A Synopsis of Biomarkers in Glioblastoma: Past and Present.

Accounting for 48% of malignant brain tumors in adults, glioblastoma has been of great interest in the last decades, especially in the biomolecular and neurosurgical fields, due to its incurable nature and notable neurological morbidity. The major advancements in neurosurgical technologies have positively influenced the extent of safe tumoral resection, while the latest progress in the biomolecular field of GBM has uncovered new potential therapeutical targets. Although GBM currently has no curative therapy, recent progress has been made in the management of this disease, both from surgical and molecular perspectives. The main current therapeutic approach is multimodal and consists of neurosurgical intervention, radiotherapy, and chemotherapy, mostly with temozolomide. Although most patients will develop treatment resistance and tumor recurrence after surgical removal, biomolecular advancements regarding GBM have contributed to a better understanding of this pathology and its therapeutic management. Over the past few decades, specific biomarkers have been discovered that have helped predict prognosis and treatment responses and contributed to improvements in survival rates.

An Overview of Systemic Targeted Therapy in Renal Cell Carcinoma, with a Focus on Metastatic Renal Cell Carcinoma and Brain Metastases.

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have many effective therapies until the end of the 1980s, as long as hormonal therapy and chemotherapy were the only options available. The outcomes were unsatisfactory due to the poor effectiveness of the available therapeutic options, but then interferon-alpha and interleukin-2 showed treatment effectiveness, providing benefits but only for less than half of the patients. However, it was not until 2004 that targeted therapies emerged, prolonging the survival rate. Currently, new technologies and strategies are being developed to improve the actual efficacy of available treatments and their prognostic aspects. This article summarizes the mechanisms of action, importance, benefits, adverse events of special interest, and efficacy of immunotherapy in metastatic renal cell carcinoma, with a focus on brain metastases.

An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma.

Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood-brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.

Oncogenic Signalling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities.

Cancer is a common name for several distinct diseases caused by uncontrolled cell growth and proliferation [...].

Glioblastoma Stem Cells-Useful Tools in the Battle against Cancer.

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.

Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy.

Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.

Transcriptomic Crosstalk between Gliomas and Telencephalic Neural Stem and Progenitor Cells for Defining Heterogeneity and Targeted Signaling Pathways.

Recent studies have begun to reveal surprising levels of cell diversity in the human brain, both in adults and during development. Distinctive cellular phenotypes point to complex molecular profiles, cellular hierarchies and signaling pathways in neural stem cells, progenitor cells, neuronal and glial cells. Several recent reports have suggested that neural stem and progenitor cell types found in the developing and adult brain share several properties and phenotypes with cells from brain primary tumors, such as gliomas. This transcriptomic crosstalk may help us to better understand the cell hierarchies and signaling pathways in both gliomas and the normal brain, and, by clarifying the phenotypes of cells at the origin of the tumor, to therapeutically address their most relevant signaling pathways.

ELTD1-An Emerging Silent Actor in Cancer Drama Play.

The epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 (ELTD1), is a member of the G-protein coupled receptors (GPCRs) superfamily. Although discovered in 2001, ELTD1 has been investigated only by a few research groups, and important data about its role in normal and tumor cells is still missing. Even though its functions and structure are not yet fully understood, recent studies show that ELTD1 has a role in both physiological and pathological angiogenesis, and it appears to be a very important biomarker and a molecular target in cancer diseases. Upregulation of ELTD1 in malignant cells has been reported, and correlated with poor cancer prognosis. This review article aims to compile the existing data and to discuss the current knowledge on ELTD1 structure and signaling, and its role in physiological and neoplastic conditions.

The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer.

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types.

ß-arrestin 1 transfection induced cell death in high grade glioma in vitro.

The best known functions of ß-arrestins (ß-arr) are to regulate G protein-coupled receptors (GPCR) signaling through receptor desensitization and internalization. Many reports also suggest that ß-arrs play important role in immune regulation and inflammatory responses, under physiological and pathological conditions. Recent studies have shown that ß-arr 1 silencing halts proliferation and increases temozolomide (TMZ) response in glioblastoma (GBM) cells. The focus of this paper is to analyze the role of ß-arr 1 overexpression in the 18 high grade glioma (HGG) cell line in terms of viability and their response to TMZ treatment. For this reason, the cell line was transfected with ß-arr 1 and the effect was analyzed after 24 h, 48 h and 72 h in terms of proliferation and treatment response. We observed that ß-arr 1 overexpression induced a time and dose dependant inhibition in the HGG cells. Unexpectedly, ß-arr transfection resulted in a very mild increase in TMZ toxicity after 24 h, becoming non-statistically significant at 72 h. In conclusion, we showed that ß-arr 1 overexpression inhibits cell proliferation in the 18 cell line but only has a very modest effect on treatment response with the alkylating agent TMZ.

The effect of temozolomide in combination with doxorubicin in glioblastoma cells in vitro.

BACKGROUND: Prior to 2000, the DNA alkylating agents nitrosoureas were used as standard treatment of glioblastoma. Current treatments for glioblastoma patients consist of surgery followed by radiation in combination with temozolomide. Despite therapeutic advances, the prognosis for glioblastoma patients remains grim, with a five-year overall survival below 15%. In this study, our team analyzed the interaction between temozolomide and doxorubicin in a glioblastoma cell line, in vitro. MATERIALS AND METHOD: The cell line, established from a patient who underwent surgery at the "Bagdasar Arseni Emergency Hospital", was exposed to 10 µM and 100 µM of temozolomide and 10 nM and 100 nM of doxorubicin, respectively, over a period of 7, 10 and 14 days, in monotherapy and in combination. RESULTS: The results showed that both temozolomide (66.5% cytotoxicity for the 10 µM dose at 14 days) de and doxorubicin (66.8% cytotoxicity for the 10 nM dose after 14 days) were very effective in killing cancer cells in monotherapy, but failed to produce a synergistic effect when used in combination. CONCLUSION: While the results may be discouraging, they present an interesting prospect into how certain drug interactions can impact treatment response.

Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches.

From all central nervous system tumors, gliomas are the most common. Nowadays, researchers are looking for more efficient treatments for these tumors, as well as ways for early diagnosis. Receptor tyrosine kinases (RTKs) are major targets for oncology and the development of small-molecule RTK inhibitors has been proven successful in cancer treatment. Mutations or aberrant activation of the RTKs and their intracellular signaling pathways are linked to several malignant diseases, including glioblastoma. The progress in the understanding of malignant glioma evolution has led to RTK targeted therapies with high capacity to improve the therapeutic response while reducing toxicity. In this review, we present the most important RTKs (i.e. EGFR, IGFR, PDGFR and VEGFR) currently used for developing cancer therapeutics together with the potential of RTK-related drugs in glioblastoma treatment. Also, we focus on some therapeutic agents that are currently at different stages of research or even in clinical phases and proved to be suitable as re-purposing candidates for glioblastoma treatment.

Assessment of efficacy of dendritic cell therapy and viral therapy in high grade glioma clinical trials. A meta-analytic review.

In recent years, immunotherapy has raised the interest of many studies and provided different perspectives for the therapeutic management of high grade glioma. Our meta-analysis focused on the effectiveness of dendritic cell (DC) therapy and viral therapy (VT) in clinical trials. Fourteen eligible studies have been evaluated and the results suggest the improvement of both OS (HR = 0.65) (p < 0.0001) and PFS (HR = 0.59) (p = 0.01) for patients receiving DC therapy. The data for VT showed a slight improvement in terms of OS (HR = 0.81), while PFS was similar to the control arms (HR = 1.06) (p = 0.41).

Platelet-Derived Growth Factor Receptor and Ionizing Radiation in High Grade Glioma Cell Lines.

Treatment of high grade gliomas (HGGs) has remained elusive due to their high heterogeneity and aggressiveness. Surgery followed by radiotherapy represents the mainstay of treatment for HGG. However, the unfavorable location of the tumor that usually limits total resection and the resistance to radiation therapy are the major therapeutic problems. Chemotherapy with DNA alkylating agent temozolomide is also used to treat HGG, despite modest effects on survival. Disregulation of several growth factor receptors (GFRs) were detected in HGG and receptor amplification in glioblastoma has been suggested to be responsible for heterogeneity propagation through clonal evolution. Molecularly targeted agents inhibiting these membrane proteins have demonstrated significant cytotoxicity in several types of cancer cells when tested in preclinical models. Platelet-derived growth factor receptors (PDGFRs) and associated signaling were found to be implicated in gliomagenesis, moreover, HGG commonly display a Platelet-derived growth factor (PDGF) autocrine pathway that is not present in normal brain tissues. We have previously shown that both the susceptibility towards PDGFR and the impact of the PDGFR inactivation on the radiation response were different in different HGG cell lines. Therefore, we decided to extend our investigation, using two other HGG cell lines that express PDGFR at the cell surface. Here, we investigated the effect of PDGFR inhibition alone or in combination with gamma radiation in 11 and 15 HGG cell lines. Our results showed that while targeting the PDGFR represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment. The PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways are the major signaling pathways emerging from the GFRs, including PDGFR. Decreased sensitivity to radiation-induced cell death are often associated with redundancy in these pro-survival signaling pathways. Here we found that Phosphoinositide 3-kinases (PI3K), Extracellular-signal-regulated kinase 1/2 (ERK1/2), or c-Jun N-terminal kinase 1/2 (JNK1/2) inactivation induced radiosensitivity in HGG cells.

Current and emerging EGFR therapies for glioblastoma.

Glioblastomas (GBMs) are the most lethal and hard to treat malignancies in clinical practice. The standard of care for treating GBM involving surgery and adjuvant radiotherapy and concomitant temozolomide (TMZ) has remained virtually unchanged in the past decade. Molecular targeted therapies against cancer-specific structures have reported mediocre results in the treatment of GBM, due to multiple factors such as the presence of the blood brain barrier or a vast array of molecular alterations which greatly hinder the action of the most therapeutic agents. One such therapy is directed against the epidermal growth factor (EGF) and its' receptor (EGFR) using either monoclonal antibodies or tyrosine kinase inhibitors. Even though anti-EGF/EGFR treatment produced encouraging results in other forms of cancer it failed to present any clinical benefit for patients with GBM. Lately, immunotherapies that focus on using the host's own immune system against cancer cells have gained popularity, with approaches like peptide vaccination being successfully used in clinical trials for different types of malignancies. These immune-based therapies could hold the key to improving both the prognosis and quality of life for patients suffering for cancers previously considered incurable, such as GBM.

The Influence of EGFR Inactivation on the Radiation Response in High Grade Glioma.

Lack of effectiveness of radiation therapy may arise from different factors such as radiation induced receptor tyrosine kinase activation and cell repopulation; cell capability to repair radiation induced DNA damage; high grade glioma (HGG) tumous heterogeneity, etc. In this study, we analyzed the potential of targeting epidermal growth factor receptor (EGFR) in inducing radiosensitivity in two human HGG cell lines (11 and 15) that displayed similar growth patterns and expressed the receptor protein at the cell surface. We found that 15 HGG cells that express more EGFR at the cell surface were more sensitive to AG556 (an EGFR inhibitor), compared to 11 HGG cells. Although in line 15 the effect of the inhibitor was greater than in line 11, it should be noted that the efficacy of this small-molecule EGFR inhibitor as monotherapy in both cell lines has been modest, at best. Our data showed a slight difference in the response to radiation of the HGG cell lines, three days after the treatment, with line 15 responding better than line 11. However, both cell lines responded to ionizing radiation in the same way, seven days after irradiation. EGFR inhibition induced radiosensitivity in 11 HGG cells, while, in 15 HGG cells, the effect of AG556 treatment on radiation response was almost nonexistent.

Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma.

The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis.

In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor-α, TNF-α) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti-cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP3.1, anti-cardiolipin IgG isotype, IgG anti-aCL) in serum of patients with eRA (early rheumatoid arthritis) and HCVrA (hepatitis C virus-related arthropathy) and to assess the utility of IL-6, TNF-α together with IgG anti-CCP and IgM-RF in distinguishing between patients with true eRA and HCVrA, in the idea of using them as differential immunomarkers. Serum samples were collected from 54 patients (30 diagnosed with eRA-subgroup 1 and 24 with HCVrA-subgroup 2) and from 28 healthy control persons. For the evaluation of serum concentrations of studied cytokines and auto-antibodies, we used immunoenzimatique techniques. The serum concentrations of both proinflammatory cytokines were statistically significantly higher in patients of subgroup 1 and subgroup 2, compared to the control group (p < 0.0001). Our study showed statistically significant differences of the mean concentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup 2. We also observed that IL-6 and TNF-α better correlated with auto-antibodies in subgroup 1 than in subgroup 2. In both subgroups of patients, ROC curves indicated that IL-6 and TNF-α have a higher diagnostic utility as markers of disease. In conclusion, we can say that, due to high sensitivity for diagnostic accuracy, determination of serum concentrations of IL-6 and TNF-α, possibly in combination with auto-antibodies, could be useful in the diagnosis and distinguishing between patients with true eRA and HCV patients with articular manifestation and may prove useful in the monitoring of the disease course.

New perspectives in glioblastoma antiangiogenic therapy.

Glioblastoma (GB) is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade). Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo. Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease.

Cancer stem cells: biological functions and therapeutically targeting.

Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.