Detailed study about Glioblastoma multiforme with treatments and newer invention in the medicines and the target therapies associated. one can know about symptoms, causes and risk factors of the disease from this presentation.
Pharmacological Management Of Glioblastoma Multiforme
1. PHARMACOLOGICAL MANAGEMENT OF
GLIOBLASTOMA MULTIFORME
PRESENTED BY: ADWITIYA MITRA
ROLL: MPH/10029/21
Department of Pharmaceutical Science and Technology
Birla Institute of Technology
Mesra
2. GLIOBLASTOMA MULTIFORME
INTRODUCTION
• Glioblastoma multiforme or GBM is the most common and aggressive
malignant primary brain tumor in human.
• It involves the glial cells and astrocytes of the brain.
• It accounts for 52% of all functional tissue of the brain tumor cases and
20% of all intracranial tissue.
• GBM are also considered as grade 4 cancers.
• It spreads and grows too rapidly.
• Glioblastoma cells make their own blood supply which mainly helps
them to grow.
• Cerebrum is the main associated part of brain in GBM.
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https://www.mayoclinic.org/diseases-
conditions/glioblastoma/cdc-20350148
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CHARACTERISTICS:
• Mostly invasive type.
• Commonly spreads to nearby tissues
• It grows rapidly
• It include distinct genetic types.
• Composed of different kind of cells like astrocytoma,
glial cells or oligodendrocytes.
• GBM generally regrow within 1- 2 cm of its site of
origin .
• It never spread to any other organ.
• Oxygenation of the malignant cell makes them more
susceptible to subsequent therapies.
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5. SYMPTOMS:
• Persistence headache.
• Loss of appetite.
• Changes in Mood.
• Change in ability to think and
learn.
• Speech difficulty.
• Double or blurred vision
• Vomiting
• Seizures.
• Sleep wake disturbances.
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CAUSES:
• Glioblastoma cells have more genetic abnormalities than the cells of other
type of astrocytoma brain cancer.
• These genetic mutations are generally caused by
a. inherited DNA defects
b. cumulative effects of exposure to chemicals and other carcinogens.
c. high dose exposure to ionic radiation.
d. additional unidentifiable triggers.
• Glioblastoma and smoking seems no relation.
• CMV or cytomegalovirus has a prominent contribution on GBM.
• Female anopheles plays an role in carrying viruses that may cause GBM.
• Lead exposure at work place may cause GBM.
OTHER RISK FACTORS:
• Age: mainly adults above 40 years.
• Ethnicity: Caucasians , Asians
• Already having low grade astrocytoma are
more susceptible to GBM
• Neurofibromatosis , tuberous sclerosis also
acts as a contributing factor.
• Men are more susceptible.
7. 7
DIAGNOSIS:
• These tumors were diagnosed by imaging studies and tumor biopsy.
• In biopsy GBM can be diagnosed by the presence of cell necrosis or cell death.
• Currently MRI is the best available imaging modality.
• CT scans are also used now a days.
• For either study an agent that provide contrast in the image is generally administered intravenously so
neurosurgeon can visualize the tumor comparing against the normal brain in the background.
https://www.researchgate.net/profile/Tom-Mikkelsen-3/publication/49844790/figure/fig2/AS:305740519624706@1449905628GTR.png
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PATHOPHYSIOLOGY
IDH Mutation:
• Mutations in IDH or Isocitrate dehydrogenase were found in all kinds of glioblastoma
but are rare in primary or grade 1 GBM.
• IDH mutation involves both a loss and gain of regular enzymatic function .
• It leads to decrease in binding affinity of isocitrate and its subsequent conversion to
the alpha ketoglutarate is also prevented.
• IDH mutation also leads to increase binding of the NADPH and results in incomplete
reaction by only reducing alpha ketoglutarate without carboxylation.
• This in turn forms 2-hydroxyglutarate instead of alpha KG .
• The abnormal accumulation of 2-HG is responsible for carcinogenesis.
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TREATMENT ASSOSCIATED
• Mutant IDH or mIDH inhibitors being identified as a whole new se of treatment.
• These target therapies help to separate proliferating cancer cells from the normal cells.
• AGI 5198 is the new molecule was successful in inhibiting the oncometabolite 2HG.
• It is mIDH1 inhibitor.
• Further optimization of AGI5198 led to another molecule AG 120 which became the first mIDH1 inhibitor to pass human
trials.
• AG120 or IVOSIDENIB is an oral preparation though not FDA approved till this date.
• AGI5198 was discovered to almost completely block the activity of mIDH1 to produce 2 HG and induced expression of
genes involved in glio genesis.
• But it failed in clinical trials due to rapid metabolism and clearance.
• AG221 or ENASIDENIB, another molecule that is orally active and approved by FDA, is a selective inhibitor of mIDH2.
• This drug has promising effect against advanced solid tumors.
• AG881 or VORASIDENIB is another orally available non specific inhibitors of mutant IDH.
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NOTCH PATHWAY:
• The Notch signaling pathway plays an important role in cell proliferation and apoptotic events in different cell types and
tissues including neurons of the CNS.
• Notch 1, Notch 2, Notch 3, and Notch 4 are four receptors associated in this pathway.
• Notch 1 is found either in tumor suppressor or an oncogene based on tissue type.
• It is found to be associated with glioma progression to determine the malignant phenotype of glioma.
• Notch 2 was determined as the prognostic marker for glioma.
• Notch 3 promotes glioma cell proliferation
• Notch 4 was found to correlate with tumor aggression.
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TREATMENT ASSOCIATED TO NOTCH PATHWAY:
• Notch pathway now seems to be a potential and effective target in treatment of grade 4 glioma.
• Inhibitors of Notch pathway are classified as alpha secretase inhibitors or gamma secretase inhibitors.
• Gamma secretase inhibitors or GSI induces activation of bone morphogenetic factor or BMP4.
• BMP4 being a member of TGF beta helps in maintaining neuronal stem cells or NSC where it regulates both self
renewal and differentiation of NSC. It significantly regulates GCSC population and hence regulates human
tumorigenesis.
• GSI didn’t achieved much importance because the efflux pumps hampers effectiveness of GSI as it acts inside the cell.
• ASI acts on the plasma membrane instead inside the cells and hence escapes the efflux pumps and are more prominent
therapy in targeting Notch pathway.
• One of the identified ASI compound is INCB3619.
• This in turn prevents ADAM10 and 17 from causing shedding and activation of epidermal growth factor.
• Non specific ADAM inhibitors decreases notch activity and inhibit epidermal growth factor.
12. 12
CERAMIDE SIGNALING:
• Acid ceramidase (ASAH1) is an enzyme that metabolizes ceramides into sphingosine and free
fatty acids.
• Ceramides promotes senescence and cell death.
• Sphingosine 1 phosphate(S1P) is the immediate product due to metabolism fosters cell
proliferation and cell survival.
• Histologically confirmed glioma cell shows a change from ceramides to sphingosine 1
phosphate that leads to higher concentration of S1P than ceramide.
• With lower amounts of ceramides apoptosis occurs less.
• Modification of ASAH1 in glioblastoma enables it to be secreted to interstitial tissues.
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TREATMENT ASSOCIATED TO CERAMIDE SIGNALING:
• ASAH1 can contribute to the development of drug resistance to tumor.
• Hence ASAH1 inhibitors have been studied as a treatment of GBM.
• ASAH1 inhibitors were found more cytotoxic than the FDA approved drugs but still the whole clinical trial reports are
unavailable.
• These class of drugs generally target U87MG cells that contains CD133 biomarker.
• ASAH1 inhibitors mainly include the molecule ARN14988.
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VASCULAR ENDOTHELIAL GROWTH FACTOR SIGNALING PATHWAY
• Vascular endothelial growth factor VEGF is a potent angiogenic cytokine.
• It stimulates the growth of new blood vessels to restore oxygen supply.
• The normal VEGF pathway starts when cells lack oxygen, that leads to hypoxia inducible factors.
• This leads to VEGF followed by its binding to VEGFR stimulating the tyrosine kinase pathway and ultimately resulting in
angiogenesis.
• Unfortunately VEGF also plays a key role in promoting angiogenesis in glioma stem cells.
• For survival of glioblastoma a vascular supply must be maintained and early extensions in growing tumor receive this vascular
supply by angiogenesis.
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TREATMENT ASSOCIATED TO VEGF:
• Blocking of VEGF pathway and thereby inhibiting angiogenesis
brings an effective strategy to treat GBM.
• Anti VEGF has shown benefits in reduction of vasogenic edema
associated with this disease.
• On recent study combination of anti VEGF and Platelet derived
growth factor PDGF inhibitors showed more promising results.
• Cediranib and vatalanib are the drugs that comes under the combined
therapy whose studies are still ongoing.
• In the clinical setting several receptor tyrosine kinase inhibitors such
as tivozanib are studied.
• Bevacizumab and TTAC001 are known VEGF antibody also playing
a major role in the treatment of GBM
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PLATELET DERIVED GROWTH
FACTOR(PDGF) SIGNALING
• PDGF signaling starts with binding of the PDGF ligands like
PDGFA, PDGFB, PDGFC to PDGF receptors.
• PDGF receptors are of further two types namely PDGF alpha and
beta.
• It promotes cell proliferation and survival.
• A PDGF autocrine loop is exhibited in glioblastoma that should be
absent in normal cells.
• PDGFA and PDGFB are overexpressed in GBM.
• The alpha gene is amplified, mutated and rearranged in GBM
tumor.
• Autocrine signalling plays an important role along with PDGF
signalling.
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TREATMENT ASSOCIATED TO PDGF SIGNALLING:
• A new molecule AG1433 was discovered as PDGF inhibitor.
• It showed actions to control cell proliferation and growth.
• Another TKI inhibitor named Imatinib was successful at enhancing the radiosensitivity and chemosensitivity
of the gliomas.
• The PDGF alpha expression also decreased.
• Tandutinib, Crenolantib are the drugs that are currently being studied which targets PDGF receptors along
with inhibiting tyrosine kinase.
• Anti PDGF antibody reduces cell viability in malignant cell but not in normal fibroblast.
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PI3K/ATK/ mTOR PATHWAY:
• This pathway is a vital pathway for regulating cell cycle.
• Phosphatidylinositol-3-kinases (PI3K) are intracellular signal transducer enzyme that can activate serine / threonine
specific protein kinase (ATK) through phosphorylation.
• ATK on the other hand activate mammalian target of rapamycin (mTOR).
• TOR have two binding partner namely mTORC1 and mTORC2.
• The mTORC1 is rapamycin sensitive and promotes glial cell growth upon activation by eukaryotic translation factor
4E binding protein 1 (E4BP1). And ribosomal protein S6K.
• mTORC2 drives glial cell proliferation, motility and survival through activation of AGC protein Kinase.
• mTORC2 is also involved in the induction of the Warburg effect, a metabolic process by which tumor cells
metabolize glucose via the aerobic glycolysis also in the presence of sufficient oxygen levels to supply the
macromolecular demand of rapidly growing cells
• The over reaction of the whole pathway reduces survival of glioma patients and increases aggression of the tumor.
• Overstimulation is also responsible for cell proliferation, survival and migration of the glioblastoma.
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TREATMENT ASSOCIATED TO PI3K/AKT/mTOR PATHWAY:
• Clinical trial showed that mTOR inhibitors to be a successful target for treatment of glioblastoma.
• The TOR inhibitors are capable of inhibiting glioblastoma growth by blocking mTORC2 activity.
• mTOR inhibitors also include temsirolimus, everolimus and siroquine.
• CC214-1 AND CC214-2 are another molecules that are orally available mTORC2 inhibitors.
• PIK3 inhibitors such as BKM120 and regorafenib , GDC0085 and fimepinostat are shown to be useful.
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FDA APPROVED CHEMOTHERAPEUTIC AGENTS:
• FDA has approved 3 chemotherapeutic agents till this date for the patients with glioblastoma.
• Temozolomide, bevacizumab and carmustine are the approved drugs.
• TMZ significantly increases the OS .
• The same study found that o-methylguanine-DNA- methyl transferase (MGMT)gene methylation is positive
prognostic indicator foe TMZ chemotherapy for newly diagnosed patients..
• Bevacizumab is an anti VEGF monoclonal antibody has shown anti glioma activity with increased PFS, but no
significant terms in OS.
• Carmustine is a nitrosourea class of drug that intercalated the DNA of the genes encoding for glioblastoma.
• It is avoided due to severe bone marrow, liver and kidney toxicity.
• Local delivery of carmustine in the form of implants in an resection cavity is given followed by surgery can
reduce these systemic effects and also improves median OS.
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LASER INTERSTITIAL THERMAL THERAPY(LITT)
• When surgical removal of tumor is unsuitable, LITT offers treatment in glioblastoma patients by destroying the
tumor cells with localized elevated temperatures.
• Thermal therapy can also be achieved by using radiofrequency, ultrasound, microwave and magnetic
nanoparticle(MNP) treatments.
• Laser induced thermotherapy offers the advantage of minimal invasiveness.
• MRI guided LITT is safe and can also destroy peritumoral blood brain barrier for therapeutic permeability.
• LITT also enhances PFS of difficult to access glioblastoma.
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TUMOR TREATING FIELDS (TTfields):
• Ttfields is a technology which creates alternating electric fields of low intensity of 1-3 v/cm and intermediate
frequency of 100 to 300 KHz,
• This interrupts the prolific cell division of the cancer cells and leaves the quiescent and non dividing cells in
human body unaffected.
• Results from clinical trials showed that Ttfields along with TMZ chemotherapy significantly increases the OS
and PFS without any serious negative impact.
• Though it limits it use because of high cost.
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IMMUNOTHERAPY:
Immunotherapy selectively targets and kills tumor cells. There are numerous strategies toward the development of an immune
response such as immune check point inhibitors, oncolytic virus therapy, vaccine therapies, modified T cells therapies and gene
therapies.
IMMUNE CHECKPOINT INHIBITORS:
• Immune checkpoints have the ability to cross the blood brain barrier.
• CPI includes nivolumab, durvalumab, atezolizumab etc.
T CELL THERAPY:
• T cell therapy has been demonstrated as promising and emerging therapy.
• T cells are engineered to express chimeric antigen receptors.
• These CAR T cells have been focussed on targeting CD70 cells, HER2 and Interleukin 13.
VIRAL THERAPY:
• Oncolytic virus exerts its effect by oncolysis, virus induced anti tumor immunity and immunoregulatory inserts.
• Highly immunosuppressive nature of glioblastoma and on the other hand immunostimulatory effect of oncolytic virus became
the concentration of the current viral therapy.
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SURGICAL THERAPY:
• The extent of surgical resection depends upon the location of the tumor and the surrounding
brain areas.
• Surgery prolongs survival but not for much time.
• Residual tumors are present in most of the cases and that causes recurrence.
• Maximal surgical resection with attention given to conservation of neurological function is
an essential goal of the treatment.
PALLIATIVE THERAPY:
• Palliative treatments are usually carried out to improve the quality of life and to achieve
longer OS.
• These includes surgery chemotherapy and radiation.
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CONCLUSION
Glioblastoma multiforme is the frequent malignant brain tumor with male predominance. It is considered as
the most devastating malignancy minimum survival rate of less than 5 percent .
But at recent times there has been a major advancement in the treatment of glioblastoma. This era of targe
therapy goes very long with the deadly disease and ongoing clinical trials of various therapy provides a hope
for the glioma patients to fight. The improvement in the lives of the patient and to increase the overall survival
rate is the foremost goal of newer invention in therapies and drug.
27. 27
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Schmainda KM. Acid ceramidase and its inhibitors: A de novo drug target and a new class of drugs for killing glioblastoma cancer
stem cells with high efficiency. Oncotarget. 2017 Dec 22;8(68):112662.
Mecca C, Giambanco I, Donato R, Arcuri C. Targeting mTOR in glioblastoma: rationale and preclinical/clinical
evidence. Disease markers. 2018 Oct;2018.
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glioma. Neoplasia. 2017 Apr 1;19(4):261-70.
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