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Advanced in Targeted Therapies in Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 29519

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Dr. Bulent Ozpolat

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Department of Nanomedicine, Methodist Neil Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
Interests: experimental; therapeutics; identification of novel molecular targets related to cell survival pathways, signaling pathways such as EF2-Kinase (EF2K), FOXM1, AXL, and KRAS signaling; RNA (siRNA, miRNA, lncRNA) therapeutics; nanotherapeutics/nanodelivery systems (lipid, polymer and metal-based); development of tumor targeted therapies, kinase inhibitors, immunotherapy; immunosuppressive tumor microenviorenment; tumor associated macrophages

Special Issue Information

Dear Colleagues,

In recent years, the focus of new drug development has shifted towards identifying and targeting molecular drivers of cancer. Targeted therapies have led to remarkable breakthroughs in cancer treatment and have allowed the completion or continued clinical trials of new agents for the treatment of patients with advanced cancer. In molecular-based targeted cancer therapy, the proteins or genes that drive the tumor growth and progression processes are being targeted, thereby interfering with a variety of oncogenic cellular processes. Monoclonal antibodies are commonly used as therapeutic agents for targeting various targets at the cell surface for interfering oncogenic signaling pathways and immunotherapy as immune check point inhibitors, which recently revolutionized the cancer therapy. Small molecule inhibitors are used to target intracellular kinases or other key proteins that regulate cell signaling or other signaling pathways are utilized for the treatment of primary, metastatic, and advanced therapy-resistant cancers, and currently more than 40 small molecule inhibitors have received approval from the FDA for the treatment of cancer. A wide variety of targets are currently under investigation, including those related to protein–protein interactions, cancer metabolism, and immune modulation. RNA interference (RNAi)-based therapeutics have been proven to have a great potential for the development of targeted therapies for cancer. Small interfering RNA (siRNA) and microRNA (miRNA) can inhibit the expression of any cancer-related genes/mRNAs. They both have entered clinical trials and, recently, three novel siRNA-based therapeutics were approved by the FDA. In addition, nanotechnology and nanotherapeutics proved to be extremely effective in enhancing the efficacy of the convention and targeted therapies and reducing the toxicity. Moreover, in recent years, cell-based therapies, including chimeric antigen receptor (CAR)-T cell therapy, natural killer (NK) cell therapy, dendritic cell (DC) therapy, or stem cell therapy, have also emerged as significant modalities in advanced targeted cancer therapy by targeting and eliminating malignant cells. We are pleased to invite you to a Special Issue entitled “Advanced in Targeted Therapies in Cancer” to highlight recent development in cancer therapies.

This Special Issue aims to provide insights into the strategies for advanced targeted therapies in cancer in the aspects of antibody-based therapies, small molecule inhibitors, RNAi-based therapies, and cell-based therapies, addressing the fundamentals of the approaches, challenges, recent preclinical and clinical studies, and state-of-the-art and future perspectives.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: targeted cancer therapy, small molecule inhibitors, antibody-based cancer therapies, non-coding RNA therapies ( i.e., miRNA and siRNA), cell-based therapies, nanotherapeutics, cell-based therapies, such as chimeric antigen receptor (CAR)-T cell therapy, natural killer (NK), CAR-NK cell therapy, and dendritic cell (DC) therapies.

I look forward to receiving your contributions to the Special Issue.

Dr. Bulent Ozpolat
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

targeted therapy
cancer, antibody therapy
small molecule inhibitor
RNAi therapy
cell-based therapy

Published Papers (12 papers)

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Research

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20 pages, 3555 KiB

Open AccessArticle

Uncovering Novel Roles of miR-122 in the Pathophysiology of the Liver: Potential Interaction with NRF1 and E2F4 Signaling

by Martha Paluschinski, Jessica Schira-Heinen, Rossella Pellegrino, Lara R. Heij, Jan Bednarsch, Ulf P. Neumann, Thomas Longerich, Kai Stuehler, Tom Luedde and Mirco Castoldi

Cancers 2023, 15(16), 4129; https://doi.org/10.3390/cancers15164129 - 16 Aug 2023

Viewed by 982

Abstract

MicroRNA miR-122 plays a pivotal role in liver function. Despite numerous studies investigating this miRNA, the global network of genes regulated by miR-122 and its contribution to the underlying pathophysiological mechanisms remain largely unknown. To gain a deeper understanding of miR-122 activity, we employed two complementary approaches. Firstly, through transcriptome analysis of polyribosome-bound RNAs, we discovered that miR-122 exhibits potential antagonistic effects on specific transcription factors known to be dysregulated in liver disease, including nuclear respiratory factor-1 (NRF1) and the E2F transcription factor 4 (E2F4). Secondly, through proteome analysis of hepatoma cells transfected with either miR-122 mimic or antagomir, we discovered changes in several proteins associated with increased malignancy. Interestingly, many of these proteins were reported to be transcriptionally regulated by NRF1 and E2F4, six of which we validated as miR-122 targets. Among these, a negative correlation was observed between miR-122 and glucose-6-phosphate dehydrogenase levels in the livers of patients with hepatitis B virus-associated hepatocellular carcinoma. This study provides novel insights into potential alterations of molecular pathway occurring at the early stages of liver disease, driven by the dysregulation of miR-122 and its associated genes. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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13 pages, 3398 KiB

Open AccessArticle

Therapeutic and Adverse Effect of Anti-PD1 Immunotherapy in Melanoma: A Retrospective, Single-Institute Study of 222 Patients

by Grethe Eikenes, Gabriella Liszkay, Tímea Balatoni, Kata Czirbesz, Karen Hunyadi, Zsófia Kozéki, Mihály Tamás Kispál, Fanni Baranyai, Tímea Danyi, Katalin Bőcs and István Kenessey

Cancers 2023, 15(15), 3966; https://doi.org/10.3390/cancers15153966 - 4 Aug 2023

Viewed by 1070

Abstract

Background: The introduction of immuno- and targeted therapeutic modalities meant a breakthrough step in the therapy of melanoma. As a checkpoint inhibitor, the more effective and less toxic anti-PD1 therapy followed an anti-CTLA4 approach. Methods: From our patient pool, 222 advanced melanoma cases were selected, where anti-PD1 (pembrolizumab, nivolumab) therapy was initiated between March 2015 and December 2020. During our retrospective analysis, the efficacy and safety of the therapy were assessed. Results: The median follow-up was 16 months (interval: 0–64 months), and 150 patients (67.6%) received therapy in the first line, while second and third line therapy was performed among 72 patients (32.4%) for the median of 7.0 months (0–60). In 50 cases, BRAF mutations were detected. Ninety-six patients showed objective response (11.3% CR, 32.0% PR). The median PFS was 10.0 months (0–60), and the median OS was 23.0 months (0–64). Autoimmune side effects were found in 79 patients (35.5%); grade 3 occurred in 6.3% of the cases, while 1 patient died due to fulminant pneumonitis (0.25%). Conclusion: Although the range of immunotherapeutic options is getting wider, in the management of melanoma patients, anti-PD1 monotherapy remains an important, effective, and safe method. However, significant correlation was found between the immune-related side effects and therapeutic efficacy. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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20 pages, 5456 KiB

Open AccessArticle

The Redox-Active Manganese(III) Porphyrin, MnTnBuOE-2-PyP⁵⁺, Impairs the Migration and Invasion of Non-Small Cell Lung Cancer Cells, Either Alone or Combined with Cisplatin

by Rita B. Soares, Rita Manguinhas, João G. Costa, Nuno Saraiva, Nuno Gil, Rafael Rosell, Sérgio P. Camões, Ines Batinic-Haberle, Ivan Spasojevic, Matilde Castro, Joana P. Miranda, Paula Guedes de Pinho, Ana S. Fernandes and Nuno G. Oliveira

Cancers 2023, 15(15), 3814; https://doi.org/10.3390/cancers15153814 - 27 Jul 2023

Cited by 1 | Viewed by 1425

Abstract

Manganese(III) porphyrin MnTnBuOE-2-PyP⁵⁺ (MnBuOE, BMX-001) is a third-generation redox-active cationic substituted pyridylporphyrin-based drug with a good safety/toxicity profile that has been studied in several types of cancer. It is currently in four phase I/II clinical trials on patients suffering from glioma, head and neck cancer, anal squamous cell carcinoma and multiple brain metastases. There is yet an insufficient understanding of the impact of MnBuOE on lung cancer. Therefore, this study aims to fill this gap by demonstrating the effects of MnBuOE on non-small cell lung cancer (NSCLC) A549 and H1975 cell lines. The cytotoxicity of MnBuOE alone or combined with cisplatin was evaluated by crystal violet (CV) and/or 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-Tetrazolium (MTS) reduction assays. Intracellular ROS levels were assessed using two fluorescent probes. Furthermore, the impact of MnBuOE alone or in combination with cisplatin on collective cell migration, individual chemotactic migration and chemoinvasion was assessed using the wound-healing and transwell assays. The expression of genes related to migration and invasion was assessed through RT-qPCR. While MnBuOE alone decreased H1975 cell viability at high concentrations, when combined with cisplatin it markedly reduced the viability of the more invasive H1975 cell line but not of A549 cell line. However, MnBuOE alone significantly decreased the migration of both cell lines. The anti-migratory effect was more pronounced when MnBuOE was combined with cisplatin. Finally, MnBuOE alone or combined with cisplatin significantly reduced cell invasion. MnBuOE alone or combined with cisplatin downregulated MMP2, MMP9, VIM, EGFR and VEGFA and upregulated CDH1 in both cell lines. Overall, our data demonstrate the anti-metastatic potential of MnBuOE for the treatment of NSCLC. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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Review

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19 pages, 1229 KiB

Open AccessReview

PIM3 Kinase: A Promising Novel Target in Solid Cancers

by Pinar Atalay and Bulent Ozpolat

Cancers 2024, 16(3), 535; https://doi.org/10.3390/cancers16030535 - 26 Jan 2024

Cited by 1 | Viewed by 1234

Abstract

PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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18 pages, 1004 KiB

Open AccessReview

The Potential of Siglecs and Sialic Acids as Biomarkers and Therapeutic Targets in Tumor Immunotherapy

by Haokang Feng, Jiale Feng, Xu Han, Ying Ying, Wenhui Lou, Liang Liu and Lei Zhang

Cancers 2024, 16(2), 289; https://doi.org/10.3390/cancers16020289 - 10 Jan 2024

Viewed by 1708

Abstract

The dysregulation of sialic acid is closely associated with oncogenesis and tumor progression. Most tumor cells exhibit sialic acid upregulation. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors that recognize sialic acid and are expressed in various immune cells. The activity of Siglecs in the tumor microenvironment promotes immune escape, mirroring the mechanisms of the well-characterized PD-1/PD-L1 pathway in cancer. Cancer cells utilize sialic acid-linked glycans to evade immune surveillance. As Siglecs exhibit similar mechanisms as the established immune checkpoint inhibitors (ICIs), they are potential therapeutic targets for different forms of cancer, especially ICI-resistant malignancies. Additionally, the upregulation of sialic acid serves as a potential tumor biomarker. This review examines the feasibility of using sialic acid and Siglecs for early malignant tumor detection and discusses the potential of targeting Siglec–sialic acid interaction as a novel cancer therapeutic strategy. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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24 pages, 1060 KiB

Open AccessReview

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers

by Jiaxuan Xu, Xiaoqing Dong, David C. S. Huang, Peipei Xu, Quan Zhao and Bing Chen

Cancers 2023, 15(20), 4957; https://doi.org/10.3390/cancers15204957 - 12 Oct 2023

Cited by 2 | Viewed by 2228

Abstract

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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15 pages, 662 KiB

Open AccessReview

Breaking the ‘Undruggable’ Barrier: Anti-PD-1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer Patients with KRAS Mutations—A Comprehensive Review and Description of Single Site Experience

by Izabela Chmielewska, Paweł Krawczyk, Anna Grenda, Magdalena Wójcik-Superczyńska, Natalia Krzyżanowska, Michał Gil and Janusz Milanowski

Cancers 2023, 15(14), 3732; https://doi.org/10.3390/cancers15143732 - 23 Jul 2023

Cited by 2 | Viewed by 2229

Abstract

Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations are among the most commonly found oncogenic alterations in non-small cell lung cancer (NSCLC) patients. Unfortunately, KRAS mutations have been considered “undruggable” for many years, making treatment options very limited. Immunotherapy targeting programmed death-ligand 1 (PD-L1), programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has emerged as a promising therapeutic option for NSCLC patients. However, some studies have suggested a lower response rate to immunotherapy in KRAS-mutated NSCLC patients with the coexistence of mutations in the STK11 (Serine/Threonine Kinase 11) gene. However, recent clinical trials have shown promising results with the combination of immunotherapy and chemotherapy or immunotherapy and KRAS inhibitors (sotorasib, adagrasib) in such patients. In other studies, the high efficacy of immunotherapy has been demonstrated in NSCLC patients with mutations in the KRAS gene that do not coexist with other mutations or coexist with the TP53 gene mutations. In this paper, we review the available literature on the efficacy of immunotherapy in KRAS-mutated NSCLC patients. In addition, we presented single-site experience on the efficacy of immunotherapy in NSCLC patients with KRAS mutations. The effectiveness of chemoimmunotherapy or immunotherapy as well as KRAS inhibitors extends the overall survival of advanced NSCLC patients with the G12C mutation in the KRAS gene to 2–3 years. This type of management has become the new standard in the treatment of NSCLC patients. Further studies are needed to clarify the potential benefits of immunotherapy in KRAS-mutated NSCLC patients and to identify potential biomarkers that may help predict response to therapy. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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27 pages, 2172 KiB

Open AccessReview

CAR-T Cells Immunotherapies for the Treatment of Acute Myeloid Leukemia—Recent Advances

by Julia Zarychta, Adrian Kowalczyk, Milena Krawczyk, Monika Lejman and Joanna Zawitkowska

Cancers 2023, 15(11), 2944; https://doi.org/10.3390/cancers15112944 - 27 May 2023

Cited by 5 | Viewed by 4157

Abstract

In order to increase the effectiveness of cancer therapies and extend the long-term survival of patients, more and more often, in addition to standard treatment, oncological patients receive also targeted therapy, i.e., CAR-T cells. These cells express a chimeric receptor (CAR) that specifically binds an antigen present on tumor cells, resulting in tumor cell lysis. The use of CAR-T cells in the therapy of relapsed and refractory B-type acute lymphoblastic leukemia (ALL) resulted in complete remission in many patients, which prompted researchers to conduct tests on the use of CAR-T cells in the treatment of other hematological malignancies, including acute myeloid leukemia (AML). AML is associated with a poorer prognosis compared to ALL due to a higher risk of relapse caused by the development of resistance to standard treatment. The 5-year relative survival rate in AML patients was estimated at 31.7%. The objective of the following review is to present the mechanism of action of CAR-T cells, and discuss the latest findings on the results of anti-CD33, -CD123, -FLT3 and -CLL-1 CAR-T cell therapy, the emerging challenges as well as the prospects for the future. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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13 pages, 817 KiB

Open AccessReview

The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

by Toby A. Eyre and John C. Riches

Cancers 2023, 15(9), 2596; https://doi.org/10.3390/cancers15092596 - 3 May 2023

Cited by 7 | Viewed by 3220

Abstract

The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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22 pages, 2892 KiB

Open AccessReview

The Chromatin Remodeler ATRX: Role and Mechanism in Biology and Cancer

by Ying Pang, Xu Chen, Tongjie Ji, Meng Cheng, Rui Wang, Chunyu Zhang, Min Liu, Jing Zhang and Chunlong Zhong

Cancers 2023, 15(8), 2228; https://doi.org/10.3390/cancers15082228 - 10 Apr 2023

Cited by 6 | Viewed by 3393

Abstract

The alpha-thalassemia mental retardation X-linked (ATRX) syndrome protein is a chromatin remodeling protein that primarily promotes the deposit of H3.3 histone variants in the telomere area. ATRX mutations not only cause ATRX syndrome but also influence development and promote cancer. The primary molecular characteristics of ATRX, including its molecular structures and normal and malignant biological roles, are reviewed in this article. We discuss the role of ATRX in its interactions with the histone variant H3.3, chromatin remodeling, DNA damage response, replication stress, and cancers, particularly gliomas, neuroblastomas, and pancreatic neuroendocrine tumors. ATRX is implicated in several important cellular processes and serves a crucial function in regulating gene expression and genomic integrity throughout embryogenesis. However, the nature of its involvement in the growth and development of cancer remains unknown. As mechanistic and molecular investigations on ATRX disclose its essential functions in cancer, customized therapies targeting ATRX will become accessible. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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18 pages, 1720 KiB

Open AccessReview

Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy

by David Andreu-Sanz and Sebastian Kobold

Cancers 2023, 15(6), 1650; https://doi.org/10.3390/cancers15061650 - 8 Mar 2023

Cited by 7 | Viewed by 4191

Abstract

Historically, CD8⁺ T cells have been considered the most relevant effector cells involved in the immune response against tumors and have therefore been the focus of most cancer immunotherapy approaches. However, CD4⁺ T cells and their secreted factors also play a crucial role in the tumor microenvironment and can orchestrate both pro- and antitumoral immune responses. Depending on the cytokine milieu to which they are exposed, CD4⁺ T cells can differentiate into several phenotypically different subsets with very divergent effects on tumor progression. In this review, we provide an overview of the current knowledge about the role of the different T helper subsets in the immune system, with special emphasis on their implication in antitumoral immune responses. Furthermore, we also summarize therapeutic applications of each subset and its associated cytokines in the adoptive cell therapy of cancer. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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15 pages, 666 KiB

Open AccessReview

Molecular Heterogeneity in BRAF-Mutant Gliomas: Diagnostic, Prognostic, and Therapeutic Implications

by Benoit Lhermitte, Thibaut Wolf, Marie Pierre Chenard, Andres Coca, Julien Todeschi, François Proust, Edouard Hirsch, Roland Schott, Georges Noel, Eric Guerin, Damien Reita, Agathe Chammas, Alexandra Salmon, Sophie Martin, Monique Dontenwill and Natacha Entz-Werlé

Cancers 2023, 15(4), 1268; https://doi.org/10.3390/cancers15041268 - 16 Feb 2023

Cited by 3 | Viewed by 2209

Abstract

Over the last few decades, deciphering the alteration of molecular pathways in brain tumors has led to impressive changes in diagnostic refinement. Among the molecular abnormalities triggering and/or driving gliomas, alterations in the MAPK pathway reign supreme in the pediatric population, as it is encountered in almost all low-grade pediatric gliomas. Activating abnormalities in the MAPK pathway are also present in both pediatric and adult high-grade gliomas. Across those alterations, BRAF p.V600E mutations seem to define homogeneous groups of tumors in terms of prognosis. The recent development of small molecules inhibiting this pathway retains the attention of neurooncologists on BRAF-altered tumors, as conventional therapies showed no significant effect, nor prolonged efficiency on the high-grade or low-grade unresectable forms. Nevertheless, tumoral heterogeneity and especially molecular alteration(s) associated with MAPK-pathway abnormalities are not fully understood with respect to how they might lead to the specific dismal prognosis of those gliomas and/or affect their response to targeted therapies. This review is an attempt to provide comprehensive information regarding molecular alterations related to the aggressiveness modulation in BRAF-mutated gliomas and the current knowledge on how to use those targeted therapies in such situations. Full article

(This article belongs to the Special Issue Advanced in Targeted Therapies in Cancer)

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