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State-of-the-Art Molecular Oncology in Brazil
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State-of-the-Art Molecular Oncology in Brazil

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 31793

Special Issue Editor

Dr. Tiago Rodrigues

E-Mail Website1 Website2
Guest Editor
Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), Santo André 09210-580, Brazil
Interests: apoptosis; autophagy; calcium; cancer; chemotherapy; mitochondria; oxidative stress; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a broad term to describe a large number of diseases characterized by the transformation of normal to abnormal tumor cells with uncontrolled proliferative capacity as a result of mutations, epigenetic alterations, exposure to toxicant and environmental conditions, and others. Tumor cells exhibit several molecular, morphological, and functional alterations, which enable them to acquire proliferative advantages, the ability to escape from the immune system and cell death, and invasiveness capacity. In this regard, many studies focused on the molecular aspects of cancer have been conducted worldwide, aiming to improve our current understanding of tumor cell functioning, to describe molecular mechanisms of therapeutic options, and to discover novel targets and drugs for cancer treatment.

This Special Issue aims to highlight recent advances in cancer research field in Brazil, focused on the molecular aspects of cancer. It includes studies conducted to unveil the molecular alterations exhibited by tumor cells, the proposal of novel targets for cancer therapy, and the mechanisms of action of drugs and drug candidates (including off-target effects and drug repurposing).

Thus, in order to provide a comprehensive view of recent advances in cancer research in Brazil, we invite researchers to submit original research papers and high-quality comprehensive reviews in the cancer research field to this Special Issue. Potential topics include but are not limited to the following:

  • Molecular aspects of tumorigenesis;
  • Mechanisms of evasion of cell death (apoptosis, necroptosis, autophagy, and others);
  • Ionic and metabolic alterations in cancer;
  • Molecular aspects of cancer therapy (mechanisms of drugs and drug candidates and new targets);
  • Drug resistance mechanisms in cancer therapy;

Prof. Dr. Tiago Rodrigues
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • apoptosis
  • autophagy
  • calcium
  • cancer
  • cell death
  • chemotherapy
  • metabolism
  • mitochondria
  • drug resistance
  • oxidative stress

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Published Papers (11 papers)

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Editorial

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3 pages, 192 KiB  
Editorial
State-of-the-Art Molecular Oncology in Brazil
by Tiago Rodrigues
Int. J. Mol. Sci. 2023, 24(11), 9452; https://doi.org/10.3390/ijms24119452 - 29 May 2023
Viewed by 1176
Abstract
Over the past few decades, the life expectancy of humankind has increased significantly due to advancements in life sciences and medical research, particularly given our increasing success in the epidemiological and pharmacological management of bacterial, fungi, and viral infections [...] Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)

Research

Jump to: Editorial, Review, Other

15 pages, 4103 KiB  
Article
Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer
by Susanne Crocamo, Renata Binato, Everton Cruz dos Santos, Bruno de Paula and Eliana Abdelhay
Int. J. Mol. Sci. 2022, 23(24), 15515; https://doi.org/10.3390/ijms232415515 - 8 Dec 2022
Cited by 3 | Viewed by 2151
Abstract
Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype [...] Read more.
Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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16 pages, 2210 KiB  
Article
A Screening of Epigenetic Therapeutic Targets for Non-Small Cell Lung Cancer Reveals PADI4 and KDM6B as Promising Candidates
by Jéssika Cristina Chagas Lesbon, Taismara Kustro Garnica, Pedro Luiz Porfírio Xavier, Arina Lázaro Rochetti, Rui Manuel Reis, Susanne Müller and Heidge Fukumasu
Int. J. Mol. Sci. 2022, 23(19), 11911; https://doi.org/10.3390/ijms231911911 - 7 Oct 2022
Cited by 3 | Viewed by 2829
Abstract
Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated [...] Read more.
Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated 38 epigenetic targets for their potential role in metastatic NSCLC. The potential candidates were ranked by a streamlined approach using in silico and in vitro experiments based on publicly available databases and evaluated by real-time qPCR target gene expression, cell viability and invasion assays, and transcriptomic analysis. The survival rate of patients with lung adenocarcinoma is inversely correlated with the gene expression of eight epigenetic targets, and a systematic review of the literature confirmed that four of them have already been identified as targets for the treatment of NSCLC. Using nontoxic doses of the remaining inhibitors, KDM6B and PADI4 were identified as potential targets affecting the invasion and migration of metastatic lung cancer cell lines. Transcriptomic analysis of KDM6B and PADI4 treated cells showed altered expression of important genes related to the metastatic process. In conclusion, we showed that KDM6B and PADI4 are promising targets for inhibiting the metastasis of lung adenocarcinoma cancer cells. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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12 pages, 1107 KiB  
Article
Analysis of Epstein–Barr Virus (EBV) and PD-L1 Expression in Nasopharyngeal Carcinoma Patients in a Non-Endemic Region
by Josiane M. Dias, Iara V. V. Santana, Vinicius D. da Silva, André L. Carvalho and Lidia M. R. B. Arantes
Int. J. Mol. Sci. 2022, 23(19), 11720; https://doi.org/10.3390/ijms231911720 - 3 Oct 2022
Cited by 5 | Viewed by 2047
Abstract
Background: The purpose of this study was to evaluate the status of Epstein–Barr virus (EBV) infection and the expression of programmed cell death ligand-1 (PD-L1) in tumor samples from patients with nasopharyngeal carcinoma (NPC). Methods: Evaluation of EBV infection was performed through the [...] Read more.
Background: The purpose of this study was to evaluate the status of Epstein–Barr virus (EBV) infection and the expression of programmed cell death ligand-1 (PD-L1) in tumor samples from patients with nasopharyngeal carcinoma (NPC). Methods: Evaluation of EBV infection was performed through the detection of EBV-encoded small ribonucleic acids (EBER) by in situ hybridization, and PD-L1 expression was performed through immunohistochemistry. Results: In total, 124 samples were evaluated for EBER and 120 for PD-L1 expression. A total of 86.3% of cases were positive for EBER and 55.8% were positive for PD-L1. There was a correlation between EBER positivity and the presence of undifferentiated carcinoma histology (p = 0.007) as well as the absence of tobacco history (p = 0.019). There was a correlation between PD-L1 expression and EBER positivity (p = 0.004). There was no statistically significant difference between overall survival (OS) and EBER (p = 0.290) or PD-L1 (p = 0.801) expression. Conclusions: This study corresponds to one of the largest cohorts of NPC in a non-endemic region. Phase III studies with checkpoint inhibitors are ongoing and may provide more data about the role of PD-L1 expression in this disease. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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15 pages, 2162 KiB  
Article
1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line
by Adrhyann Jullyanne de Sousa Portilho, Emerson Lucena da Silva, Emanuel Cintra Austregésilo Bezerra, Carinne Borges de Souza Moraes Rego Gomes, Vitor Ferreira, Maria Elisabete Amaral de Moraes, David Rodrigues da Rocha, Rommel Mário Rodriguez Burbano, Caroline Aquino Moreira-Nunes and Raquel Carvalho Montenegro
Int. J. Mol. Sci. 2022, 23(15), 8105; https://doi.org/10.3390/ijms23158105 - 23 Jul 2022
Cited by 10 | Viewed by 3212
Abstract
The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase [...] Read more.
The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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16 pages, 3028 KiB  
Article
Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines
by Renato José da Silva-Oliveira, Izabela Natalia Faria Gomes, Luciane Sussuchi da Silva, André van Helvoort Lengert, Ana Carolina Laus, Matias Eliseo Melendez, Carla Carolina Munari, Fernanda de Paula Cury, Giovanna Barbarini Longato and Rui Manuel Reis
Int. J. Mol. Sci. 2022, 23(14), 7774; https://doi.org/10.3390/ijms23147774 - 14 Jul 2022
Cited by 5 | Viewed by 2930
Abstract
Background: EGFR mutations are present in approximately 15–50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive [...] Read more.
Background: EGFR mutations are present in approximately 15–50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype. Methods: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors’ activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index. Results: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored. Conclusions: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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12 pages, 2369 KiB  
Article
Regulation of VEGFA, KRAS, and NFE2L2 Oncogenes by MicroRNAs in Head and Neck Cancer
by Caroline Izak Cuzziol, Ludimila Leite Marzochi, Vitória Scavacini Possebon, Rosa Sayoko Kawasaki-Oyama, Marlon Fraga Mattos, Vilson Serafim Junior, Letícia Antunes Muniz Ferreira, Érika Cristina Pavarino, Márcia Maria Urbanin Castanhole-Nunes and Eny Maria Goloni-Bertollo
Int. J. Mol. Sci. 2022, 23(13), 7483; https://doi.org/10.3390/ijms23137483 - 5 Jul 2022
Cited by 9 | Viewed by 2692
Abstract
Mutations and alterations in the expression of VEGFA, KRAS, and NFE2L2 oncogenes play a key role in cancer initiation and progression. These genes are enrolled not only in cell proliferation control, but also in angiogenesis, drug resistance, metastasis, and survival of [...] Read more.
Mutations and alterations in the expression of VEGFA, KRAS, and NFE2L2 oncogenes play a key role in cancer initiation and progression. These genes are enrolled not only in cell proliferation control, but also in angiogenesis, drug resistance, metastasis, and survival of tumor cells. MicroRNAs (miRNAs) are small, non-coding regulatory RNA molecules that can regulate post-transcriptional expression of multiple target genes. We aimed to investigate if miRNAs hsa-miR-17-5p, hsa-miR-140-5p, and hsa-miR-874-3p could interfere in VEGFA, KRAS, and NFE2L2 expression in cell lines derived from head and neck cancer (HNC). FADU (pharyngeal cancer) and HN13 (oral cavity cancer) cell lines were transfected with miR-17-5p, miR-140-5p, and miR-874-3p microRNA mimics. RNA and protein expression analyses revealed that miR-17-5p, miR-140-5p and miR-874-3p overexpression led to a downregulation of VEGFA, KRAS, and NFE2L2 gene expression in both cell lines analyzed. Taken together, our results provide evidence for the establishment of new biomarkers in the diagnosis and treatment of HNC. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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13 pages, 1369 KiB  
Article
miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma
by Claudio B. Murta, Tatiane K. Furuya, Alexis G. M. Carrasco, Miyuki Uno, Laura Sichero, Luisa L. Villa, Sheila F. Faraj, Rafael F. Coelho, Giuliano B. Guglielmetti, Mauricio D. Cordeiro, Katia R. M. Leite, William C. Nahas, Roger Chammas and José Pontes, Jr.
Int. J. Mol. Sci. 2022, 23(13), 7103; https://doi.org/10.3390/ijms23137103 - 26 Jun 2022
Cited by 6 | Viewed by 2333
Abstract
Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other [...] Read more.
Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA–miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA–miRNA regulation during disease progression. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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17 pages, 4073 KiB  
Article
Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells
by Najla Santos Pacheco de Campos, Adriano de Oliveira Beserra, Pedro Henrique Barbosa Pereira, Alexandre Silva Chaves, Fernando Luiz Affonso Fonseca, Tiago da Silva Medina, Tiago Goss dos Santos, Yufei Wang, Wayne Anthony Marasco and Eloah Rabello Suarez
Int. J. Mol. Sci. 2022, 23(10), 5448; https://doi.org/10.3390/ijms23105448 - 13 May 2022
Cited by 9 | Viewed by 4099
Abstract
The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to ≅108 CAR T cells/kg renewed the potential of this target to treat ccRCC and [...] Read more.
The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to ≅108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a ≅107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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Review

Jump to: Editorial, Research, Other

19 pages, 1612 KiB  
Review
Plant Kunitz Inhibitors and Their Interaction with Proteases: Current and Potential Pharmacological Targets
by Camila Ramalho Bonturi, Ana Beatriz Silva Teixeira, Vitória Morais Rocha, Penélope Ferreira Valente, Juliana Rodrigues Oliveira, Clovis Macêdo Bezerra Filho, Isabel Fátima Correia Batista and Maria Luiza Vilela Oliva
Int. J. Mol. Sci. 2022, 23(9), 4742; https://doi.org/10.3390/ijms23094742 - 25 Apr 2022
Cited by 23 | Viewed by 4394
Abstract
The action of proteases can be controlled by several mechanisms, including regulation through gene expression; post-translational modifications, such as glycosylation; zymogen activation; targeting specific compartments, such as lysosomes and mitochondria; and blocking proteolysis using endogenous inhibitors. Protease inhibitors are important molecules to be [...] Read more.
The action of proteases can be controlled by several mechanisms, including regulation through gene expression; post-translational modifications, such as glycosylation; zymogen activation; targeting specific compartments, such as lysosomes and mitochondria; and blocking proteolysis using endogenous inhibitors. Protease inhibitors are important molecules to be explored for the control of proteolytic processes in organisms because of their ability to act on several proteases. In this context, plants synthesize numerous proteins that contribute to protection against attacks by microorganisms (fungi and bacteria) and/or invertebrates (insects and nematodes) through the inhibition of proteases in these organisms. These proteins are widely distributed in the plant kingdom, and are present in higher concentrations in legume seeds (compared to other organs and other botanical families), motivating studies on their inhibitory effects in various organisms, including humans. In most cases, the biological roles of these proteins have been assigned based mostly on their in vitro action, as is the case with enzyme inhibitors. This review highlights the structural evolution, function, and wide variety of effects of plant Kunitz protease inhibitors, and their potential for pharmaceutical application based on their interactions with different proteases. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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Graphical abstract

Other

9 pages, 4615 KiB  
Case Report
Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report
by Douglas Dias e Silva, Guilherme Bes Borba, Juliana Rodrigues Beal, Gehan Botrus, Akemi Osawa, Sérgio Eduardo Alonso Araújo, Fernando Moura, Rafael Aliosha Kaliks Guendelmann and Pedro Luiz Serrano Uson Junior
Int. J. Mol. Sci. 2023, 24(4), 4209; https://doi.org/10.3390/ijms24044209 - 20 Feb 2023
Cited by 4 | Viewed by 2781
Abstract
Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and [...] Read more.
Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil)
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