Summary: In recent research, scientists have discovered that the blood vessels supplying high-grade glioma brain tumors contain high levels of LDL receptors (LDLRs). The study found that using nanoparticle therapies containing drugs to target these receptors may be a new way to treat cancer. Gliomas are the most common primary brain tumors and, due to their very aggressive nature, have a poor prognosis with an average survival of only 4.6 months without treatment and around 14 months with optimal multimodal treatments. This research could pave the way for treating glioma brain tumors with nanoparticle therapies that target LDL receptors, cutting off the energy supply to cancer cells.
Source: University of Nottingham
New research has shown that the blood vessels that feed aggressive brain tumors have receptors that could allow a new type of drug-containing nanoparticle to be used to rob tumors of the energy they use to grow and grow. spread, and also disrupt their operation. adapted existence, even committing suicide.
Scientists from the University of Nottingham and Duke University have found that many blood vessels that supply high-grade glioma brain tumors contain high levels of low-density lipoprotein (LDL) receptors (LDLR). The results pave the way for the use of drugs already in development at both institutions that could target these receptors and thus be taken up by tumors.
The results have just been published in Pharmacy.
Gliomas are the most common primary brain tumors and arise from glial cells in the brain. It is a heterogeneous spectrum ranging from slowly growing tumors to very aggressive infiltrating tumors.
Almost half of all gliomas are classified as high-grade gliomas (HGG) and, due to their very aggressive nature, have a poor prognosis with an average survival of only 4.6 months without treatment and around 14 months with current optimal multimodal treatments.
The researchers examined tissue microarrays of intra- and inter-tumor regions from 36 adult patients and 133 pediatric patients to confirm that LDLR was a therapeutic target. Expression levels in three representative cell line models were also tested to confirm their future utility for testing uptake, retention, and cytotoxicity of LDLR-targeted nanoparticles.
They showed widespread expression of LDLR in adult and pediatric cohorts and, importantly, also categorized the observed intra-tumoral variation between the nucleus and peripheral or invasive regions of adult high-grade gliomas.
Dr Ruman Rahman from the University of Nottingham School of Medicine led the study and said: “Brain tumors can be very difficult to treat with currently available techniques because many of the drugs or nanoparticles that he has been shown to work in cells, when used in clinical treatment tests it cannot penetrate the blood-brain barrier behind which many tumors are found. It is therefore essential that we look for new ways to deal with them.
These findings are an important step in understanding the biology of tumors and how they gather energy to grow and spread from lipoprotein particles containing body fats and proteins. The key now is to use nanoparticles of drugs and prodrugs to target these receptors and cut off the energy supply to cancer cells.
David Needham, Professor of Translational Therapeutics at the University of Nottingham School of Pharmacy and Professor of Mechanical Engineering and Materials Science at Duke University, has worked on developing new, more clinically effective formulations of a common metabolic inhibitor (niclosamide) that cuts cells’ energy and could be modified as a treatment for a number of diseases, including cancer.
In its original antiparasitic application, niclosamide has been used for over 60 years, taken as oral tablets, killing tapeworms on contact in the gut by inhibiting their crucial metabolic pathway and cutting off their energy supply.
This same ability to reduce the energy input into a cell has shown that niclosamide can also reduce the energy a virus needs to replicate (another formulation that Needham recently developed as a nasal spray and throat for early treatment of COVID-19 and other respiratory diseases). viral infections.
For sprays, Needham discovered how to increase the solubility of niclosamide in simple pH buffered solutions (Needham 2022, Needham 2023). However, niclosamide’s low water solubility makes it very difficult to use elsewhere, such as in an intravenous (IV) injection or infusion.
Professor Needham, who has been studying this drug as a possible cancer treatment for a number of years and has led research in this area and is co-author of this study, said: ‘We know that niclosamide works by turn down the dimmer of host cells in the body, such as in the nose, as a preventative against COVID19 and other infections.
“Cancer is thought to have evolved additional strategies to survive and therefore has very different metabolic processes than normal cells. Niclosamide not only targets energy production in cells, but also triggers other processes that lead to what is called apoptosis (self-destruction) in cells.
“And now that we know that brain tumors have LDL receptors that we believe are used to fuel their growth and metastatic spread, we can work to modify the drug to target them and starve cancer cells of their energy. . Since cancers feed on LDLS, our strategy is to make the drug look like cancer food.
Professor Needham and the Duke team have developed ‘Bricks to Rocks Technology’ (B2RT) which transforms this common low solubility drug (commonly known as ‘brick dust’) into even less soluble ‘rocks’ with the expressed aim of fabricate pure prodrug nanoparticles.
They converted niclosamide into a new, less soluble prodrug (niclosamide stearate) that allows the formation of injectable or implantable nanoparticles. With the data we have already obtained, the so-called “niclosamide stearate prodrug therapy” (NSPT) can arrest the formation of lung metastases in a mouse model of osteosarcoma (Reddy, Kerr et al. 2020), and also cure some dogs in a small canine feasibility study (Eward, Needham et al. 2023).
Professor Needham continues: “This technology is now ready to be applied to other cancers, and Nottingham is ideally placed to develop it with the expertise of the Center for Childhood Brain Tumor Research.
“The next step will be to test B2RT with Ruman and his colleagues specifically in brain tumor cells, animal models and, if it shows promise, transfer it to patients as quickly and safely as possible. We want to determine if and to what extent LDLR-targeting anti-cancer drug and prodrug nanoparticles may have activity in brain cancer, both injected intravenously and/or as post-surgical depots.
Such LDLR-targeted nanoparticles have already been developed as a workable formulation by fellow School of Pharmacy researcher Jonathan Burley and his recent PhD graduate George Bebawy, who have shown to enhance cell uptake. tumours.
Professor Needham adds: “We are now actively seeking partners from industry as well as governments and infectious disease institutes to help continue pre-clinical and possibly clinical trials. We look forward to hearing from anyone who thinks they can help move the testing and development of this new technology forward.
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About this brain cancer research news
Author: Jane Ike
Source: University of Nottingham
Contact: Jane Icke – University of Nottingham
Picture: Image is in public domain
Original research: Free access.
“The low-density lipoprotein pathway is a pervasive metabolic vulnerability in high-grade glioma amenable to nanotherapy delivery” by David Needham et al. Pharmacy
Abstract
The low-density lipoprotein pathway is a pervasive metabolic vulnerability in high-grade glioma that is amenable to nanotherapeutic delivery
Metabolic reprogramming, through increased uptake of cholesterol in the form of low-density lipoprotein (LDL), is one way cancer cells, including high-grade gliomas (HGGs), maintain their rapid growth.
In this study, we determined LDL receptor (LDLR) expression in HGGs using immunohistochemistry on tissue microarrays from intra and intertumoral regions of 36 adults and 133 pediatric patients to confirm that LDLR is a target therapeutic.
Additionally, we analyzed expression levels in three representative cell line models to confirm their future utility for testing uptake, retention, and cytotoxicity of LDLR-targeted nanoparticles.
Our data show widespread expression of LDLR in adult and pediatric cohorts, but with significant intra-tumor variation observed between the nucleus and peripheral or invasive regions of adult HGG.
Expression was independent of pediatric tumor grade or identified clinicopathologic factors. LDLR-expressing tumor cells preferentially localized to perivascular niches, also with significant intra-tumoral variation in adults. We demonstrated variable levels of LDLR expression in all cell lines, confirming their relevance as models to test LDLR-targeted nanotherapy delivery.
Taken together, our study reveals that the LDLR pathway is a pervasive metabolic vulnerability in high-grade gliomas across all ages, lending itself to future investigation of LDL-mediated nanoparticle/drug delivery to potentially circumvent the LDLR pathway. tumor heterogeneity.