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The Blood Brain Barrier: Drug Delivery in Glioblastoma

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The blood brain barrier (obemereier 2013)

The blood-brain barrier (BBB) is a highly selective and specialized membrane that separates circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS). It is composed of tightly-packed endothelial cells lining the capillaries in the brain, as well as surrounding astrocyte cells, pericytes, and basal lamina.

The BBB plays a critical role in maintaining the homeostasis of the brain microenvironment by preventing the entry of many substances from the bloodstream into the brain, including toxins, pathogens, and most drugs.

In glioblastoma, the BBB becomes disrupted and leaky due to the formation of new blood vessels in the tumor, a process known as angiogenesis. The endothelial cells that make up the BBB become damaged and lose their tight junctions, allowing larger molecules to enter the brain. However, the tumor cells themselves can also actively modulate the BBB by secreting various factors that increase its permeability.

The disrupted BBB in glioblastoma can have both positive and negative effects on treatment outcomes. On the one hand, it allows certain therapeutic agents to cross the BBB and reach the tumor, which can improve treatment efficacy. And on the other hand, it allows the tumor cells to evade the immune system and promotes tumor growth in other body parts.

Researchers are actively studying ways to exploit the leaky BBB in glioblastoma to improve treatment outcomes. One approach involves using drugs that can selectively target the tumor cells while minimizing damage to healthy brain tissue. Another approach involves using nanoparticles that can bypass the BBB and deliver therapeutic agents directly to the tumor cells.

Nanocarriers have a wide range of applications. One example is their use in transporting small non coding mRNA molecules that target brain tumor tissue and stop proliferation. The nano carriers protect the RNA from nuclease degradation and promote effective regulation of target genes, especially in brain tumors such as glioblastomas (GBMs) that are somehow protected from chemotherapeutic drugs by the blood–brain barrier (BBB).

Nano carriers crossing the BBB (Dubois 2014)

This image attempts to clarify the action of miRNAs in brain-cancer cells, through nano carriers capable of crossing through the BBB.

A question that was brought up in class on Wednesday was whether or not this drug delivery technique is specific to the tumor cells, and does not damage other cells in the immediate vicinity of the tumor, and the answer to that I found in a research study that reviewed the use of CDs, nano particles in drug delivery. The review article reported that the over-expression of transferrin receptors on both tumor cells and the BBB’s endothelial cells allows CDs to be specifically targeted to cancerous cells when conjugated with transferrin.

The authors supported this by referencing Hettiarachchi et al, who designed a triple-conjugated CD-based nano carrier (DDS) that targeted glioblastoma with transferrin, epirubicin, and temozolomide. The results showed that a much lower concentration of the triple-conjugated system (C-dots-transferrin-epirubicin-temozolomide (C-DT)) was required to reduce tumor cell viability compared to non-transferrin systems (NT) and dual-conjugated systems, namely CDs-transferrin-temozolomide (C-TT) and CDs-transferrin-epirubicin (C-ET). These findings suggest that CDs can be loaded with multiple therapeutic agents, resulting in a synergistic effect on antitumor efficiency.

The ideal method for transporting drugs across the BBB would be controllable and not damage the barrier. Among the various presently available approaches, nano-biotechnology-based delivery methods are the most promising .

References:

Dubois et al. Researchgate.net. Retrieved March 24, 2023, from https://www.researchgate.net/publication/273138648_Gliomas_and_the_vascular_fragility_of_the_blood_brain_barrier

Obermeier, B., Daneman, R. & Ransohoff, R. Development, maintenance and disruption of the blood-brain barrier. Nat Med 19, 1584–1596 (2013). https://doi.org/10.1038/nm.3407

Qian, Z. M., Li, H., Sun, H., & Ho, K. (2002). Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacological Reviews, 54(4), 561–587. https://doi.org/10.1124/pr.54.4.561

Zhang, W., Sigdel, G., Mintz, K. J., Seven, E. S., Zhou, Y., Wang, C., & Leblanc, R. M. (2021). Carbon dots: A future blood-brain barrier penetrating nanomedicine and drug nanocarrier. International Journal of Nanomedicine, 16, 5003–5016. https://doi.org/10.2147/IJN.S318732

Disease/Health

The devastating truth of Glioblastomas

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Introduction

Glioblastomas (GBMs) are an invasive and aggressive form of malignant brain cancer that are treatment resistant due to the inability of treatments to pass through the blood brain barrier (BBB). GBM formation is either primary or secondary and is classified as four different subtypes. Primary formation occurs de novo, rapidly, and without pre-existing symptoms whereas, secondary GBM develop from low grade glioma tumors. The classification of the four subtypes of GBMs are:

Classical: Amplification of the epidermal growth factor receptor (EGFR) gene and point mutations.

Mesenchymal: Increased rate of neurofibromin 1 (NF1) and phosphatase and tensin homolog (PTEN) mutations.

Proneural: High expression of platelet derived growth factor receptor alpha (PDGFRA) and isocitrate dehydrogenase 1 (IDH1) and TP53 mutations.

Neural: No notable gene amplifications or mutations.

Pathways

MAPK

Hyperactivation of MAPK through epidermal growth factor (EGF) binding to the respective tyrosine kinase receptor (RTK). The increase activation of the pathway leads to cell proliferation, cell survival, and metastasis resulting in poor patient survival. The hyperactivation of the MAPK pathway results from the inactivation of the NF1 regulator gene.

 

                                                                                                                             Figure 1. MAPK pathway

PI3K

PI3K is made up of two subunits, p110 and p85 and is activated by growth factor stimulation of RTKs. The hyperactivation of the PI3K pathway leads to cell invasion, adhesion, and proliferation. PTEN is used to suppress the PI3K pathway which is mutated.

 

 

                                                                                                            Figure 2. PI3K pathway

cAMP

In GBMs cAMP is hypoactivated. cAMP activates PKA which goes and inhibits Raf, ultimately increasing MAPK signaling. The lowered expression of cAMP is a result of altered adenylyl cyclase and PDE expression. Therefore, elevating cAMP via PDE inhibition has been linked to a decrease in tumor growth and promotes GMB cell apoptosis.

 

                                                                                                                                       Figure 3. cAMP pathway

Pathway crosstalk

PI3K and MAPK pathways cross regulate each other by both being activated by RTKs and MAPKs proteins Ras and GRB can activate PI3K. Therefore, if only one pathway was targeted to treat the GBM to tumor could manipulate the pathway and continue metastasizing.

                                                                                                                    Figure 4. Crosstalk between
                                                                                                                    MAPK, PI3K, and cAMP pathways.

MMPs

Matric metalloproteinases (MMPs) are zinc dependent proteolytic enzymes that are upregulated in the brain in the presences of glioblastomas. Gelatinase MMPs 2 and 9 degrade denatured collagen in result in the degradation of the tight junctions in the BBB, leading to leaking of the BBB. MMP-9 results in tumor growth and both MMP-2/9 are responsible for blood vessel growth. In GBMs blood vessel growth is a negative factor because the tumor redirects blood flow to itself and allows it to continue to grow in size. MMPs are expressed in healthy individuals but are broken down by tissue inhibitors of metalloproteinases (TIMPs).

Treatments

A potential target for treatment would be CREB, since the MAPK, PI3K, and cAMP pathways all converge on CREB. Since CREB is responsible for cell survival, invasion, and proliferation targeting this site may stop tumor cell growth. This target may also lessen the effect of drug resistance since the tumor cannot begin utilizing another pathway to get to CREB. Additionally, CREB is an ideal target because there is less risk for toxicity to occur. However, CREB targeted treatments may still need to be paired with surgery, chemotherapy, or radiation therapy to give the patient the best hope for survival.

Conclusion

Glioblastomas are aggressive and invasive malignant brain tumors that can form as primary of secondary tumors and devastate individuals lives. Since current treatments have been shown to be ineffective at riding the brain of glioblastomas the various pathways involved in GBMs were investigated. The primary pathways are MAPK, PI3K, and cAMP which all converge at CREB. Therefore, targeting CREB may slow tumor growth and spread and give the individual a chance at survival.

References

  1. Fung, Nok Him; Grima, Corrina A.; Widodo, Samuel S.; Kaye, Andrew H.; Whitehead, Clarissa A.; Stylli, Stanley S.; Mantamadiotis, Theo. Understanding and exploiting cell signaling convergence nodes and pathway cross-talk in malignant brain cancer. Elsevier, 2019.

 

Disease/Health

Understanding Glioblastoma: Exploring Environmental Factors and Treatments

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Magnetic resonance imaging Finding 5 cm isodense mass with ill-defined margin and surrounding edema at Left frontal lobe. Glioblastoma, brain metastasis.science and education mri brain background. [1]
Glioblastoma, a highly aggressive type of brain cancer, can have a significant impact on cognitive function and mental health. The location of the tumor and the treatments used to combat it can affect brain function, leading to problems with memory, attention, and other cognitive abilities. Additionally, the diagnosis of glioblastoma can have a profound psychological impact on patients and their families, leading to depression, anxiety, and other mental health challenges. Understanding and addressing the cognitive and mental health effects of glioblastoma is crucial for providing holistic care to patients and improving their quality of life throughout the course of their treatment and beyond. This may involve a range of interventions, including supportive therapy, rehabilitation, and medication management.

 

How do cancers get bigger?

Cancer cells stay in the specific body tissue from which they have developed. Cancer cells grow and divide to create more cells and create a tumor that can consist of millions of cancer cells. Cancer cells can stay within the membrane of a specific body tissue, or it can be invasive (breaks through the membrane). As the tumor gets bigger the center of it gets further away from the blood vessels which means it has less oxygen and nutrients. Without a blood supply tumor can’t grow bigger than a pin head. Cancer cells send signals, called angiogenic factors that stimulate 100s of new small blood vessels that allow tumors to continue growing.

The MAPK, PI3K, and cAMP pathways [4] play important roles in the development and progression of glioblastoma. The MAPK pathway is involved in cell growth and survival, and mutations in this pathway have been identified in a significant proportion of glioblastoma cases. The PI3K pathway is also important in cell growth and survival and is frequently activated in glioblastoma. In addition, the cAMP pathway has been shown to play a role in regulating glioblastoma cell proliferation and differentiation. Targeting these pathways with specific inhibitors has shown promise as a potential therapeutic approach for glioblastoma treatment, and research in this area is ongoing.

Treatments [6]

Glioblastoma treatment depends on various factors such as the age and health of the patient, the size and location of the tumor, and whether the tumor has spread to other parts of the brain. The current standard treatment for glioblastoma usually involves a combination of surgery, radiation therapy, and chemotherapy.

  • Surgery: Surgery is the first line of treatment for glioblastoma, and the goal is to remove as much of the tumor as possible without causing damage to the surrounding healthy brain tissue.
  • Radiation Therapy: Radiation therapy uses high-energy X-rays or other types of radiation to kill cancer cells and shrink tumors. It is often given after surgery to destroy any remaining cancer cells.
  • Chemotherapy: Chemotherapy uses drugs to kill cancer cells. It can be given orally or intravenously, and it is often used in combination with radiation therapy.
  • Tumor Treating Fields: Tumor Treating Fields (TTFields) is a new treatment option that involves using electric fields to disrupt the division of cancer cells. This treatment is usually used in combination with chemotherapy.
  • Immunotherapy: Immunotherapy is a type of treatment that helps the immune system fight cancer. It is still being studied for its effectiveness in treating glioblastoma.
  • Clinical Trials: Clinical trials are research studies that test new treatments for glioblastoma. Patients who participate in clinical trials may have access to new treatments that are not yet available to the general public.


Alternative medicine

Alternative medicine has been explored as a potential adjunct therapy in the treatment of glioblastoma. Some alternative therapies, such as meditation and acupuncture, may help manage symptoms such as pain, nausea, and anxiety. Others, like herbal supplements and dietary modifications, may have potential as adjuvant therapies, though more research is needed to establish their efficacy and safety. While alternative medicine should not be used as a substitute for conventional medical treatments, integrating complementary therapies into a comprehensive treatment plan may improve quality of life for glioblastoma patients and may help support their overall health and well-being.


[5]


Environmental Factors

There is ongoing research exploring the potential role of environmental factors in the development of glioblastoma. Exposure to certain chemicals, such as pesticides and industrial solvents, has been linked to an increased risk of developing brain tumors, including glioblastoma. Additionally, some studies have suggested that radiation exposure, particularly during childhood, may also increase the risk of developing glioblastoma later in life. While the link between environmental factors and glioblastoma is not fully understood, these findings highlight the importance of understanding the potential risk factors associated with this disease and taking steps to minimize exposure to harmful substances.


[7]

 

Sources

[1] Kasa, T. (n.d.). Magnetic resonance imaging finding 5 cm isodense mass with… iStock. Retrieved March 22, 2023, from https://www.istockphoto.com/photo/magnetic-resonance-imaging-finding-5-cm-isodense-mass-with-ill-defined-margin-and-gm1339217716-419614241?utm_campaign=srp_photos_noresults&utm_content=https%3A%2F%2Fwww.pexels.com%2Fsearch%2Fglioblastoma%2F&utm_medium=affiliate&utm_source=pexels&utm_term=glioblastoma

[2] Brain tumor development. Brainlab.org. (n.d.). Retrieved March 22, 2023, from https://www.brainlab.org/get-educated/brain-tumors/learn-brain-anatomy-basics/brain-tumor-development/

[3] How cancers grow. Cancer Research UK. (2021, February 8). Retrieved March 22, 2023, from https://www.cancerresearchuk.org/about-cancer/what-is-cancer/how-cancers-grow

[4] Daniel, P. M., Ebert, P. J. R., Massard, C., Shankar, D. B., Dworkin, S., Sengupta, R., Butcher, R. W., Fonseca, B. D., Carriere, A., Yu, C. F., Maehama, T., Alessi, D. R., Kleber, S., Chuang, C. F., Okada, S., Chiu, W.-T., Brown, C. K., Stylli, S. S., Verhaak, R. G. W., … Network, C. G. A. R. (2019, January 30). Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer. Cellular Signalling. Retrieved March 22, 2023, from https://www.sciencedirect.com/science/article/pii/S0898656819300208?via%3Dihub

[5] Elsevier Masson. (2021, July 19). Natural bioactive molecules: An alternative approach to the treatment and control of glioblastoma multiforme. Biomedicine & Pharmacotherapy. Retrieved March 22, 2023, from https://www.sciencedirect.com/science/article/pii/S0753332221007101

[6] Glioblastoma multiforme. AANS. (n.d.). Retrieved March 22, 2023, from https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme

[7] Grochans, S., Cybulska, A. M., Simińska, D., Korbecki, J., Kojder, K., Chlubek, D., & Baranowska-Bosiacka, I. (2022, May 13). Epidemiology of glioblastoma multiforme–literature review. MDPI. Retrieved March 22, 2023, from https://www.mdpi.com/2072-6694/14/10/2412

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TP53 Proteins and Their Role in Cancer

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Tumor Protein 53

Tumor protein 53 (TP53) is a regulatory protein that helps regulate the progression through the cell cycle, apoptosis (cell death), and the stability of the genome. It does this through a few different ways:

  • When noticing DNA damage, it activates DNA repair proteins. This is important in a lot of functions to do with aging.
  • It can stop the cell cycle when DNA damage occurs, which allows DNA repair proteins to fix the damage, then will stimulate the cell to continue through its growth cycle.
  • It will initiate apoptosis when DNA damage is irreparable

TP53 is often regarded as the ‘guardian of the genome‘ for it’s role in preventing mutations and conserving stability. Specifically in vertebrates (like humans) this protein prevents cancer formation.

How Does It Work?

TP53 acts a cellular distress sensor, normally kept at low levels. TP53 is activated when there is cellular stress such as DNA damage (caused by UV or IR radiation, or chemical agents), or oxidative stress. This activation causes 2 major things:

  1. The half-life of TP53 is greatly increased, which leads to a quick accumulation in stressed cells
  2. TP53 undergoes a structural change that allows it to act as a transcription regulator in the stressed cells

The transcription regulating characteristic of activated TP53 allows it to convert DNA to RNA, which will go on to create cellular responses to the stress that is happening. To link it to TP53s main ways of regulating cells, the RNA can code for DNA repair proteins, or proteins that will initiate apoptosis if the cell damage is irreparable.

Role in Cancer

TP53 is mutated or deleted from the genome in over 50% of all human tumors. When the TP53 gene is damaged tumor suppression is compromised, are people with this are likely to develop tumors in early adulthood. Well maybe increasing levels of TP53 can be a good solution to preventing tumors or the spread of tumors. While this has been researched, this can cause early aging in a person, which is something that not a lot of people are too keen about. However research has been done in aiding to restore functionality of already existing TP53 in order to treat cancer. In 2003 a gene therapy called Gendicine was approved in China for the treatment of head and neck squamous cell carcinoma caner.

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Let’s Talk about Brain Cancer

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What is Glioblastoma?

In short, glioblastoma (GBM) is brain cancer. More specifically, it is a very lethal brain tumor, sometimes becoming invasive to other parts of the body, such as the spine. There are two different forms that GBM can take: primary and secondary. In their article, Understanding and exploiting cell signaling convergence nodes and pathway crosstalk in malignant brain cancer, Fang and associates define these two types of brain tumor. Primary tumors develop quite fast, most of the time without any symptoms that show the development of the tumor. Secondary tumors grow from smaller tumors until they become malignant. In Figure 1, it can be seen how primary tumors just “show up” with no warning, and secondary tumors grow and grow.

Figure 1. The development of primary and secondary tumors in the brain.

GBM biology

GBM can be classified into two main groups, primary and secondary, but those groups can also be divided into four subtypes. These four subtypes are classified as Classical GBM, Mesenchymal GBM, Proneural GBM, and Neural GBM. These tumors are classified into these one of these four groups based on their transcription factors. Understanding the tumor type of each patient could lead to therapeutic techniques and precise target treatments. Figure 2, pictured below, details each of the four subtypes of GBM. There are different categories for how each subtype is categorized. For example, prognosis for each, different genomic alterations, as well as what proteins may influence these tumors.

Figure 2. Four different subtypes of GBM. Each is classified by their own genomic alterations, and transcription factors.

Why is it so hard to fight tumors?

Tumors, and cancer in general, can be hard to fight. One of the main reasons GBM is so resistant to therapy is because of the impenetrable blood brain barrier (BBB). The BBB is the brains filtering mechanism, allowing for certain chemicals to pass to and from the BBB, it protects the brain from the bloodstream environment, and provides nutrients that is required for normal functioning. The BBB is composed of cells that are fit tightly together, allowing for some, but not all substances to pass through. To deliver therapeutic drugs to the brain, they need to pass through the BBB. And, if the BBB cannot be penetrated by these drugs, they are not going to be effective. There are many researchers who are trying to address this problem. Many methods have been developed to try and improve permeability of the BBB. Author Quanguo Ho and associates go into detail about these methods in their article, Towards Improvements for Penetrating the Blood-Brain Barrier- Recent Progress from a Material and Pharmaceutical Perspective.

Figure 3. The Blood Brain Barrier (BBB) schematic.

 

 

 

 

 

 

 

What is a tumor made of?

Tumors consist of a microenvironment, the small-scale environment of an organism. In this make up are T-cells, tumor-infiltrating dendritic cells, tumor-associated macrophages, and other complex components. Each environment is heterogenous, or diverse, in its own way. There are no two environments for a tumor that are the same. Each component of these microenvironments acts on each other in different ways. So, tumor survival depends a lot on what is involved in the environment. Figure 4 shows an example of these microenvironments and what is all at play.

Figure 4. Microenvironment of a tumor.

 

 

 

 

 

 

 

 

 

 

Molecular Pathways of a tumor

There are three main molecular pathways that tumors thrive on. All three will be shown below in more detail. These pathways include cAMP, MAPK, and PI3K. Everyone has these pathways in their body, but if something goes wrong, it allows tumors to prosper. For example, if the MAPK pathway becomes phosphorylated, or hyperactive, there is poor patient survival in those with GBM. The PI3K pathway regulates multiple cellular functions within the body. Shown in Figure 6 and Figure 5, there are intricate details to how the pathways operate.

Figure 5. MAPK pathway.
Figure 6. PI3K pathway.

Unlike the MAPK pathway, cAMP and Pi3K are hypoactive. It has been hypothesized that there is most likely a mutation or amplification that occurs on the EGFR protein. This mutation activates other mutations in the pathway which eventually leads to the inactivation of the tumor suppressor gene, PTEN.

The last pathway, pictured in Figure 7, is the cAMP pathway. The two pathways mentioned above regulate multiple cellular functions, cAMP does that as well. However, the cAMP pathway has been studied less than the other two because it seems to be less prominent in tumors. There is a significant reduction in cAMP signaling which may be the reason for tumor production and growth. Figures 5 through 7 show a greater in depth explanation of the three pathways.

 

Figure 7. cAMP signaling.

 

 

So, what?

With all this information, why should you care? Understanding how these pathways lead to tumor growth is just one way to fight GBM. Specific drugs are able to target different aspects involved in these pathways. But, like mentioned before, the main issue here is the BBB and whether or not the drug can penetrate it. It has been researched that if a specific portion of one pathway is inhibited which results in tumor suppression. However, sometimes the tumor will just migrate and hinder another pathway to help itself grow.

Understanding the mechanism of these pathways and how they and tumors interact with one another will lead to further research in finding a cure for GBM.

References

DeCordova, S., Shastri, A., Tsolaki, A., Yasmin, H., Klein, L., Singh, S., & Kishore, U. (2020, June 01). Molecular heterogeneity and immunosuppressive microenvironment in glioblastoma. Retrieved March 22, 2023, from https://www.frontiersin.org/articles/10.3389/fimmu.2020.01402/full

He, Q., Liu, J., Liang, J., Liu, X., Li, W., Liu, Z., . . . Tuo, D. (2018, March 23). Towards improvements for penetrating the blood-brain barrier-recent progress from a material and pharmaceutical perspective. Retrieved March 22, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946101/

Fung NH;Grima CA;Widodo SS;Kaye AH;Whitehead CA;Stylli SS;Mantamadiotis T;. (n.d.). Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer. Retrieved March 22, 2023, from https://pubmed.ncbi.nlm.nih.gov/30710631/

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Glioblastoma Current Treatment Plans

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Glioblastoma is a brain cancer that happens in astrocytes. Astrocytes are a type of glial cells, the most abundant cells in the CNS. According to the National Brain Tumor Society, 13,000 Americans get diagnosed with GBM. Their next factoid is that 10,000 Americans “succumb” to Glioblastoma each year. Succumb really sticks out for a Medical National Society to use. With GBM’s current treatment plans and outlook, it is very fitting. Even in today’s day and age, treatment is very limited. Surgery, radiation, and chemotherapy have been the only approved treatment. Yet survival rates are trending up. Although the extension of 2-4 years may not be ideal, it is something. Especially for the diagnosis. 


Why is it so limited?

 

The human body is just amazing and so complex. It almost has its own security or fail-safe plans. When everything is going as planned it is wonderful. When things aren’t, our body’s own security systems may interfere with external care that needs to happen.

Glioblastoma is very difficult to treat. Functions of glial cells are to maintain (promote formation of blood vessels for nutrition) and add structure to neurons in the CNS. Their spider web shape allows for them intwine in the brain to deliver proper nutrients. Which are vital for survival. Yet when cancer happens in these cells, the natural functions aids for this cancer be so aggressive and resilient. The shape of the tumors makes clean safe surgical removal of the tumor toilsome and dangerous. A 2021 article done by Stanford’s Neurology and Oncology departments found that there is a correlation between size of tumor removed to length of survival. The extent of surgical possibilities must be uniquely planed out. Glioblastomas are surrounded by brain matter patients physical or cognitive functions may be a risk.

The blood brain barrier is like a filtration system which allows only small fat-soluble molecules or ones that can bind to membrane proteins can bind. Transportation is only limited to certain areas of the brain. It is a great defense system, it’s your brain. You don’t want just anything to be able to get into your brain. Unless you have cancer and need treatment. Temozolomide is a very common medication the treat GBM, is it small and has fat like properties. TMZ targets the cancers DNA and adds a methyl group to DNA’s bases which stops its ability to replicate. Radiation is also used to disrupt the DNA and can shrink the tumors.


Ongoing Plans


Yet there is hope, many clinical trials are happening as we speak. According to a 2022 article, there hasn’t been a new drug approved as treatment since 2009. This article used ClinicalTrials.gov to find at the time 157 clinical trials. Currently in the US there are 231 studies happening right now focusing on glioblastoma from just over the 25,000 clinical trials currently happening.
Medical treatment advances do still happen, but we are starting to catch up with our capabilities in this technology era. Over the last 10 years, success rates of clinical trials have dropped. Why you might ask. Well without more major advances, only certain minor advancements can happen. I kind of like to think of it like when the first microscope was created, I believe in the 1600s. There was only a limited things we can learn (at the time they were huge advancements.) Yes, it opened doors and caused a cascade allowing technology and science to be what it is today. In a way there is always a fluctuating limit of what we can advance at a given time. Still it is happening it just may need a miraculous discovery first to help. New clinical trials for treatments are looking into Nano therapy, inhibitor therapy, and immunotherapy. A neurosurgeon believes that the “groundbreaking” discoveries in treatment will be with immunotherapy

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Disease/Health

Glioblastoma: A Biological Understanding Giving Hope to Thousands Diagnosed

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What is Glioblastoma?

Glioblastoma (GBM) is the rapid overgrowth of cells in the brain or spinal cord. These brain tumors affect around 12,000 American citizens per year and are incredibly difficult to treat. Treatment options such as chemotherapy and radiation do not cure this form of cancer, but can help to slow the growth of the tumor and invasive surgery is often required. GBM is highly invasive to neighboring brain tissue, but is unlikely to metastasize beyond the brain or central nervous system. 

Tumor Development

Cancerous, or malignant, tumors can develop from genetic disorders, age, irritants (smoking, radiation), or environmental factors. Once a mutation is created in a cell from one of these factors, the cell is triggered to divide and multiply at a rapid rate. Additional mutations may occur, in which we see metastasis or the bodywide spread of tumors. 

Signaling Effects on GBM

MAPK, PI3K, and cAMP signaling pathways all play a key role in GBM. 

MAPK

The MAPK pathway is activated by the binding of growth factor ligands to their corresponding receptor tyrosine kinase (RTK) receptor. When the ligand binds, the RTK is dimerized and autophosphorylates which leads to recruitment of adaptor proteins to the receptor which begins an activating cascade of Ras, then RAF, MEK, and finally MAPK is activated. MAPK contributes to cell proliferation and survival. In GBM, MAPK signaling is over-activated. 

PI3K

The PI3K pathway is activated by ligand binding to its corresponding RTK, the receptor is dimerized and phosphorylated. PI3K is then recruited to the receptor. A receptor subunit converts PIP2 to PIP3 which causes AKT to be phosphorylated and promote cell survival and proliferation. In GBM, PI3K signaling is over-active. 

cAMP

cAMP signaling begins with the binding of a ligand to a G-protein coupled receptor (GPCR). This causes the alpha subunit of the G-protein to activate adenylyl cyclase which converts ATP to cAMP. cAMP signaling interacts with MAPK by the activation of protein kinase A (PKA) which inhibits the MAPK pathway, and PI3K pathways previously mentioned. This convergence is shown below.

Convergence of MAPK, PI3K, and cAMP signaling pathways

cAMP levels and tumor malignancy have an inverse relationship, meaning that cAMP levels are low in GBM. It is shown that increasing cAMP levels can inhibit growth and differentiation and promote apoptosis in GBM cells. 

Treatment

Recalling that MAPK and PI3K signaling is elevated in GBM, it can be concluded that inhibiting these pathways can be a great start in treating GBM. Increasing cAMP is one way, since, as previously stated, PKA inhibits MAPK signaling. Buparlisib is a PI3K inhibitor that is currently used to treat breast cancer and GBM, and Venurafenib is a MAPK inhibitor that is currently used to treat late-stage melanoma. However, GBM is incredibly prone to drug resistance due to the multiple signaling pathways it utilizes – when one pathway is blocked, the cancer finds a way around it. Combining drugs can prevent this circumvention by inhibiting multiple pathways at once. Consequently, toxicity can occur with such combination, so it must be researched and monitored thoroughly. 

There is hope for patients diagnosed with GBM. Understanding these signaling pathways is a big leap in the future treatment of this cancer, and hopefully this knowledge is enough to improve the outcome of those affected by this disease. 

References

https://www.mayoclinic.org/diseases-conditions/glioblastoma/cdc-20350148

https://www.ncbi.nlm.nih.gov/books/NBK9963/#:~:text=Tumors%20are%20initiated%20by%20mutations,development%20of%20some%20human%20cancers.

https://www.sciencedirect.com/science/article/abs/pii/S0898656819300208?via%3Dihub

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Treatment of Glioblastoma Through EGFR and CREB

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Artstract Created by Hailey Puppe

Glioblastoma is an aggressive, fast-growing malignant brain tumor. It has a very low survival rate. Only 5% of those with Glioblastoma will live past 5 years. Treatment usually consists of surgery, radiation, and chemotherapy.1

There are two main types of Glioblastoma, primary and secondary.

  • Primary Glioblastoma effects elderly people and represents around 90% of Glioblastoma cases. This is characterized by EGFR amplification and is fast growing and very aggressive. EGFR is epidermal growth factor receptor. Overexpression allows for continual cell growth.
  • Secondary Glioblastoma effects younger people. First signs of this appears in childhood prior to puberty. Children will often experience excessive headaches. Once children reach puberty, the tumors will die out. Unfortunately, these tumors come back later, prior to 50 years of age. Secondary Glioblastoma has a better response to chemo than primary due to a genetic component that shuts off DNA repair that occurs after damage done by chemo treatment. This allows the tumors to die.

Pathways Involved

In Glioblastoma there are a few things that go wrong in signaling. As discussed previously, EGFR is amplified in Glioblastoma. This leads excess cellular signaling to produce new cells. Some pathways included in this are cAMP, MAPK, and PI3K.

  • When a ligand like epidermal growth factor bind to the RTK receptor, signaling occurs that activates RAS. In turn, RAS activates RAF, MEF, and then MAPK. MAPK then activates CREB to lead to cell production. In Glioblastoma, MAPK becomes hyperactivated which leads to increased cell production.
  • When a growth factor binds to the RTK receptor. PI3K is recruited to the receptor and allows for cellular signaling in the cell that leads to CREB becoming activated. In Glioblastoma PI3K amplified and CREB is hyperactivation causes increased cell production.
  • When a ligand binds to the G-coupled protein receptor, adenylyl cyclase converts ATP to cAMP. cAMP activates PKA which inhibits tumor growth by activating gene transcription. cAMP is lower in Glioblastoma and cannot activate PKA. PDE degrades cAMP in Glioblastoma and tumor growth is not inhibited.1

Each of these pathways can be targeted for the treatment of Glioblastoma. This figure shows how each pathway is involved in gene transcription and how different medications may effect these pathways.

Possible Treatments

Two major factors involved in increased cell production in Glioblastoma is EGFR amplification and CREB hyperactivation.

EGFR gene amplification is also found in other cancers. Unfortunately, targeting EGFR in cancer treatment has not shown to be effective against Glioblastoma. EGFR inhibitors have helped with other cancers, but trials with Glioblastoma have not shown promise. A specific genetic variant of EGFR, ΔEGFR, is specific to tumors. Treatment with a ΔEGFR monoclonal antibody has shown to decrease tumor growth and increase cell death.2

CREB inhibition on the other hand shows more promise. Other medications that inhibit signaling in RTK receptors leads to decreased CREB activation. This was shown to decrease tumor cells. CREB inhibitors are currently in pre-clinical trials for the treatment of cancer and could be a potential treatment of Glioblastoma.3

Glioblastoma is a very aggressive and difficult disease to treat. Exploring the different pathways involved in Glioblastoma can provide new solutions to treatment. Targeting EGFR and CREB has shown some promise, but different aspects of these pathways need additional discovery.

  1. https://doi.org/10.1016/j.cellsig.2019.01.011
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464093/
  3. https://www.mdpi.com/2072-6694/12/11/3166 
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Complexity of Glioblastoma – Types, Treatment Options, and More

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What is Glioblastoma? 

Glioblastoma (GBM) is a fast-growing and aggressive malignant brain tumor. It is a very invasive form of cancer which means it has one of the worst survival rates across all types of cancer. GBM accounts for about 50% of all malignant cancers and the 5-year survival rate is around 6%. It is also estimated that almost 10,000 Americans will succumb to GBM every single year.

The symptoms of GBM can include things like headaches that keep getting worse, seizures, nausea, changes in personality, weakness in one side of body, memory loss and speech difficulty. These symptoms can be seen in MANY other diseases, which makes GBM hard to discover and diagnose. The median amount of time before discovery of the tumor is around 330 days, which allows a lot of time for the tumor to grow to nearby cells of the brain.

Subtypes of GBM?

There are four subtypes of GBM that have been discovered and researched.

  1. Classical
    • Over expression of epidermal growth factor receptors and responds best to aggressive treatment.
  2. Mesenchymal
    • Over expression of regulatory components of MAPK and PI3K pathways. Responds best to aggressive treatment.
  3. Proneural
    • Occurs in younger patients and has an over expression on chromosome 4q12. Less responsive to aggressive treatment, but has longer survival time.
  4. Neural
    • No obvious pattern of over expression or mutation. Worst survival rate and no improvement with aggressive treatment.

What is Going Wrong?

MAPK Pathway:

  • This pathway is activated by a ligand binding to its receptor tyrosine kinase (RTK) which results in a cascade of activation and phosphorylation. RAS activates RAF which activates MEK which activates ERK/MAPK. In GBM, NF1 is being over expressed which is inhibited the activation of RAS, which stops the activation of the molecules after that.

 

PI3K Pathway:

  • This pathway is activated by a ligand binding to its receptor tyrosine kinase (RTK) which results in a cascade of activation and phosphorylation. PI3K is recruited to the RTK by the p85 subunit which then activates another subunit p110. The p110 subunit converts PIP2 to PIP3, and PIP3 activates AKT which then activates mTOR, promoting cell survival. In GBM, PTEN inhibits the conversion of PIP2 to PIP3, which stops the activation after that.

cAMP Pathway:

  • This pathway is activated by aa ligand binding to G-Protein Coupled Receptors (GPCR). Adenylyl Cyclase converts ATP to cAMP which in turn activates PKA to inhibit tumors. In GBM, PDE is inhibiting this pathway meaning it is under expressed, which results in tumor growth.

 

There are three different pathways involved in GBM, which makes treating it extremely difficult. These pathways are over and under expressed so finding the ‘sweet spot’ for each pathway is a difficult task. These pathways can also cross over into each other adding more confusion when trying to treat GBM.

GBM Treatment: 

Because of the complexity of GBM, finding the proper treatment is just as complex. Treatment options include surgery, radiation therapy, chemotherapy, and antibody therapy.

Antibody therapy uses the immune system to help attack cancer cells. Monoclonal antibodies are made in the lab to mimic the bodies natural antibodies. They are infused into the body and are made to attack cancer cells, disrupt the cell membrane of cancer cells, and help T-cells kill cancer cells.

While there are many treatment options to choose from when dealing with GBM, it can can cost a lot of money as well as take an emotional and physical toll on the body. There are many natural ways to try and treat cancer without having to spend most of the time in a hospital bed. Things such as acupuncture, exercise, meditation, cognitive behavior therapy, and music therapies are just a few ways to naturally treat cancer. It is important for the person diagnosed with these types of diseases to consider the ways they want to spend their limited amount of days. Some people may want to try every medical advancement to treat themselves while others may want to find natural ways to spend the rest of their days at peace with themselves. Either way, it is important to understand the statistics of GBM, what is happening in the body, and the options for treatment.

 

References:

braintumor.org/…ss-day/about-glioblastoma

pubmed.ncbi.nlm.nih.gov/29727799

mayoclinic.org/…glioblastoma/cdc-20350148

cancer.gov/…therapy/monoclonal-antibodies

https://doi.org/10.1016/j.cellsig.2019.01.011

 

 

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Addicted Brains Explained

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Addiction is defined as having a craving or dependence to a substance, thing, or activity. Addiction can be tied to a natural reward such as sleep, food, etc. whereas it can also be tied to an unnatural reward such as substances. Unnatural addictions such as drugs or alcohol can be life threatening at times and turn into a horrific cycling pattern if trying to withdraw and stop usage.

In the brain there are three areas of the brain an addiction behavior can go through:

  1. The first is the basal ganglia, the portion of the brain that controls the reward response to the substance use and helps to form the habits around substance use.
  2. The second is the extended amygdala that associates with the feelings of discomfort, anxiety, stress that usually follows substance withdrawal.
  3. The third is the prefrontal cortex which controls the ability to have control over the substance usage.

 

Figure 1: The different areas of the brain affected by addiction. https://www.ncbi.nlm.nih.gov/books/NBK424849/

The overwhelming effects of addiction occurs when this cycle repeats itself and the addiction grows stronger after making those rewarding affects attainable with the substance rather than without.

Studies suggest that individuals with an addiction to substances have a reduction in sensitivity for the brain’s reward system (brain circuits with dopamine receptors). Therefore, once pleasurable or stimulating activities no longer have the same effect as they once did, an individual going through withdrawal symptoms will want to regain the same pleasurable feelings the reward system once provided but only be able to do this through the substance.

At the more neuronal level, during the withdrawal stage there is an activation of the stress neurotransmitters in the extended amygdala. These NTs include corticotrophin-releasing factor (CRF), norepinephrine, and dynorphin. These neurotransmitters have been shown to play a key role in negative feelings associated with withdrawal. Therefore, to get rid of the negative emotions from withdrawal a lot of individuals tend to use the substance again. In other words, the individual is experiencing negative reinforcement every time they use the substance again to rid themselves of the negative emotions and this is how the cycle continues.

Taking a closer look at the brain it is important to understand the difference between an addicted brain versus an unaddicted brain to a substance. In the control brain, VTA dopaminergic neurons project to NAc whereas with the addicted brain neurons there is an increase of dopamine in NAc (Nucleus accumbens) leading to tolerance, sensitization, and adaptation to the substance. In the addicted brain, the VTA neuron appears smaller as the NAc portion is larger in size with more branching, leading to the effects of becoming addicted to a substance and unable to stop.

Figure 2: Image of neurons in the brain from Nestler article (2005).

Overall, addiction starts as a choice and turns into a gray area where the choice of using a substance is no longer there. As there has been some controversy on whether addiction is a disease, in the future when we learn more about addiction and what more is happening in the brain can we decipher if the individual has a choice or if that choice is no longer there once the brain creates tolerance, sensitization, and adaptation to the substance.

 

References:

Substance Abuse and Mental Health Services Administration (US), Office of the Surgeon General (US), and US Department of Health and Human Services. 2016. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK424849/

Nestler, Eric. 2005. Is there a common molecular pathway for addiction? Nature Neuroscience: Neurobiology of Addiction.

Leyton, Marco. 2013. Are addictions diseases or choices? Journal of Psychiatry & Neuroscience. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692718/

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