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. The 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 172 overlapping genes that changed both at the DNA and RNA levels from the literature summary of whole exome sequencing and RNA expression from GEO databases. Furthermore, we use KEGG pathways to determine a significant pathway among the gene variants. KEGG includes 50 genes that have significant enrichment pathways. In order to find genes that are specifically expressed in ovary tissue, we prioritize genes using the GTEx database. Based on their TPKM levels, we found 7 genes that were highly expressed in ovary tissue. The genes found were COL12A1, PDGFRA, C7, MYH11, MMP2, C3, and FOS. Interestingly, MYH11 was found in each sample histotype and 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, suggesting an explanation of tumorigenesis progression in endometriosis to ovarian cancer. Through this analysis, it has attempted to provide variants fortified for future in vivo research through this analysis. More importantly, a comprehensive study of endometriosis-associated diseases associated with ovarian cancer may open new possibilities for identifying and treating these diseases.

Lung Cancer has taken over all cancers in terms of diagnosis and mortality worldwide, which is why it is on the World Health Organisation’s (WHO) priority list. As per the data reported by the WHO, cancer has caused 10 million death each year, and lung cancer alone caused 1.80 million deaths in 2020. Also, the FDA has approved almost 100 drugs against lung cancer, but it is not curable as most drugs target a single protein or block a single pathway. In this study, we screened the Drug Bank library against three major proteins- Ribosomal protein S6 kinase alpha-6, Cyclic-dependent protein kinase-2, and Insulin-like growth factor-1 of lung cancer- and identified the compound 5-Nitroindazole as a multitargeted inhibitor that potentially can treat lung cancer. For the screening, we deployed multisampling algorithms such as HTVS, SP and XP, followed by the MM\GBSA calculation, and the study was extended to molecular fingerprinting analysis, ADMET calculations and Molecular Dynamics simulation analysis to understand the complex’s stability. The docking scores against the proteins 6G77, 1AQ1 and 1K3A were -6.884 Kcal/mol, -7.515 Kcal/mol and -6.754 Kcal/mol, respectively, considered in a good scoring category. Also, the compound has shown all the values satisfying the ADMET criteria, and the fingerprint analysis has shown wide similarities. The molecular dynamics of each complex have shown a cumulative deviation of less than 2 Å, which is considered best for the biomolecules, especially for the protein-ligand complexes. The best feature of the proposed drug candidate is that it targets multiple proteins of lung cancer at the same time, the chance of developing resistance is relatively less, and it drastically can reduce the burden of the pharma industry.

Decitabine (DAC) is an anti-cancer hypomethylating drug used to activate silenced genes by promoter demethylation. DAC induced the expression of the New York esophageal squamous cell carcinoma (NY-ESO-1), a highly immunogenic cancer testis antigen known to induce both humoral and cellular immune responses. However, DAC would increase Programmed Death Ligand-1 (PD-L1) expression in tumor cells leading to resistance to cancer therapy. Vitamin C (Vit-C) is a novel epigenetic regulator of DNA demethylation and is capable of downregulating transcription factors involved in the modulation of PD-L1 expression. Therefore, our major aim is to investigate whether Vit-C could improve the effect of DAC by reducing PD-L1 and to determine the effect of a combination of Vit-C and DAC in colorectal cancer cells.

We treated the HCT-116 colon cancer cell line with DAC (20 µM) and Vit-C (1 mM) alone or in combination for 48h, then cell proliferation was assessed using CCK-8. The differential expression of immune-regulatory and pro-apoptotic markers was quantified using Western Blotting and quantitative real-time PCR. Cell apoptosis and cell cycle profile were analyzed using flow cytometry.

Treatment with DAC alone induces the expression of NY-ESO-1 and upregulates the expression of PD-L1 at mRNA and protein levels compared to untreated cells. Interestingly, the combination of Vit-C with DAC decreased significantly PD-L1 expression compared to DAC alone. Further, the cytotoxic effect of DAC was primarily due to apoptosis shown by overexpression of caspase 8 and cleavage of PARP and caspase 3. This apoptotic effect was confirmed by FACS and was enhanced when Vit-C was used in combination with DAC.

Vit-C prevented the upregulation of PD-L1 and enhanced the cytotoxic effect of the chemotherapeutic drug DAC. Our findings suggest Vit-C as an attractive adjuvant therapy that will promote the immune response and help to overcome immune resistance to DAC in colon cancer patients.

Adipose-derived stem cells (rADSC) play a multifaceted role in cancer metabolism and constitute a potential target for oncologic therapies. Local delivery of TNF-related apoptosis-inducing ligand (TRAIL) can limit tumour growth by selective binding to the death receptor (DR5) in cancer cells. In most healthy cells this pathway is blocked by decoy antagonists such as osteoprotegerin (OPG). This in-vitro study aimed to evaluate an oncologic treatment based on the delivery of TRAIL-transduced rADSC to the vicinity of breast adenocarcinoma cells.

A plasmid containing transgene was produced using the Cloning HD system(TakaraBio) based on Plvx-EF1a-IRES-PURO plasmid and amplified TRAIL gene from the Sprague-Dawley rat kidney. Lentiviral particles were produced using VSV-G Single Shots(TakaraBio) in HEK293T cells. Cytotoxicity of TRAIL against rADSC and RBA (rat adenocarcinoma of the mammary gland) was measured using MTS Assay. Quantitative PCR and Western Blot analyses were conducted to confirm transgene overexpression and measure OPG and DR5 expression in both cell lines. Direct cytotoxicity of RBA cells to transduced rADSC was measured using exposure to a supernatant of TRAIL-expressing rADSC. Data analysis was done using the student’s t-test.

Cells were successfully transduced, and TRAIL expression was 400-fold higher in transduced cells (P<0.01) than in controls. The expression of TRAIL-dependent receptors was higher in rADSC (OPG – 30-fold (P<0.01) and DR5 - 6-fold (P<0.05)). RBA cells were susceptible to exogenous TRAIL and the cell supernatant – IC50 was equal to 200 ng/ml, while rADSC were resistant to TRAIL.

The results show that TRAIL-transduced rADSC are cytotoxic against adenocarcinoma cells. Overexpression of TRAIL by rADSC also stimulates their growth leading to an increased cancer microenvironment penetration. Such active surveillance based on stable local production of anticancer cytokine can limit cancer recurrence when transplanted into the vicinity of cancer tissue.

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. GBM usually arises from the glial cells known as astrocytes and it is commonly located in the supratentorial region (cortical lobes),usually affecting the frontal lobe. A unique feature of this tumor is its rapid local growth and spread making the prognosis very poor with a 5-year survival rate less than 5 %.Treatment of GBM remains challenging. Multiple therapeutic interventions are used for GBM including 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 an oncolytic viral therapy using an autonomous rat parvovirus H-1 (H-1PV). Our hypothesis combines the beneficial effects of simulated microgravity and oncolytic viral therapy to lyse tumor cells through induction of apoptosis, decreased cell proliferation and or induction of an immune response. This proposal provides the foundations to construct novel breakthroughs in the treatment of GBM.

Earlier we have shown that prolonged treatment of MCF-7 breast cancer cells with mTOR inhibitors, rapamycin or metformin, results in the development of the resistant clones that characterized with constitutive activation of growth-related pathways. Because the activation of bypass growth signaling is among the key features of the acquired hormonal resistance we proposed the existence of the common mechanisms respondent for formation of the cell resistance to both mTOR-targeting and hormonal agents.

The experiments were performed on the MCF-7 breast cancer cells and rapamycin- and tamoxifen-resistant sublines developed under prolonged treatment of the parent cells with rapamycin or tamoxifen, respectively. The comparative analysis of the cell sensitivity to indicated drugs revealed the high level of cross-resistance to rapamycin and tamoxifen in the both sublines. Similar to rapamycin-resistant subline, the tamoxifen-resistant cells were characterized with the constitutive activation of PI3K/Akt signaling along with the suppression of estrogen receptor activity. Analysis of the epigenetic machinery revealed the common features in the expression of DNA methyltransferases: significant suppression of the DNMT3A expression in the both resistant sublines, which correlated with a global change in DNA methylation detected by demethylation of LINE-1 elements. Knockdown of the DNMT3A by siRNA resulted in the partial resistance of the MCF-7 cells to tamoxifen and rapamycin. 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 changes in the epigenetic regulation of cell signaling.

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 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 its 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 cell culture, the knock-out (KO) of Lztr1 in a mouse model with Kras G12D oncogenic mutation 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 by 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 the tumor cells, can affect the tumor microenvironment composition. Our results suggest that 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 the drug response and lead to therapy resistance.

Metastasis is a major problem in the management of cancer, remaining as the principal cause of cancer death. Despite recent advances, treatment options are still limited. Naphthalimide (1H-benzo[de]isoquinoline-1,3-(2H)-dione) analogs have been considered as promising anticancer agents against different tumor types. However, antimetastatic potential of naphthalimides has not been previously established. The aim of this work was to evaluate the possible antimetastatic activity of a panel of 21 naphthalimides which were synthesized in the laboratory. We studied the inhibitory effects of these compounds on cancer proliferation, clonogenicity and cell cycle progression. We identified 5 naphthalimides with a potent and selective inhibition of growth in SW620 metastatic cells compared to CRL1790 non-tumoral ones. In addition, these 5 naphthalimides induced a significant arrest at S and G2/M phase in SW620 cells. Finally, we selected the leading compound 20B, which inhibited clonogenic expansion in SW620 cells even at 10 µM. These results shed light on 20B naphthalimide as an emerging antimetastatic agent. Future studies are required to determine its mechanism of action.

Cervical cancer is the fourth most common cancer amongst women, accounting for approximately 6.5% of all female cancer cases globally. The Cancer Genome Atlas (TCGA) is a public funded project that aims to catalogue and discover major cancer-causing genomic alterations to create a comprehensive “atlas” of cancer genomic profiles. NFE2L2 is a gene which encodes for the transcription factor NRF2 (nuclear factor erythroid 2-related factor) which is the key regulator of oxidative stress in normal cells. Mutations in NFE2L2 gene have been identified across many cancers including cervical squamous cell carcinoma (CSCC) and the dysregulation of the NRF2 pathway due to these mutations leads to tumorigenesis, drug and radioresistance. Identification of biomarkers associated with these mutations allows the researchers and clinicians to identify the personalized medicine and quicker diagnosis. In our current study, we carried out an integrated, multi-omics, multi-database analysis of exome, transcriptomics data's of NFE2L2 mutated TCGA- Cervical squamous cell carcinoma patients against non-mutated counterparts. Finally, we discovered the genes associated with NFE2L2 mutations, identified the prognostic genes which could be used as potential biomarkers in the NFE2L2 mutated CSCC patients. Our finding might be useful to identify the early diagnosis of NFE2L2 mutated CSCC patients.

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

Cells with resistance to antiestrogen hydroxytamoxifen were obtained by long-term incubation of parental MCF7 cells with this drug. Estrogen receptor α expression was analyzed by immunoblotting. The resistant MCF7/HT cells were found not to lose ERα expression. These cells were found to have fairly high ERα activity, as assessed by reporter gene assays. Akt kinase belongs to the PI3K/Akt/mTOR signaling pathway, its increased activity was detected in resistant cells. 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, when 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 an IC₅₀ value of 14 and 18 nM respectively. Thus, the obtained hydroxytamoxifen-resistant cells were found to partially retain hormone signaling. Increased Akt activity was observed in resistant cells, which associated with their sensitivity to selective Akt inhibitors. The best effects were discovered for HSP90-Akt blocker luminespib with IC₅₀ value of about 20 nM.