Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized.

Cyclic Peptides in Pipeline: What Future for These Great Molecules?

Cluster of differentiation 36 (CD36) is a cell surface scavenger receptor that plays critical roles in many different types of cancer, notably breast, brain, and ovarian cancers. While it is arguably most well-known for its fatty acid uptake functions, it is also involved in regulating cellular adhesion, immune response, and apoptosis depending on the cellular and environmental contexts. Here, we discuss the multifaceted role of CD36 in cancer biology, such as its role in mediating metastasis, drug resistance, and immune evasion to showcase its potential as a therapeutic target. We will also review existing approaches to targeting CD36 in pre-clinical studies, as well as discuss the only CD36-targeting drug to advance to late-stage clinical trials, VT1021. Given the roles of CD36 in the etiology of metabolic disorders, such as atherosclerosis, diabetes, and non-alcoholic fatty liver disease, the clinical implications of CD36-targeted therapy are wide-reaching, even beyond cancer.

/pdf/the-role-of-cd36-in-cancer-progression-and-its-value-as-a-3cbqix0a.pdf

The Role of CD36 in Cancer Progression and Its Value as a Therapeutic Target

Glioblastoma (GBM) is one of the most aggressive tumors of the central nervous system, characterized by a wide range of inter- and intratumor heterogeneity. Accumulation of fatty acids (FA) metabolites was associated with a low survival rate in high-grade glioma patients. The diversity of brain lipids, especially polyunsaturated fatty acids (PUFAs), is greater than in all other organs and several classes of proteins, such as FA transport proteins (FATPs), and FA translocases are considered principal candidates for PUFAs transport through BBB and delivery of PUFAs to brain cells. Among these, the CD36 FA translocase promotes long-chain FA uptake as well as oxidated lipoproteins. Moreover, CD36 binds and recognizes thrombospondin-1 (TSP-1), an extracellular matrix protein that was shown to play a multifaceted role in cancer as part of the tumor microenvironment. Effects on tumor cells are mediated by TSP-1 through the interaction with CD36 as well as CD47, a member of the immunoglobulin superfamily. TSP-1/CD47 interactions have an important role in the modulation of glioma cell invasion and angiogenesis in GBM. Separately, FA, the two membrane receptors CD36, CD47, and their joint ligand TSP-1 all play a part in GBM pathogenesis. The last research has put in light their interconnection/interrelationship in order to exert a cumulative effect in the modulation of the GBM molecular network.

/pdf/fatty-acids-cd36-thrombospondin-1-and-cd47-in-glioblastoma-1hyu7txo.pdf

Fatty Acids, CD36, Thrombospondin-1, and CD47 in Glioblastoma: Together and/or Separately?

A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

Lipid droplets provide metabolic flexibility for cancer progression.

Abstract Hepatocellular carcinoma is the prevailing malignant neoplasm affecting the liver, often diagnosed at an advanced stage and associated with an unfavorable overall prognosis. Sorafenib and Lenvatinib have emerged as first-line therapeutic drugs for advanced hepatocellular carcinoma, improving the prognosis for these patients. Nevertheless, the issue of tyrosine kinase inhibitor (TKI) resistance poses a substantial obstacle in the management of advanced hepatocellular carcinoma. The pathogenesis and advancement of hepatocellular carcinoma exhibit a close association with metabolic reprogramming, yet the attention given to lipid metabolism dysregulation in hepatocellular carcinoma development remains relatively restricted. This review summarizes the potential significance and research progress of lipid metabolism dysfunction in Sorafenib and Lenvatinib resistance in hepatocellular carcinoma. Targeting hepatocellular carcinoma lipid metabolism holds promising potential as an effective strategy to overcome hepatocellular carcinoma drug resistance in the future.

Advances in Targeted Drug Resistance Associated with Dysregulation of Lipid Metabolism in Hepatocellular Carcinoma

Background VT1021, a cyclic pentapeptide, reprograms myeloid-derived suppressor cells (MDSCs) and induces the production of thrombospondin-1 (Tsp-1) in the tumor microenvironment (TME). Tsp-1, via binding to CD36 and CD47, induces apoptosis in tumor and endothelial cells, blocks the ‘do-not-eat-me’ signal, increases the M1:M2 macrophage ratio and activates cytotoxic T lymphocytes (CTLs). Preclinical studies showed robust anti-tumor activities of VT1021 in multiple animal models. Methods This is a first-in-human, Ph 1/2, open-label, multicenter dose escalation and expansion study in advanced solid tumors. The primary objectives are to determine the recommended Phase 2 dose (RP2D) and characterize the safety and tolerability of VT1021. Secondary objectives are to characterize the adverse event (AE) profile, evaluate pharmacokinetics (PK), and describe preliminary efficacy. Exploratory objectives include evaluation of pharmacodynamic effects of VT1021 in tumor, TME, and peripheral blood. The expansion phase focuses on ovarian, pancreatic, triple negative breast cancer, glioblastoma, and a basket cohort with high CD36-expressing tumors. Results In the escalation phase, 46 subjects received between 0.5–15.6 mg/kg of VT1021 by IV infusion twice weekly. VT1021 has been well tolerated through all doses tested. One patient dosed at 1.0 mg/kg developed a grade 3 infusion reaction and 3 patients dosed at 1.0, 6.6, and 8.8 mg/kg respectively developed grade 2 infusion reactions. Other drug related AEs included grade 1–2 fatigue (n=7), nausea (n=4), constipation (n=2), increased aspartate aminotransferase (n=2) and blood bilirubin (n=2), hypomagnesaemia (n=2), and dizziness (n=2). Dose proportionality was observed in PK analysis. Among 28 evaluable subjects, one partial response (thymoma, 372+ days on treatment) and 11 stable disease (SD) in 9 different solid tumors have been observed for a disease control rate of 43%. Seven of eleven SDs had high CD36 AND high CD47 expression with an average duration of 162 days on study. VT1021 induced Tsp-1 production in peripheral blood cells at most dose levels. In addition, on-study biopsies exhibited increased Tsp-1 expression in the TME by activation of p53 in MDSCs, increased CTL infiltration, increased M1:M2 macrophage ratio, and reduced regulatory T cells in the TME. The RP2D was declared to be 11.8 mg/kg and enrollment in tumor-specific expansions is on-going. Conclusions Through all doses tested, VT1021 was safe and well tolerated, with dose proportional PK properties. In addition, VT1021 has demonstrated activities in reprogramming the TME which resulted in a high disease control rate in subjects with tumors expressing both high CD36 and high CD47. Trial Registration NCT03364400 Ethics Approval The study was approved by Northwestern University Medical School institutional review board (IRB), approval number 00000418, Horizon Oncology Center IRB, approval number 00001313, South Texas Accelerated Research Therapeutic IRB, approval number 00003657, University of Oklahoma Health Sciences Center IRB, approval number 00006075, Cleveland Clinic IRB, approval number 00000536, Florida Cancer Specialists IRB, approval number 00006075, Case Western IRB, approval number 00000536, Beth Israel Deaconess Hospital and Dana Farber Cancer Institute IRB, approval number 00000753 and MD Anderson IRB, approval number 00006023.

https://jitc.bmj.com/content/jitc/8/Suppl_3/A228.1.full.pdf

374 A first-in-human Phase 1/2 open label trial evaluating the safety, pharmacology, and preliminary efficacy of VT1021 in subjects with advanced solid tumors

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Lou Vaickus

Author Tools

Chat about Author

Papers

374 A first-in-human Phase 1/2 open label trial evaluating the safety, pharmacology, and preliminary efficacy of VT1021 in subjects with advanced solid tumors