This clinical trial was conducted on 30 participants with hemorrhoids, aged > 18 years. All the participants received Safūf Zāj for sitz baths and Marham-e-Māzū to be applied twice daily for 2 weeks. Primary outcome measures were: change in pain intensity, anal itching, and defecate discomfort assessed on 100 mm VAS scale and per-rectal bleeding assessed on 4-point scale. Secondary outcome measures were: change in the size of the external hemorrhoidal mass assessed on 5-point scale, grade of internal hemorrhoid assessed by Goligher classification and quality of life (QoL) assessed on SF-12 questionnaire. The per-protocol analysis was done on 30 participants and statistically significant improvement was seen in primary and secondary outcome measures. Moreover, both the mental and psychological components of QoL were improved. The study inferred that therapeutic approach of Safūf Zāj and Marham-e-Mazu is safe and efficacious in hemorrhoids. Future studies with well-designed RCTs are highly recommended. Supplementary Information The online version contains supplementary material available at 10.1007/s13596-022-00634-6.

| S-EPMC8819210 | biostudies-literature

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