A research team from the University of Georgia’s Regenerative Bioscience Center has found that a compound molecule used for drug delivery of insulin could be used to treat glioblastoma, an aggressive, usually fatal form of brain cancer.
Glioblastoma, also known as GBM, is a fast-growing, web-like tumor that arises from supportive tissue around the brain and resists surgical treatment.
Described by some as “sand in grass,” GBM cells are hard to remove and tend to reach out in a tentacle-like fashion through surrounding healthy brain tissue.
According to the National Foundation for Cancer Research, more than half of newly diagnosed GBM patients die within the first 15 months. Late U.S. Sens. John McCain and Ted Kennedy both died from GBM, raising national awareness of the deadly disease.
Surfen, a compound molecule first described in 1938, is a pharmaceutical agent used to optimize insulin delivery.
The UGA researchers identified that surfen-treated cells were “blocked” from tumor growth, and the spread of tumor cells in the brain.
“This study shows that we can stifle the growth of invasive brain tumors with a compound that has a substantial clinical advantage, and can aid in the reduction or refinement of mainstream treatments, particularly radiation and/or chemo,” said Lohitash Karumbaiah, associate professor of regenerative medicine in UGA’s College of Agricultural and Environmental Sciences.
Published ahead of print in the FASEB Journal, the study is the first known use of surfen as an application to treat GBM. To test the approach, the research team first used cultured cells to observe binding properties of the surfen compound.
Next, they introduced live rodent models with cells that could grow into invasive tumors.
The researchers found that surfen-treated animals demonstrated smaller tumors and substantially reduced brain hemorrhage volume than control animals.
“In basic terms, surfen is highly positively charged and will bind to negatively charged things,” said Meghan Logun, a graduate student working with Karumbaiah.
“Since we study sugars in the brain, which are highly negatively charged, we then asked, ‘Why not try using positive charges to block off the negative ones?’”
Logun is studying how brain cancer takes advantage of highly charged elements in brain tissue to aid in invasion.
“In the surfen-treated animals, we saw that the tumors were actually much more constrained and had more defined boundaries,” she said.
To explore the surfen molecule further, the team worked with Leidong Mao, associate professor in UGA’s College of Engineering and co-developer of a microfluidic device used to examine glycosaminoglycans (GAGs)–highly negatively charged molecules produced by brain tumors. Designed to mimic the neural pathways of the brain, the device allows for real-time monitoring of tumor cell adhesion and growth.
“We did not expect to see such a robust response,” Mao said. “Blocking off the charged GAGs from the tumor cells really did dampen their ability to invade.”
Based on the study’s discovery that surfen had isolated the tumor, the team also analyzed MRI images to gauge the treatment’s effectiveness.
Lohitash Karumbaiah. The image is credited to UGA.
“In the MRI image you can see [the effects of the surfen treatment] pretty drastically, not in terms of killing the GBM but in blocking its prey,” said Qun Zhao, associate professor of physics in the UGA Franklin College of Arts and Sciences and another RBC collaborator on the project.
“In the non-treated image, you see rampant invasive growth, compared to the surfen-models where you see a nicely contained and almost circular-shaped tumor.”
“The tumor may still grow, but at least now it doesn’t have any invasive inroads to creep into other parts of the brain,” said Karumbaiah.
“That could be clinically beneficial for a surgeon wanting to remove the tumor and not having to worry about rogue cancer cells.”
Looking ahead, Karumbaiah is hopeful that repurposing a compound known to be safe, with proven and beneficial binding properties, could help accelerate review and approval of this potential new therapeutic, and advance consideration in helping to expedite the drug approval process.
“Our hope is that, in the wake of this discovery, lives can be saved, and we can finally change the scope of this life-threatening disease,” said Karumbaiah. “In my five years at UGA, this is the highest profile cancer paper I’ve ever had.”
Funding: This study was funded by the National Institutes of Health and UGA’s Clinical and Translational Research Unit. The Regenerative Bioscience Center is a unit of the UGA Office of Research, with generous support from the College of Agriculture and Environmental Sciences and its Department of Animal and Dairy Science.
Glioblastoma multiform (GBM) is a malignant tumor originating from glial cells. It is the most frequent brain tumor, representing 30% of all central nervous system tumors (CNST), 45% of malignant CNST and 80% of primary malignant CNST.
It leads to 225,000 deaths per year in the entire word. It has an incidence of 5 per 100,000 persons, affects 1.5 times more men than women, and is diagnosed at an average age of 64 (Bush et al., 2017).
Due to the relatively limited number of people suffering from GBM, it is difficult to determine with certainty the causes of this disease.
The only well-established GBM risk factor is exposure to radiation. Radiofrequency electromagnetic fields such as those produced by mobile phones have been classified as IIB and may also play a role in GBM appearance (Armstrong et al., 2011).
By contrast to other types of cancers, it appears uncertain that GBM incidence can be decreased by changing certain environmental factors such as alcohol or tobacco consumption. Since the majority of GBM appear for the first time, i.e., only ~40% originates from tumors of lower grades, it also seems rather uneasy to anticipate GBM from the presence of another disease or condition.
Among the four different forms of glioma, grade IV corresponds to GBM. It is the most deadly grade, due to its frequent relapse and resistance to all current therapies and is the topic of this review.
GBM current standard of care (SOC) includes maximal safe resection followed by radiotherapy and chemotherapy using temozolomide (TMZ). Such treatment hardly increases patient survival and leads to a median overall survival (OS) of only 12–18 months following diagnosis (Stupp et al., 2005; Wen and Kesari, 2008).
Efficient treatment against GBM is difficult to develop for a series of reasons that are summarized below. First, GBM is characterized by many dysregulated pathways that can hardly be all blocked and repaired at the same time with a single therapy (Alifieris and Trafalis, 2015).
Second, GBM partly consists of infiltrating cells that cannot easily be all removed by surgery. Full tumor resection would require very precise imaging and surgical tools to enable the visualization and removal of all GBM infiltrating cells.
Third, GBM early diagnosis, which may improve treatment efficacy by enabling the removal of tumors of small sizes, is not carried out routinely.
In fact, the first signs of GBM, such as vomiting and strong headache, often appear at a late stage of this disease, and sensitive imaging techniques, such as MRI, which could possibly enable early diagnosis, still seem too expensive to be carried out on a regular basis over the whole population.
Fourth, the optimization of a clinical protocol for GBM treatment requires the use of an accurate and representative preclinical GBM model. Different types of mouse and rats models have been developed, each one with its own advantages and drawbacks.
It therefore appears necessary to test GBM drug efficacy on a combination of several of these models to grasp sufficient information for optimal design of the clinical protocol. Furthermore, mouse and rats GBM tumors are typically ~103-104 smaller than human GBM. The optimization of the clinical protocol would therefore certainly benefit from preclinical efficacy tests carried out on larger animals such as dogs.
Fifth, the blood brain barrier (BBB) often prevents drugs from efficiently reaching glioblastoma cells, and methods to enable drugs to efficiently cross the BBB should therefore be developed.
Here, I review the different drugs and medical devices, which are under development or commercialized by companies, have been pre-clinically or clinically tested, most frequently involve medical teams, and either result in direct GBM cell destruction or are part of a GBM treatment protocol, e.g., through GBM imaging.
I focus on GBM treatments that have been the subject of at least one publication listed in the pubmed search database.
I also discuss several scientific, societal, and industrial issues related to early GBM diagnosis, an adapted preclinical model, different methods to yield efficient drug delivery to GBM tumor, program to accelerate the development of GBM therapies, patents protecting various GBM treatments, the different actors tackling GBM, the cost associated with GBM treatment, GBM market figures, and finally a financial analysis of the different companies involved in the development of GBM treatment.
The different GBM treatments commercialized or under development
The different drugs and medical devices used for GBM Treatments are summarized in Figures Figures11 and and2.2. The type of drug, name of company developping it, proposed drug made of section are indicated in Table Table1.1. The preclinical/clinical result obtained with these drug are listed in Table Table22.
A schematic diagram presenting the different GBM treatments relying on chemical and immunological mechanisms. These treatments are classified as drugs, since their dominant mode of action is immunological, metabolic, or pharmacological. GBM drugs with their associated mode of action are listed.
A schematic diagram presenting the different GBM treatments relying on physical mechanisms. These treatments (except Cotara and KU-60019) are classified as medical devices, since their dominant mode of action is not immunological, metabolic, or pharmacological. These GBM treatments with their associated mode of action are listed.
Source:
University of Georgia
Media Contacts:
Charlene Betourney – University of Georgia
Image Source:
The image is credited to UGA.
Original Research: Closed access
“Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion”. Meghan T. Logun, Kallie E. Wynens, Gregory Simchick, Wujun Zhao, Leidong Mao, Qun Zhao, Subhas Mukherjee, Daniel J. Brat, and Lohitash Karumbaiah.
The FASEB Journal doi:10.1096/fj.201802610RR
