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Pharmaceuticals
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Therapeutic Agents for the Treatment of Tumors in the CNS
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Therapeutic Agents for the Treatment of Tumors in the CNS

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 25 January 2025 | Viewed by 9183

Special Issue Editors

Dr. Gautham Gampa

E-Mail Website
Guest Editor
1. Department of Pharmaceutics, University of Minnesota Twin Cities, MN, USA
2. Genentech Inc., San Francisco, CA, USA
Interests: CNS drug delivery; oncology; pharmacokinetics/pharmacodynamics (PK/PD)
Dr. Sani H. Kizilbash

E-Mail Website
Guest Editor
Mayo Clinic, Rochester, MN, United States
Interests: gliomas; clinical trials; CNS malignancies
Dr. Shannon P. Fortin Ensign

E-Mail Website
Guest Editor
Mayo Clinic, Phoenix, AZ, USA
Interests: gliomas; brain metastases; translational research

Special Issue Information

Dear Colleagues,

This Special Issue aims to create a platform for the exchange of ideas and findings related to treatments for tumors in the central nervous system (CNS). The current shortage of disease-modifying treatments for patients with both primary and metastatic brain tumors represents one of the most significant unmet needs of our time. Our ability to effectively tap into otherwise-promising anti-cancer therapies is challenged by the blood–brain barrier, which severely restricts the entry of systemic/orally delivered therapeutic agents into the brain. We seek innovative thoughts, research, and approaches to tackling critical questions relevant to the treatment of debilitating brain tumors.

We welcome contributions at the forefront of basic and translational neuro-oncology with potential to improve the diagnosis and treatment of tumors in the brain. This Special Issue aims to highlight the latest advances in treatments with transformative potential in neuro-oncology from experts in relevant fields such as pharmaceutical sciences, neuroscience, pharmacology, medical oncology, drug delivery, and clinical neuro-surgery. Along with original research articles, we encourage authors to submit comprehensive up-to-date reviews that detail the current status of these treatments and that provide perspectives or future directions. We aim to help the scientific community in finding better treatment options for patients afflicted with devastating CNS tumors.

Dr. Gautham Gampa
Dr. Sani H. Kizilbash
Dr. Shannon P. Fortin Ensign 
Guest Editors

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. Pharmaceuticals is an international peer-reviewed open access monthly 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

  • primary brain tumors
  • glioblastoma
  • brain metastases (BMs)
  • neuro-oncology
  • blood–brain barrier (BBB)
  • drug delivery
  • preclinical PK/PD
  • molecularly targeted agents
  • immunotherapy
  • new modalities

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Published Papers (5 papers)

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Research

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15 pages, 2350 KiB  
Article
Transcranial Magnetic Stimulation Enhances the Therapeutic Effect of IGF-Trap in Intracerebral Glioma Models
by Stephanie Perrino, Udi Vazana, Ofer Prager, Lior Schori, Gal Ben-Arie, Anna Minarik, Yinhsuan Michely Chen, Orçun Haçariz, Masakazu Hashimoto, Yiftach Roth, Gabriel S. Pell, Alon Friedman and Pnina Brodt
Pharmaceuticals 2024, 17(12), 1607; https://doi.org/10.3390/ph17121607 - 28 Nov 2024
Viewed by 500
Abstract
Background: Glioblastoma multiforme is an aggressive malignancy with a dismal 5-year survival rate of 5–10%. Current therapeutic options are limited, due in part to drug exclusion by the blood–brain barrier (BBB). We have previously shown that high-amplitude repetitive transcranial magnetic stimulation (rTMS) in [...] Read more.
Background: Glioblastoma multiforme is an aggressive malignancy with a dismal 5-year survival rate of 5–10%. Current therapeutic options are limited, due in part to drug exclusion by the blood–brain barrier (BBB). We have previously shown that high-amplitude repetitive transcranial magnetic stimulation (rTMS) in rats allowed the delivery across the BBB of an IGF signaling inhibitor—IGF-Trap. The objective of this study was to assess the therapeutic effect of IGF-Trap when delivered in conjunction with rTMS on the intracerebral growth of glioma. Results: We found that systemic administration of IGF-Trap without rTMS had a minimal effect on the growth of orthotopically injected glioma cells in rats and mice, compared to control animals injected with vehicle only or treated with sham rTMS. In rats treated with a combination of rTMS and IGF-Trap, we observed a growth retardation of C6 tumors for up to 14 days post-tumor cell injection, although tumors eventually progressed. In mice, tumors were detectable in all control groups by 14–17 days post-injection of glioma GL261 cells and progressed rapidly thereafter. In mice treated with rTMS prior to IGF-Trap administration, tumor growth was inhibited or delayed, although the tumors also eventually progressed. Conclusion: The results showed that rTMS could increase the anti-tumor effect of IGF-Trap during the early phases of tumor growth. Further optimization of the rTMS protocol is required to improve survival outcomes. Full article
(This article belongs to the Special Issue Therapeutic Agents for the Treatment of Tumors in the CNS)
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15 pages, 3143 KiB  
Article
Differential Interactions of Flavonoids with the Aryl Hydrocarbon Receptor In Silico and Their Impact on Receptor Activity In Vitro
by Monique Reis de Santana, Ylanna Bonfim dos Santos, Késsia Souza Santos, Manoelito Coelho Santos Junior, Mauricio Moraes Victor, Gabriel dos Santos Ramos, Ravena Pereira do Nascimento and Silvia Lima Costa
Pharmaceuticals 2024, 17(8), 980; https://doi.org/10.3390/ph17080980 - 24 Jul 2024
Viewed by 970
Abstract
The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy [...] Read more.
The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR’s activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin’s newly described antagonistic potential. It underscores the importance of understanding flavonoid’s molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules. Full article
(This article belongs to the Special Issue Therapeutic Agents for the Treatment of Tumors in the CNS)
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16 pages, 5455 KiB  
Article
Fatty Acid Amides Suppress Proliferation via Cannabinoid Receptors and Promote the Apoptosis of C6 Glioma Cells in Association with Akt Signaling Pathway Inhibition
by Nágila Monteiro da Silva, Izabella Carla Silva Lopes, Adan Jesus Galué-Parra, Irlon Maciel Ferreira, Chubert Bernardo Castro de Sena, Edilene Oliveira da Silva, Barbarella de Matos Macchi, Fábio Rodrigues de Oliveira and José Luiz Martins do Nascimento
Pharmaceuticals 2024, 17(7), 873; https://doi.org/10.3390/ph17070873 - 2 Jul 2024
Viewed by 1278
Abstract
A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after [...] Read more.
A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after diagnosis. Due to factors such as intratumoral cell variability, inefficient chemotherapy drugs, adaptive resistance development to drugs and tumor recurrence after resection, the search continues for new drugs that can inhibit glioma cell growth. As such, analogues of endocannabinoids, such as fatty acid amides (FAAs), represent interesting alternatives for inhibiting tumor growth, since FAAs can modulate several metabolic pathways linked to cancer and, thus, may hold potential for managing glioblastoma. The aim of this study was to investigate the in vitro effects of two fatty ethanolamides (FAA1 and FAA2), synthetized via direct amidation from andiroba oil (Carapa guianensis Aublet), on C6 glioma cells. FAA1 and FAA2 reduced C6 cell viability, proliferation and migratory potential in a dose-dependent manner and were not toxic to normal retina glial cells. Both FAAs caused apoptotic cell death through the loss of mitochondrial integrity (ΔΨm), probably by activating cannabinoid receptors, and inhibiting the PI3K/Akt pathway. In conclusion, FAAs derived from natural products may have the potential to treat glioma-type brain cancer. Full article
(This article belongs to the Special Issue Therapeutic Agents for the Treatment of Tumors in the CNS)
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Review

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20 pages, 576 KiB  
Review
A Review of Therapeutic Agents Given by Convection-Enhanced Delivery for Adult Glioblastoma
by Nathaniel W. Rolfe, Nicholas B. Dadario, Peter Canoll and Jeffrey N. Bruce
Pharmaceuticals 2024, 17(8), 973; https://doi.org/10.3390/ph17080973 - 23 Jul 2024
Cited by 1 | Viewed by 1334
Abstract
Glioblastoma remains a devastating disease with a bleak prognosis despite continued research and numerous clinical trials. Convection-enhanced delivery offers researchers and clinicians a platform to bypass the blood–brain barrier and administer drugs directly to the brain parenchyma. While not without significant technological challenges, [...] Read more.
Glioblastoma remains a devastating disease with a bleak prognosis despite continued research and numerous clinical trials. Convection-enhanced delivery offers researchers and clinicians a platform to bypass the blood–brain barrier and administer drugs directly to the brain parenchyma. While not without significant technological challenges, convection-enhanced delivery theoretically allows for a wide range of therapeutic agents to be delivered to the tumoral space while preventing systemic toxicities. This article provides a comprehensive review of the antitumor agents studied in clinical trials of convection-enhanced delivery to treat adult high-grade gliomas. Agents are grouped by classes, and preclinical evidence for these agents is summarized, as is a brief description of their mechanism of action. The strengths and weaknesses of each clinical trial are also outlined. By doing so, the difficulty of untangling the efficacy of a drug from the technological challenges of convection-enhanced delivery is highlighted. Finally, this article provides a focused review of some therapeutics that might stand to benefit from future clinical trials for glioblastoma using convection-enhanced delivery. Full article
(This article belongs to the Special Issue Therapeutic Agents for the Treatment of Tumors in the CNS)
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25 pages, 964 KiB  
Review
Current Status and Challenges of Oncolytic Virotherapy for the Treatment of Glioblastoma
by Mason J. Webb, Ugur Sener and Richard G. Vile
Pharmaceuticals 2023, 16(6), 793; https://doi.org/10.3390/ph16060793 - 26 May 2023
Cited by 10 | Viewed by 3826
Abstract
Despite decades of research and numerous clinical trials, the prognosis of patients diagnosed with glioblastoma (GBM) remains dire with median observed survival at 8 months. There is a critical need for novel treatments for GBM, which is the most common malignant primary brain [...] Read more.
Despite decades of research and numerous clinical trials, the prognosis of patients diagnosed with glioblastoma (GBM) remains dire with median observed survival at 8 months. There is a critical need for novel treatments for GBM, which is the most common malignant primary brain tumor. Major advances in cancer therapeutics such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy have not yet led to improved outcomes for GBM. Conventional therapy of surgery followed by chemoradiation with or without tumor treating fields remains the standard of care. One of the many approaches to GBM therapy currently being explored is viral therapies. These typically work by selectively lysing target neoplastic cells, called oncolysis, or by the targeted delivery of a therapeutic transgene via a viral vector. In this review, we discuss the underlying mechanisms of action and describe both recent and current human clinical trials using these viruses with an emphasis on promising viral therapeutics that may ultimately break the field’s current stagnant paradigm. Full article
(This article belongs to the Special Issue Therapeutic Agents for the Treatment of Tumors in the CNS)
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