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4 pages, 982 KiB

Open AccessProceeding Paper

Multi-Omics Analysis of NFE2L2-Altered TCGA-Cervical Squamous Cell Carcinoma Patients

by Sri Vidya Ramisetti and Akhileshwar Namani

Med. Sci. Forum 2023, 20(1), 1; https://doi.org/10.3390/IECC2023-14223 - 16 Mar 2023

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Genetic alterations in the NFE2L2 gene have been identified across various cancers, and the dysregulation of the NRF2 pathway due to these alterations leads to drug and radioresistance in several cancers. Identification of biomarkers associated with these alterations allows researchers and clinicians to [...] Read more.

Genetic alterations in the NFE2L2 gene have been identified across various cancers, and the dysregulation of the NRF2 pathway due to these alterations leads to drug and radioresistance in several cancers. Identification of biomarkers associated with these alterations allows researchers and clinicians to provide personalized medicine and a quicker diagnosis. In this current study, we carried out an integrated, multi-omics, multi-database analysis of exome and transcriptomic data of NFE2L2-altered TCGA-Cervical squamous cell carcinoma (CSCC) patients against wild-type counterparts. Finally, we discovered the genes associated with NFE2L2 alterations and identified the prognostic genes which could be used as potential biomarkers in the NFE2L2-mutated CSCC patients. Our findings might be useful in the early diagnosis of NFE2L2-mutated CSCC patients. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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4 pages, 1057 KiB

Open AccessProceeding Paper

RUNX1-Regulated Pathways and Biomarkers in Acute Myeloid Leukaemia

by Deepesh Kumar Verma, Hrishika Singh Chauhan and Akhileshwar Namani

Med. Sci. Forum 2023, 20(1), 2; https://doi.org/10.3390/IECC2023-14279 - 24 Mar 2023

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Abstract

Runt-related transcription factor 1 gene (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), plays a crucial role in the pathogenesis of AML. RUNX1/AML1 is one of the most frequently mutated leukaemias associated with a poor prognosis in AML. Researchers [...] Read more.

Runt-related transcription factor 1 gene (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), plays a crucial role in the pathogenesis of AML. RUNX1/AML1 is one of the most frequently mutated leukaemias associated with a poor prognosis in AML. Researchers and clinicians can develop personalized medicines and improve diagnosis by identifying the biomarkers associated with mutations. In the current study, we used the genome and transcriptome data from The Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-AML) cohort. We analysed RUNX1 mutant AML patients compared to non-mutant patients using an integrated multi-omics, multi-database analysis of exome, and transcriptomics data. Finally, we identified the gene signature associated with RUNX1 mutations, including prognostic genes that significantly influenced the overexpression of RUNX1 mutation-associated genes in AML patients. Our results can help to diagnose AML patients with RUNX1 mutations at an early stage. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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4 pages, 544 KiB

Open AccessProceeding Paper

Synergistic Effect of the Combination of the Recombinant Toxin DARPin-LoPE and PDT against HER2-Positive Breast Cancer In Vitro

by Liubov V. Krylova, Maria A. Karpova, Alexey A. Shulga, Elena V. Konovalova, Evgenii L. Guryev, Sergey M. Deyev and Irina V. Balalaeva

Med. Sci. Forum 2023, 20(1), 3; https://doi.org/10.3390/IECC2023-14225 - 16 Mar 2023

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Abstract

A promising strategy to enhance the therapeutic effectiveness for the treatment of oncological diseases involves the development of combined therapeutic schemes. In our work, we showed the therapeutic potential of the combined action of the anticancer targeted toxin and PDT against HER2-positive breast [...] Read more.

A promising strategy to enhance the therapeutic effectiveness for the treatment of oncological diseases involves the development of combined therapeutic schemes. In our work, we showed the therapeutic potential of the combined action of the anticancer targeted toxin and PDT against HER2-positive breast cancer in vitro. Photodynamic treatment led to photoinduced cell death with IC50 0.64 µM, and after incubation with the toxin for 48 h, IC50 was 2.8 pM. When using two therapeutic agents at IC50 doses, significant increases in the effectiveness were observed; the viability of the combination-treated cell culture did not exceed 10%. The calculated combination index was 0.07, indicating a significant synergistic effect caused by the agents. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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6 pages, 711 KiB

Open AccessProceeding Paper

Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells

by Alexander M. Scherbakov, Fedor B. Bogdanov, Alexandra L. Mikhaylova, Olga E. Andreeva and Diana I. Salnikova

Med. Sci. Forum 2023, 20(1), 4; https://doi.org/10.3390/IECC2023-14224 - 16 Mar 2023

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Abstract

More than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamoxifen (HT) [...] Read more.

More than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamoxifen (HT) halting estrogen-induced tumor growth is among the most effective drugs in current anticancer therapy. The purpose of this work was to investigate approaches to overcome breast cancer cell resistance to hydroxytamoxifen. Cells with resistance to the antiestrogen hydroxytamoxifen were obtained by long-term incubation of parental MCF7 cells with this drug. Estrogen receptor α (ERα) expression and progesterone receptor (PR) expression were analyzed by immunoblotting. The resistant MCF7/HT cells were found not to lose ERα expression. These cells were found to have slightly reduced ERα activity when compared to parental MCF7 cells. The expression of PR, one of the ERα targets, was downregulated in hydroxytamoxifen-resistant cells. AKT kinase belongs to the PI3K/AKT/mTOR signaling pathway, and its activity is associated with resistance. Three types of AKT inhibitors were evaluated, including AKT inhibitor IV (6-(2-benzothiazolyl)-1-ethyl-2-[2-(methylphenylamino)ethenyl]-3-phenyl-1H-benzimidazolium, monoiodide), 10-DEBC (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), and luminespib (HSP90 inhibitor, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide). All three compounds showed high antiproliferative activity against hydroxytamoxifen-resistant cells. The IC₅₀ value of 10-DEBC was 4.2 µM, and this was when the AKT inhibitor IV was more active with IC₅₀ value of 390 nM. The HSP90 inhibitor luminespib, which reduces AKT expression, showed the highest activity against parental and hydroxytamoxifen-resistant breast cancer cells, with IC₅₀ values of 14 and 18 nM, respectively. Thus, the hydroxytamoxifen-resistant cells were found to partially retain hormone signaling and to be sensitive to selective AKT inhibitors. The best effects were discovered for HSP90-AKT blocker luminespib, with an IC₅₀ value of about 20 nM. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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5 pages, 1284 KiB

Open AccessProceeding Paper

The Phenomenon of the Cross-Resistance of Breast Cancer to Target and Hormonal Drugs: The Role of Epigenetic Reconstruction

by Olga E. Andreeva, Yuri Y. Shchegolev, Alexander M. Scherbakov, Danila V. Sorokin, Svetlana V. Vinokurova, Alexey N. Katargin, Diana I. Salnikova and Mikhail A. Krasil’nikov

Med. Sci. Forum 2023, 20(1), 5; https://doi.org/10.3390/IECC2023-14220 - 16 Mar 2023

Cited by 1 | Viewed by 1073

Abstract

The rearrangement of molecular pathways and the activation of bypass signaling determine the progression of tumor cell resistance to various drugs that specifically block target signaling proteins. The present work was performed on the MCF-7 breast cancer cells and established sublines, resistant to [...] Read more.

The rearrangement of molecular pathways and the activation of bypass signaling determine the progression of tumor cell resistance to various drugs that specifically block target signaling proteins. The present work was performed on the MCF-7 breast cancer cells and established sublines, resistant to mTOR inhibitor rapamycin or antiestrogen tamoxifen, developed under prolonged cell treatment with rapamycin or tamoxifen, respectively. We have shown that both resistant sublines demonstrate the cross-resistance to rapamycin and tamoxifen and are characterized with the common signaling changes, namely—blocking of the estrogen receptor α (ERα) transcriptional activity and constitutive activation of Akt signaling. Analysis of the epigenetic machinery revealed the drastic suppression of the level of DNA methyltransferase 3A (DNMT3A) in both the resistant sublines that were correlated with the demethylation of the LINE-1 repeats. Knockdown of the DNMT3A via siRNA results in the progression of partial resistance of MCF-7 cells to both tamoxifen and rapamycin, supporting the important role of DNA methylation in the formation of the resistant phenotype. Totally, the results obtained highlight the possible mechanism of the tumor cell resistance to targeting/hormonal drugs based on the rearrangement of DNA methylation profile and activation of the bypass signaling pathways. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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4 pages, 206 KiB

Open AccessProceeding Paper

Novel Therapeutic Approaches for KRAS-Mutated Lung Cancer Involving LZTR1 Genetic Alteration

by Raj N. Sewduth, Tonci Ivanisevic, Peihua Zhao and Anna A. Sablina

Med. Sci. Forum 2023, 20(1), 6; https://doi.org/10.3390/IECC2023-14221 - 16 Mar 2023

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Abstract

A total of 30% of lung adenocarcinoma are driven by activating KRAS mutations. The treatment options for KRAS-mutant lung cancer are still limited as a challenge for therapy is the high heterogeneity within KRAS mutant tumors. Co-existing genetic events alter RAS signaling, such [...] Read more.

A total of 30% of lung adenocarcinoma are driven by activating KRAS mutations. The treatment options for KRAS-mutant lung cancer are still limited as a challenge for therapy is the high heterogeneity within KRAS mutant tumors. Co-existing genetic events alter RAS signaling, such as the genetic alteration of the ubiquitin ligase leucine zipper-like transcriptional regulator 1 (LZTR1). LZTR1 is an adaptor of CUL3 E3 ligase that controls the localization and expression levels of RAS proteins by regulating their ubiquitination. Recent studies demonstrated that the loss of LZTR1 leads to resistance to the tyrosine kinase inhibitor and the multi-kinase inhibitor, suggesting that LZTR1 loss might be associated with the drug resistance of KRAS-mutated lung tumors. TCGA analysis indicated that LZTR1 loss affected progression survival in KRAS mutant LUAD patients, with a significant co-occurrence of LZTR1 loss and KRAS mutations. While LZTR1 depletion in LUAD cell lines did not affect proliferation in the cell culture, the knock-out (KO) of Lztr1 in a mouse model with Kras G12D oncogenic mutations caused a clear and significant acceleration of tumor progression in the Lztr1 loss groups, indicating that Lztr1 can affect tumor onset and progression. To study the alterations of the RAS pathway triggered by LZTR1 loss, we performed a global OMICS analysis on both in vitro and in vivo systems, identifying potential therapeutic targets. The characterization of immune populations in the tumors of flow cytometry also revealed changes in immune infiltrate in the KO mouse. We are now investigating how the changes caused by Lztr1 deletion on KRAS signaling heterogeneity within tumor cells can affect the tumor microenvironment composition. Our results suggest that the dysregulation of KRAS function by Lztr1 deletion contributes to cancer progression by affecting tumor cell communication with the microenvironment. Our work could explain how Lztr1 loss can affect drug response and lead to therapy resistance. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

7 pages, 236 KiB

Open AccessProceeding Paper

Potential Candidate Gene and Underlying Molecular Mechanism Involving in Tumorigenesis of Endometriosis-Associated Ovarian Cancer (EAOC) in Asian Populations

by Rut Christine Inggriani, Che-Chang Chang and Wei-Chung Yang

Med. Sci. Forum 2023, 20(1), 7; https://doi.org/10.3390/IECC2023-14214 - 16 Mar 2023

Cited by 1 | Viewed by 1128

Abstract

Molecular aberrations in endometriosis were known to be associated with an increased risk of epithelial ovarian cancer (EOCs), especially endometrioid ovarian cancer (EnOC) and ovarian clear cell carcinoma (OCCC). Causal genetic evidence currently remains elusive. An integrated study of related prognostic markers will [...] Read more.

Molecular aberrations in endometriosis were known to be associated with an increased risk of epithelial ovarian cancer (EOCs), especially endometrioid ovarian cancer (EnOC) and ovarian clear cell carcinoma (OCCC). Causal genetic evidence currently remains elusive. An integrated study of related prognostic markers will help to identify the tumorigenesis pathways in endometriosis-associated ovarian cancer (EAOC). The objective of this study was to gain a better understanding of the tumorigenesis mechanisms that occur in the endometriosis-associated genetic variation-progressed ovarian cancer risk. We found 104 overlapping genes from the KEGG and GO results using WGCNA analysis. To determine whether the same genes were found in one or two types of the histotypes in the EAOC, we overlapped data from the WES and WGCNA results and found three genes, MYH11 (found in all histotypes), KRT5 (found in endometriosis and OCCC), and PDGFRA (found in endometriosis and EnOC). Interestingly, the MYH11 and PDGFRA are involved in the role of the actin cytoskeleton. Several proteins influence the migratory and metastatic phenotype of tumor cells, directly or indirectly, as well as myosin protein and the protein platelet-derived growth factor, suggesting an explanation for the tumorigenesis progression from endometriosis to ovarian cancer. This analysis has provided the fortification of variants for further investigation in this research. With the limitation of the computational study, it can still prove to be an asset for the identification and treatment of endometriosis-associated ovarian cancer diseases associated with the target gene. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

6 pages, 1457 KiB

Open AccessProceeding Paper

PLGA Nanoparticles Loaded with Cinnamon Extract and Coated with PVA/Poloxamer188

by Fatemeh Madani, Masood Khosravani and Mahdi Adabi

Med. Sci. Forum 2023, 20(1), 8; https://doi.org/10.3390/IECC2023-14262 - 17 Mar 2023

Cited by 1 | Viewed by 1326

Abstract

Cinnamon extract has received significant attention due to its significant antibacterial, antifungal, antioxidant, and even anti-cancer properties. The purpose of this study was to create cinnamon-extract-loaded PLGA nanoparticles and evaluate their physiochemical characteristics and cytotoxicity against the C6 cell line. Physiochemical characteristics, such [...] Read more.

Cinnamon extract has received significant attention due to its significant antibacterial, antifungal, antioxidant, and even anti-cancer properties. The purpose of this study was to create cinnamon-extract-loaded PLGA nanoparticles and evaluate their physiochemical characteristics and cytotoxicity against the C6 cell line. Physiochemical characteristics, such as the mean diameter, zeta potential, and drug loading potential, were measured. The antioxidant activity and cytotoxicity of nanoparticles were investigated by DPPH and MTT studies, respectively. The mean diameter of nanoparticles was 120 ± 24 nm. The antioxidant activity of the cinnamon extract was mostly preserved in nanoparticles and the toxicity effect on cancer cells was investigated. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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1291 KiB

Open AccessProceeding Paper

Amelioration of Glioblastoma Multiforme via the Combination of Simulated Microgravity and Oncolytic Viral Therapy

by Tarek Elshourbagy and James Robert Brašić

Med. Sci. Forum 2023, 20(1), 9; https://doi.org/10.3390/IECC2023-14219 - 16 Mar 2023

Cited by 1 | Viewed by 1105

Abstract

Glioblastoma multiforme (GBM) is the most common aggressive malignant primary brain tumor, afflicting approximately 3.19 per 100,000 persons in the United States with an incidence 1.6 times higher in males compared to females. Arising from the glial cells known as astrocytes, GBM is [...] Read more.

Glioblastoma multiforme (GBM) is the most common aggressive malignant primary brain tumor, afflicting approximately 3.19 per 100,000 persons in the United States with an incidence 1.6 times higher in males compared to females. Arising from the glial cells known as astrocytes, GBM is commonly located in the supratentorial region (cortical lobes) affecting the frontal lobes. A unique feature of this tumor is its rapid local growth and spread making the prognosis very poor with a 5-year survival rate of 6.9%. The treatment of GBM remains challenging. Multiple therapeutic interventions are used for GBM, including the surgical resection of the tumor, radiotherapy and chemotherapy. Other experimental methods for the treatment of GBM include immune therapy, gene therapy, simulated microgravity therapy and oncolytic viral therapy. We propose a combination therapy of simulated microgravity using a clinostat-based three-dimensional culture system with oncolytic viral therapy using an autonomous rat parvovirus H1. Our hypothesis combines the beneficial effects of simulated microgravity and oncolytic viral therapy to lyse tumor cells through the induction of apoptosis, decreased cell proliferation and/or the induction of an immune response. This proposal provides the foundations to construct novel breakthroughs in the treatment of GBM. Full article

(This article belongs to the Proceedings of The 3rd International Electronic Conference on Cancers: New Targets for Cancer Therapies)

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