Research

16 pages, 3786 KiB

Open AccessArticle

RTK25: A Comprehensive Molecular Profiling Strategy in Cholangiocarcinoma Using an Integrated Bioinformatics Approach

by Brinda Balasubramanian, Simran Venkatraman, Tavan Janvilisri, Tuangporn Suthiphongchai, Siriporn Jitkaew, Jittiyawadee Sripa and Rutaiwan Tohtong

Pharmaceuticals 2021, 14(9), 898; https://doi.org/10.3390/ph14090898 - 03 Sep 2021

Cited by 6 | Viewed by 2845

Abstract

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that primarily originate from the bile duct. Tumor heterogeneity is a prime characteristic of CCA and considering the scarcity of approved targeted therapy drugs, this makes precision oncology impractical in CCA. Stratifying patients based on [...] Read more.

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that primarily originate from the bile duct. Tumor heterogeneity is a prime characteristic of CCA and considering the scarcity of approved targeted therapy drugs, this makes precision oncology impractical in CCA. Stratifying patients based on their molecular signature and biomarker-guided therapy may offer a conducive solution. Receptors tyrosine kinases (RTK) are potential targets for novel therapeutic strategies in CCA as RTK signaling is dysregulated in CCA. This study aims to identify targetable RTK profile in CCA using a bioinformatic approach. We discovered that CCA samples could be grouped into molecular subtypes based on the gene expression profile of selected RTKs (RTK25). Using the RTK25 gene list, we discovered five distinct molecular subtypes of CCA in this cohort. Tyrosine kinase inhibitors that target each RTK profile and their subsequent molecular signatures were also discovered. These results suggest that certain RTKs correlate with each other, indicating that tailored dual inhibition of RTKs may be more favorable than monotherapy. The results from this study can direct future investigative attention towards validating this concept in in vivo and in vitro systems. Ultimately, this will facilitate biomarker-guided clinical trials for the successful approval of novel therapeutic options in CCA. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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16 pages, 2290 KiB

Open AccessArticle

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma

by Nelly Etienne-Selloum, Julien Prades, Diana Bello-Roufai, Mathieu Boone, Henri Sevestre, Stéphanie Trudel, Pascal Caillet, Alexandre Coutte, Christine Desenclos, Jean-Marc Constans, Sophie Martin, Laurence Choulier, Bruno Chauffert and Monique Dontenwill

Pharmaceuticals 2021, 14(9), 882; https://doi.org/10.3390/ph14090882 - 30 Aug 2021

Cited by 3 | Viewed by 2039

Abstract

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the [...] Read more.

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031–2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168–4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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17 pages, 1117 KiB

Open AccessArticle

Actinomycin D Arrests Cell Cycle of Hepatocellular Carcinoma Cell Lines and Induces p53-Dependent Cell Death: A Study of the Molecular Mechanism Involved in the Protective Effect of IRS-4

by Luis G. Guijarro, Patricia Sanmartin-Salinas, Eva Pérez-Cuevas, M. Val Toledo-Lobo, Jorge Monserrat, Sofia Zoullas, Miguel A. Sáez, Miguel Angel Álvarez-Mon, Julia Bujan, Fernando Noguerales-Fraguas, Eduardo Arilla-Ferreiro, Melchor Álvarez-Mon and Miguel A. Ortega

Pharmaceuticals 2021, 14(9), 845; https://doi.org/10.3390/ph14090845 - 25 Aug 2021

Cited by 5 | Viewed by 3233

Abstract

Actinomycin D (ActD) is an FDA-approved NCI oncology drug that specifically targets and downregulates stem cell transcription factors, which leads to a depletion of stem cells within the tumor bulk. Recently, our research group demonstrated the importance of IRS-4 in the development of [...] Read more.

Actinomycin D (ActD) is an FDA-approved NCI oncology drug that specifically targets and downregulates stem cell transcription factors, which leads to a depletion of stem cells within the tumor bulk. Recently, our research group demonstrated the importance of IRS-4 in the development of liver cancer. In this study, we evaluated the protective effects of IRS-4 against ActD. For this study, three hepatocellular carcinoma cell lines (HepG2, Huh7, and Chang cells) were used to study the mechanism of actinomycin D. Most assays were carried out in the Hep G2 cell line, due to the high expression of stem cell biomarkers. We found that ActD caused HepG2 cell necroptosis characterized by DNA fragmentation, decreased mitochondrial membrane potential, cytochrome c depletion, and decreased the levels of reduced glutathione. However, we did not observe a clear increase in apoptosis markers such as annexin V presence, caspase 3 activation, or PARP fragmentation. ActD produced an activation of MAP kinases (ERK, p38, and JNK) and AKT. ActD-induced activation of AKT and MAP kinases produced an activation of the Rb-E2F cascade together with a blockage of cell cycle transitions, due to c-jun depletion. ActD led to the inhibition of pCdK1 and pH3 along with DNA fragmentation resulting in cell cycle arrest and the subsequent activation of p53-dependent cell death in the HepG2 cell line. Only JNK and AKT inhibitors were protective against the effects of ActD. N-Acetyl-L-cysteine also had a protective effect as it restored GSH levels. A likely mechanism for this is IRS-4 stimulating GCL-GSH and inhibiting the Brk-CHK1-p53 pathway. The assessment of the IRS-4 in cancer biopsies could be of interest to carry out a personalized treatment with ActD. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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13 pages, 1970 KiB

Open AccessArticle

The Positive Correlations between the Expression of Histopathological Ubiquitin-Conjugating Enzyme 2O Staining and Prostate Cancer Advancement

by Jae-Heon Kim, Hee-Jo Yang, Chang-Ho Lee, Youn-Soo Jeon, Jae-Joon Park, Kwang-Woo Lee, Jae-Ho Kim, Su-Yeon Park, Su-Jung Song, Yon-Hee Kim, Ah-Rim Moon, Ji-Hye Lee and Yun-Seob Song

Pharmaceuticals 2021, 14(8), 778; https://doi.org/10.3390/ph14080778 - 08 Aug 2021

Cited by 3 | Viewed by 1885

Abstract

Background: The mTOR signaling pathway is inactivated by AMPK’s tumor-suppressing function. It is recognized that ubiquitin conjugating enzyme 2O (UBE2O), which directly targets AMPK for ubiquitination and degradation, is intensified in human cancers. Methods: This study investigated the clinical data about prostate cancer. [...] Read more.

Background: The mTOR signaling pathway is inactivated by AMPK’s tumor-suppressing function. It is recognized that ubiquitin conjugating enzyme 2O (UBE2O), which directly targets AMPK for ubiquitination and degradation, is intensified in human cancers. Methods: This study investigated the clinical data about prostate cancer. Examination was also carried out into tissue microarrays (TMA) of human prostate cancer (n = 382) and adjacent non-neoplastic tissues around prostate cancer (n = 61). The TMA slides were incubated with antibodies against UBE2O, and the cores were scored by the pathologist blind to cancer results. Results: Very strong positive correlations were identified between the expression of UBE2O staining and high PSA and pathological stage of prostate cancer. Cox’s proportional hazard analysis established correlations between the following: (1) positive surgical margin and biochemical recurrence free survival, (2) PSA grade and clinical recurrence free survival, (3) regional lymph node positive and clinical recurrence free survival, (4) adjuvant treatment and overall survival, and (5) pathological T stage and overall survival. Conclusion: There is a positive correlation between the expression of UBE2O staining and prognosis for prostate cancer. Thus, a prostate cancer prognosis can be assessed with the expression of UBE2O staining. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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13 pages, 870 KiB

Open AccessArticle

GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients

by Clemens Schotten, Bastian Ostertag, Jan-Peter Sowa, Paul Manka, Lars P. Bechmann, Gudrun Hilgard, Claudio Marquardt, Marc Wichert, Hidenori Toyoda, Christian M. Lange, Ali Canbay, Philip Johnson, Heiner Wedemeyer and Jan Best

Pharmaceuticals 2021, 14(8), 735; https://doi.org/10.3390/ph14080735 - 27 Jul 2021

Cited by 25 | Viewed by 3880

Abstract

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, [...] Read more.

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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12 pages, 1916 KiB

Open AccessArticle

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer

by Gianluca Tedaldi, Chiara Molinari, Celina São José, Rita Barbosa-Matos, Ana André, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Luca Saragoni, Paolo Morgagni, Francesca Rebuzzi, Matteo Canale, Sara Pignatta, Elisa Ferracci, Giovanni Martinelli, Guglielmina Nadia Ranzani, Carla Oliveira, Daniele Calistri and Paola Ulivi

Pharmaceuticals 2021, 14(5), 457; https://doi.org/10.3390/ph14050457 - 12 May 2021

Cited by 12 | Viewed by 2969

Abstract

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter [...] Read more.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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9 pages, 1169 KiB

Open AccessCommunication

The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer

by Zachary Heinzman, Connor Schmidt, Marek K. Sliwinski and Nalin C. W. Goonesekere

Pharmaceuticals 2021, 14(3), 209; https://doi.org/10.3390/ph14030209 - 03 Mar 2021

Cited by 2 | Viewed by 1877

Abstract

The high mortality rate for pancreatic cancer (PC) is due to the lack of specific symptoms at early tumor stages and a high biological aggressiveness. Reliable biomarkers and new therapeutic targets would help to improve outlook in PC. In this study, we analyzed [...] Read more.

The high mortality rate for pancreatic cancer (PC) is due to the lack of specific symptoms at early tumor stages and a high biological aggressiveness. Reliable biomarkers and new therapeutic targets would help to improve outlook in PC. In this study, we analyzed the expression of GNMT in a panel of pancreatic cancer cell lines and in early-stage paired patient tissue samples (normal and diseased) by quantitative reverse transcription-PCR (qRT-PCR). We also investigated the effect of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a therapeutic agent for PC. We find that GNMT is markedly downregulated (p < 0.05), in a majority of PC cell lines. Similar results are observed in early-stage patient tissue samples, where GNMT expression can be reduced by a 100-fold or more. We also show that PGG is a strong inhibitor of PC cell proliferation, with an IC₅₀ value of 12 ng/mL, and PGG upregulates GNMT expression in a dose-dependent manner. In conclusion, our data show that GNMT has promise as a biomarker and as a therapeutic target for PC. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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20 pages, 3447 KiB

Open AccessArticle

Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

by Zohaib Rana, Joel D. A. Tyndall, Muhammad Hanif, Christian G. Hartinger and Rhonda J. Rosengren

Pharmaceuticals 2021, 14(2), 103; https://doi.org/10.3390/ph14020103 - 29 Jan 2021

Cited by 10 | Viewed by 2121

Abstract

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the [...] Read more.

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G₀/G₁ arrest in AR-null cells, whereas Jazz167 leads to a G₀/G₁ arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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9 pages, 649 KiB

Open AccessArticle

Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk

by Micaela Almeida, Mafalda Soares, José Fonseca-Moutinho, Ana Cristina Ramalhinho and Luiza Breitenfeld

Pharmaceuticals 2021, 14(2), 94; https://doi.org/10.3390/ph14020094 - 27 Jan 2021

Cited by 5 | Viewed by 2242

Abstract

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact [...] Read more.

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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14 pages, 931 KiB

Open AccessArticle

Evaluation of Tissue and Circulating miR-21 as Potential Biomarker of Response to Chemoradiotherapy in Rectal Cancer

by Susana Ourô, Cláudia Mourato, Marisa P. Ferreira, Diogo Albergaria, André Cardador, Rui E. Castro, Rui Maio and Cecília M. P. Rodrigues

Pharmaceuticals 2020, 13(9), 246; https://doi.org/10.3390/ph13090246 - 14 Sep 2020

Cited by 2 | Viewed by 2869

Abstract

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (RC) is quite variable and it is urgent to find predictive biomarkers of response. We investigated miR-21 as tissue and plasma biomarker of response to CRT in a prospective cohort of RC [...] Read more.

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (RC) is quite variable and it is urgent to find predictive biomarkers of response. We investigated miR-21 as tissue and plasma biomarker of response to CRT in a prospective cohort of RC patients; The expression of miR-21 was analyzed in pre- and post-CRT rectal tissue and plasma in 37 patients with RC. Two groups were defined: Pathological responders (TRG 0, 1 and 2) and non-responders (TRG 3). The association between miR-21, clinical and oncological outcomes was assessed; miR-21 was upregulated in tumor tissue and we found increased odds of overexpression in pre-CRT tumor tissue (OR: 1.63; 95% CI: 0.40–6.63, p = 0.498) and pre-CRT plasma (OR: 1.79; 95% CI: 0.45–7.19, p = 0.414) of non-responders. The overall recurrence risk increased with miR-21 overexpression in pre-CRT tumor tissue (HR: 2.175, p = 0.37); Significantly higher miR-21 expression is observed in tumor tissue comparing with non-neoplastic. Increased odds of non-response is reported in patients expressing higher miR-21, although without statistical significance. This is one of the first studies on circulating miR-21 as a potential biomarker of response to CRT in RC patients. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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Review

Jump to: Research, Other

27 pages, 2197 KiB

Open AccessReview

Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

by Lucas Cruz, Paula Soares and Marcelo Correia

Pharmaceuticals 2021, 14(9), 848; https://doi.org/10.3390/ph14090848 - 26 Aug 2021

Cited by 31 | Viewed by 4454

Abstract

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action [...] Read more.

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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19 pages, 3666 KiB

Open AccessReview

LRP1B: A Giant Lost in Cancer Translation

by Catarina Príncipe, Isabel J. Dionísio de Sousa, Hugo Prazeres, Paula Soares and Raquel T. Lima

Pharmaceuticals 2021, 14(9), 836; https://doi.org/10.3390/ph14090836 - 24 Aug 2021

Cited by 24 | Viewed by 4535

Abstract

Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes [...] Read more.

Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes in human cancer overall. Found frequently inactivated by several genetic and epigenetic mechanisms, it has mostly been regarded as a putative tumor suppressor. Still, limitations in LRP1B studies exist, in particular associated with its huge size. Therefore, LRP1B expression and function in cancer remains to be fully unveiled. This review addresses the current understanding of LRP1B and the studies that shed a light on the LRP1B structure and ligands. It goes further in presenting increasing knowledge brought by technical and methodological advances that allow to better manipulate LRP1B expression in cells and to more thoroughly explore its expression and mutation status. New evidence is pushing towards the increased relevance of LRP1B in cancer as a potential target or translational prognosis and response to therapy biomarker. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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21 pages, 1886 KiB

Open AccessReview

Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis

by Laura Sofia Carvalho, Nélio Gonçalves, Nuno André Fonseca and João Nuno Moreira

Pharmaceuticals 2021, 14(1), 60; https://doi.org/10.3390/ph14010060 - 13 Jan 2021

Cited by 25 | Viewed by 6188

Abstract

Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth [...] Read more.

Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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23 pages, 2543 KiB

Open AccessReview

First line Immunotherapy for Non-Small Cell Lung Cancer

by Nicola J. Nasser, Miguel Gorenberg and Abed Agbarya

Pharmaceuticals 2020, 13(11), 373; https://doi.org/10.3390/ph13110373 - 08 Nov 2020

Cited by 50 | Viewed by 11576

Abstract

Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The [...] Read more.

Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 < 50% are candidates for immunotherapy with pembrolizumab as a single agent if PL-1 > 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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76 pages, 4014 KiB

Open AccessReview

Autophagy as a Potential Therapy for Malignant Glioma

by Angel Escamilla-Ramírez, Rosa A. Castillo-Rodríguez, Sergio Zavala-Vega, Dolores Jimenez-Farfan, Isabel Anaya-Rubio, Eduardo Briseño, Guadalupe Palencia, Patricia Guevara, Arturo Cruz-Salgado, Julio Sotelo and Cristina Trejo-Solís

Pharmaceuticals 2020, 13(7), 156; https://doi.org/10.3390/ph13070156 - 19 Jul 2020

Cited by 54 | Viewed by 6341

Abstract

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, [...] Read more.

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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Other

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9 pages, 585 KiB

Open AccessCase Report

Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature

by Ottavia Bernocchi, Marianna Sirico, Silvia Paola Corona, Carla Strina, Manuela Milani, Maria Rosa Cappelletti, Giuseppina Ferrero, Nicoletta Ziglioli, Valeria Cervoni, Andrea Macchiavelli, Giandomenico Roviello and Daniele Generali

Pharmaceuticals 2021, 14(2), 159; https://doi.org/10.3390/ph14020159 - 16 Feb 2021

Cited by 5 | Viewed by 3177

Abstract

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting [...] Read more.

Background: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. Discussion: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. Conclusions: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with. Full article

(This article belongs to the Special Issue Cancer Translational Biomarkers and Targeted Therapies)

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