Cancer🧬 Flashcards
(8 cards)
EBL: Describe the molecular mechanisms of the development of epilepsy. What is autoimmune epilepsy and paraneoplastic autoimmune epilepsy? Which are the therapeutic approaches used in each case?
1) Excitatory and Inhibitory Neurotransmitter Imbalance
Increased excitation / Decreased inhibition: Seizures can result from an imbalance between excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmission.
Synapsin mutations: Genes like SYN1 and SYN2, which regulate neurotransmitter release, are linked to epilepsy. Their deletion may disrupt excitatory/inhibitory balance and lead to seizures.
2) Abnormal Synaptic Plasticity and Network Hyperexcitability
Ion channel mutations (e.g., sodium, potassium, GABA receptors) impair ion flow, promoting abnormal firing.
Autoantibodies and CD8+ T cells can block neuronal ion channels, altering excitability.
Synaptic plasticity (changes in synapse strength) may enhance hyperexcitable networks, especially when inhibitory synapses are weakened.
3) Inflammation & Immune Dysregulation
Cytokines (e.g., IL-6, TNF-α) can increase neuronal excitability and promote seizures.
Blood-brain barrier (BBB) disruption allows entry of autoantibodies (e.g., IgG), contributing to autoimmune epilepsy.
Encephalitis and COX-2 upregulation can cause neuronal damage and trigger epileptogenesis.
What is autoimmune epilepsy?
Autoimmune epilepsy is a general term for epilepsy mediated by or associated with antibodies sometimes linked to cancer. Causes:
Autoimmune encephalitis (most common cause): immune-mediated attack on neuronal tissue, often targeting cell surface or intracellular antigens.
Surface antigen antibodies are directly pathogenic and commonly associated with acute symptomatic seizures (e.g. anti-NMDAR, LGI1, CASPR2, GABAaR, AMPAR)
Intracellular antigen antibodies are typically associated with T-cell mediated neuronal injury, a higher risk of chronic epilepsy, and poorer immunotherapy response (e.g. GAD65, ANNA-1, Ma2)
Clinical Features: frequent/refractory seizures, cognitive and psychiatric symptoms, new-onset refractory status epilepticus (NORSE) or febrile infection-related epilepsy syndrome (FIRES).
Rasmussen syndrome: unilateral brain inflammation, mediated by cytotoxic T cells -> leading to drug-resistant focal seizures, cognitive decline, and hemiparesis.
Seizures often persist despite immunotherapy -> surgical intervention (hemispherectomy) may be considered.
Paraneoplastic Epilepsy: subset of autoimmune epilepsy
triggered by an immune response to tumours that express onconeural antigens also found in normal brain tissue.
Commonly associated with antibodies to intracellular antigens (e.g. ANNA-1 [anti-Hu], Ma2, PCA-1)
Typically results from T-cell mediated damage, often in lung, breast or ovarian cancers
Show limited response to immunotherapy due to irreversible neuronal injury.
Which are the therapeutic approaches used in each case?
Autoimmune Epilepsy: Seizure medicines usually don’t control these seizures well.
immunotherapy may be very effective in AE. Immunotherapy is a way of treating the inflammation in the brain.
The treatment is typically steroids (such as methylprednisolone or prednisone) given by mouth or into the blood stream (intravenous, IV).
Immunoglobulin (IVIg) may also be given into the bloodstream -> receptor CD20 expressed on surface of B cells -> prevent B cells from producing antibodies
Target Interleukins, Human Growth Factor
Starting immunotherapy early in non-paraneoplastic AE is important to quickly stop seizures and prevent injury to brain cells.
Paraneoplastic Epilepsy:
Generally, those with cancer-related autoimmune epilepsy may not do as well as people with antibodies that target the surface of brain cells (e.g., NMDA receptor antibody or LGI-1 antibody encephalitis).
In paraneoplastic AE, treating the underlying tumor is also critical where feasible.
Abnormal ATP production in mitochondria
Selectively inhibit cells of immune system which produce antibodies -> b cells
EBL: Discuss novel approaches of formulation and drug targeting, such as implants, responsive pump systems, repurposing of drugs, novel formulations changing PK, PEGylation of colloids, nano-formulation.
Novel approaches in drug formulation and targeting are advancing the precision and efficacy of therapies. Key strategies include:
Implants for controlled release - solid dosage forms inserted into the body, offering sustained drug release for chronic conditions (e.g. contraceptives, cancer therapies)
Responsive pump systems - devices that release drugs based on external stimuli (e.g. temperature or pH) allowing personalised, on-demand drug delivery
Drug repurposing - investigating existing drugs for new therapeutic used which can reduce developmental time and cost (e.g. thalidomide for cancer treatment)
Modifying pharmacokinetics - altering drug formulations (e.g. prodrugs, extended-release) to optimise absorption, distribution, and metabolism to improve patient compliance
PEGylation of colloids - attaching polyethylene glycol to drugs or nanoparticles to enhance circulation time, reduce immune response, and improve solubility (e.g. pegylated liposomal Doxorubicin)
Nano-formulation - using nanoparticles for targeted delivery, improved solubility, and controlled release, often applied in cancer therapy and gene delivery
Smart drug delivery systems - systems that release drugs in response to specific physiological cues (e.g. pH, temperature) enabling more precise treatment
These innovations aim to improve drug efficacy, reduce side effects, and enhance patient adherence, particularly for complex and chronic conditions.
Gliadel wafers are small, implantable devices used in brain tumor surgery to deliver the chemotherapy drug carmustine directly to the tumor and surrounding area. They are placed during the tumor removal procedure by a neurosurgeon. Gliadel wafers are a treatment option for glioblastoma multiforme (GBM) and high-grade glioma.
Responsive Neurostimulation (RNS) is a surgical treatment for epilepsy that involves implanting a device in the skull to monitor brain activity and deliver electrical pulses when it detects potential seizure activity, potentially stopping seizures before they start. The RNS System is designed to reduce seizure frequency and improve quality of life for individuals with medically refractory epilepsy.
Repurposing drugs - only metformin is approved in uk
PEGylation, the process of attaching polyethylene glycol (PEG) to a drug or molecule to improve drug delivery and efficacy. Reduces immune response
EBL: What are the recommended antiepileptic drugs for managing epilepsy during pregnancy, and what specific considerations should pharmacists keep in mind when counselling pregnant women on these medications?
The recommended antiepileptic drugs for managin epilepsy during pregnancy…
Lamotigrine
Levetiracetam (kepra)
The Commission on Human Medicines has confirmed that lamotrigine (Lamictal) and levetiracetam (Keppra) are the safer of the medicines reviewed during pregnancy.They’re associated with a lower risk of birth defects and better neurodevelopmental outcomes than older AED like valproate.
Levetiracetam and lamotrigine both cross the placenta during pregnancy but don’t cause toxicity to foetus
EBL: List the common drug-drug interactions between anti-epileptic drugs and cancer chemotherapeutics and what the expected outcome is from the interaction, aswell as the mechanism of how this occurs.
Enzyme inducing AEDs - common antiepileptic drugs e.g phenytoin, carbamazepine and phenobarbital are strong inducers of cytochrome P450 enzymes e.g CYP3A4, which increases the metabolism of many chemotherapeutic agents and lowers their plasma concentrations. Overall causes a reduced efficacy of chemotherapy and risks treatment failure. This affects chemo therapies such as irinotecan, cyclophosphamide, methotrexate, paclitaxel, etoposide, imatinib.
Valproate is an enzyme inhibitor (especially UGT) and may increase levels of drugs that are metabolised by UGT e.g irinotecan. Also increases hematologic toxicity when used with certain chemotherapies.
Phenytoin + 5-FU/Capecitabine: increased phenytoin levels due to inhibition of phenytoin metabolism, which can lead to toxicity such as ataxia, nystagmus, confusion.
Phenytoin + Cisplatin: can lead to decreased plasma concentrations of phenytoin, leading to reduced seizure control and risk of seizure breakthrough. .
Valproate + Methotrexate: both compete for hepatic metabolism, increased risk of CNS toxicity or hepatotoxicity.
Carbamazepine + Cyclophosphamide: enhanced cyclophosphamide metabolism to toxic intermediates which can lead to increased risk of myelosuppression
Levetiracetam is most commonly used and has minimal interactions.
Lamotrigine is also mostly safe and rarely affects chemo agents, but does have some UGT interactions.
EBL: Considering the hallmarks of cancer explain the rationale for the use of temozolamide in the treatment of brain tumours? What is its mechanism of action? Which are the mechanisms of resistance to temozolomide therapy?
Slowing cell growth and reducing tumour volume can help limit the ability of cancer cells to invade nearby brain tissue (invasion and metastasis).
Adding methyl groups to DNA bases, particularly O6-guanine , leads to replication errors and ultimately cell death. This directly interferes with the tumour’s ability to sustain uncontrolled growth and resist cell death.
Temozolomide increases instability by introducing additional DNA errors, past the point of recovery (genome instability and mutation).
If the MGMT gene is active (DNA repair enzyme), the tumour is more resistant to treatment. But if the MGMT promoter is methylated, meaning the gene is silenced, the tumour cells can’t repair the damage, making them more sensitive to temozolomide.
Can pass BBB
Alkylating agent that adds methyl groups to DNA bases, primarily at the O6 and N7 position of guanine. This methylation leads to base mispairing during DNA replication, triggering a mismatch repair response. When the repair repeatedly fails, it results in DNA strand breaks and ultimately induces cell cycle arrest and apoptosis.
EBL: Outline the name and mechanism of action of at least SIX susceptibility genes associated with epileptic symptoms in patients with neurological tumours, and their role in the screening of high-risk patients and primary prevention
Polymorphism of SLC7A11, GluR1 and AMPA (genes involved in glutamate release)
SLC7A11 (or xCT) is responsible for importing cystine into the cell in exchange for exporting glutamate. Overexpression can cause hyperexcitability and increasing seizure risk due to increases in glutamate
Glioma cells release glutamate, which causes excitotoxic death of surrounding neurons. The release of glutamate occurs primarily via a Na+ independent cystine-glutamate exchanger and may contribute to seizures that start in the peri-tumoral regions.
GABA-B dysfunction
Dysfunction of both pre- and postsynaptic GABA-B receptor mediated processes contributes to temporal lobe epilepsy.
GABA may also play a direct immunomodulatory role in the brain which may cause neurochemical changes in intra- and peri-tumoral regions, thereby affecting tumour growth as well as tumour-associated seizures.
Polymorphisms of interleukins (IL) IL- 1β-511
Cytokines have modulating effects on neurotoxic neurotransmitters during excitation and inflammation in the CNS.
Immune-mediated neuronal damage of the peri-tumoral brain area, coupled with the balance between stimulatory and inhibitory cytokines, may contribute to the development of tumour-related epilepsy
Polymorphisms of apolipoprotein E (ApoE)
High levels of amyloid β. ApoE isoforms, particularly APOE4, can alter pre- and post-synaptic molecules and increase neuron excitability.
Polymorphisms of prodynorphin gene promoter (PDYN)
Endogenous dynorphin is an opioid with several physiological effects including a role in the regulation of hippocampal excitability, indicating a probable anticonvulsant effect. Patients with temporal lobe epilepsy carrying the low frequency PDYN allele showed a higher risk of developing secondary generalized seizures and status epilepticus.
Polymorphism of serotonin receptor 5-HT7
Variations in serotonergic activity are linked to both the development of epileptic foci and the severity of seizures. Decreased serotonin is associated with seizure susceptibility however increases in serotonin like in serotonin syndrome can also cause seizures.
Brain-derived neurotrophic factor (BDNF)
Brain-derived neurotrophic factor (BDNF) regulates neuronal formation and has neuroprotective effects by increasing NMDA receptor activity, thus increasing neural excitability
Increased BDNF expression and other neurotrophic factors in the brain may be involved in the growth regulation of tumours of glioneuronal origin.
Glial cell line-derived neurotrophic factor (GDNF)
GDNF usually provides a neuroprotective effect and increases GABA. Decreased activity of GDNF means reduced GABA and increased risk of seizures.
P53 tumour suppressor.
EGFR
Cyclin-dependent kinases (CDKs): Cyclin D1 is a protein that regulates cell cycle progression by forming complexes with cyclin-dependent kinases (CDKs) like CDK4 and CDK6, primarily in the G1 phase of the cell cycle. These complexes phosphorylate and inactivate the retinoblastoma protein (Rb), which then releases E2F transcription factors, ultimately promoting cell cycle progression.
Appolipto protein E
EBL
Considering the hallmarks of cancer explain the rationale for the use of temozolamide in the treatment of brain tumours? What is its mechanism of action? Which are the mechanisms of resistance to temozolomide therapy?
Model
SPC States - Temozolomide is a triazene, which undergoes rapid chemical
conversion at physiologic pH to the active monomethyl
triazenoimidazole
carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the 06 position of guanine with additional alkylation also occurring at the N? position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl
adduct.
MGMT Methylation
The O6-methylguanine-DNA methyl- transferase (MGMT) gene is located on chromosome 10q26.3, and encodes a highly evolutionarily conserved and ubiquitously expressed enzyme involved in DNA repair.
MGMT acts by removing alkyl adducts from the O position of guanine at DNA level, thus antagonizing the lethal effects of alkylating agents.
MGMT gene promoter methylation induces loss/low levels of functional MGMT protein, thus producing inadequate repair of DNA alkylation in response to alkylating chemotherapy
Ours
Slowing cell growth and reducing tumour volume can help limit the ability of cancer cells to invade nearby brain tissue (invasion and metastasis).
Adding methyl groups to DNA bases, particularly O6-guanine , leads to replication errors and ultimately cell death. This directly interferes with the tumour’s ability to sustain uncontrolled growth and resist cell death.
Temozolomide increases instability by introducing additional DNA errors, past the point of recovery (genome instability and mutation). (alkylation)
If the MGMT gene is active (DNA repair enzyme), the tumour is more resistant to treatment. But if the MGMT promoter is methylated, meaning the gene is silenced, the tumour cells can’t repair the damage, making them more sensitive to temozolomide. (removes methyl group,)
Can pass BBB
Alkylating agent that adds methyl groups to DNA bases, primarily at the O6 and N7 position of guanine. This methylation leads to base mispairing during DNA replication, triggering a mismatch repair response. When the repair repeatedly fails, it results in DNA strand breaks and ultimately induces cell cycle arrest and apoptosis.
EBL
Outline the name and mechanism of action of at least SIX susceptibility genes associated with epileptic symptoms in patients with neurological tumours, and their role in the screening of high-risk patients and primary prevention
Model
- Gamma-aminobutyric acid (GABA) acts on the type A and type B receptor to control
neurotransmitter release and postsynaptic silencing of excitatory neurotransmission.
Dysfunction of both pre- and postsynaptic GABA-B receptor mediated processes
contributes to temporal lobe epilepsy. Several reports support a possible role of GABA in
glioma development. GABA may also play a direct immunomodulatory role in the brain which
may cause neurochemical changes in intra- and peri-tumoral regions, thereby affecting
tumour growth as well as tumour-associated seizures - A role for glutamate in both tumour-associated seizures and in glioma is widely accepted.
Glioma cells release glutamate, which causes excitotoxic death of surrounding neurons as
one of the mechanisms for their destructive and invasive growth in the brain. The release of
glutamate occurs primarily via a Na+-independent cystine-glutamate exchanger and may
also contribute to seizures that start in the peri-tumoral regions. Thus, genes involved in
glutamate release, including GluR1, the most abundant AMPA (α-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid) receptor subunit in gliomas, and the Na+-independent
cystine-glutamate exchanger, might be associated with glioma-associated seizures. - Brain-derived neurotrophic factor (BDNF) regulates neuronal morphology and
synaptogenesis and exhibits neuroprotective effects in diverse areas of the central nervous
system during development. BDNF modulates synaptic transmission by increasing NMDA
(N-methyl-D-aspartic) receptor activity. BDNF expression has been shown in the neuronal
component of gangliogliomas and co-localizes with NMDA receptors in these tumours. Thus,
BDNF and other neurotrophic factors in the brain may be involved in the growth regulation
and epileptogenesis of tumours of glioneuronal origin. - Polymorphisms in several cell cycle control and DNA repair genes have been associated
with glioma risk. Analysis of epilepsy-associated gangliogliomas revealed increased
expression levels of cyclin D1 (CCND1) and cyclin-dependent kinases (CDK) compared
to normal control tissues, suggesting a role for these genes in the pathogenesis and possibly
also the epileptogenesis of these lesions. - Apolipoprotein E (ApoE) ε4 allele is a potential susceptibility gene for temporal lobe
epilepsy and plays a role in glioma through delivery of lipids to tumour cells. - The cystine/glutamate transporter System xc− (SXC) and its catalytic subunit SLC7A11 is
the major pathway for glutamate release from gliomas and SLC7A11 expression predicts
accelerated growth and tumour-associated seizures.
Ours
Polymorphisms of interleukins (IL) IL- 1β-511
Cytokines have modulating effects on neurotoxic neurotransmitters during excitation and inflammation in the CNS.
Immune-mediated neuronal damage of the peri-tumoral brain area, coupled with the balance between stimulatory and inhibitory cytokines, may contribute to the development of tumour-related epilepsy
Polymorphisms of apolipoprotein E (ApoE)
High levels of amyloid β. ApoE isoforms, particularly APOE4, can alter pre- and post-synaptic molecules and increase neuron excitability.
Polymorphisms of prodynorphin gene promoter (PDYN)
Endogenous dynorphin is an opioid with several physiological effects including a role in the regulation of hippocampal excitability, indicating a probable anticonvulsant effect. Patients with temporal lobe epilepsy carrying the low frequency PDYN allele showed a higher risk of developing secondary generalized seizures and status epilepticus.
GABA-B dysfunction
Dysfunction of both pre- and postsynaptic GABA-B receptor mediated processes contributes to temporal lobe epilepsy.
GABA may also play a direct immunomodulatory role in the brain which may cause neurochemical changes in intra- and peri-tumoral regions, thereby affecting tumour growth as well as tumour-associated seizures.
Polymorphism of serotonin receptor 5-HT7
Variations in serotonergic activity are linked to both the development of epileptic foci and the severity of seizures. Decreased serotonin is associated with seizure susceptibility however increases in serotonin like in serotonin syndrome can also cause seizures.
Polymorphism of SLC7A11, GluR1 and AMPA (genes involved in glutamate release)
SLC7A11 (or xCT) is responsible for importing cystine into the cell in exchange for exporting glutamate. Overexpression can cause hyperexcitability and increasing seizure risk due to increases in glutamate
Glioma cells release glutamate, which causes excitotoxic death of surrounding neurons. The release of glutamate occurs primarily via a Na+ independent cystine-glutamate exchanger and may contribute to seizures that start in the peri-tumoral regions.
Brain-derived neurotrophic factor (BDNF)
Brain-derived neurotrophic factor (BDNF) regulates neuronal formation and has neuroprotective effects by increasing NMDA receptor activity, thus increasing neural excitability
Increased BDNF expression and other neurotrophic factors in the brain may be involved in the growth regulation of tumours of glioneuronal origin.
Glial cell line-derived neurotrophic factor (GDNF)
GDNF usually provides a neuroprotective effect and increases GABA. Decreased activity of GDNF means reduced GABA and increased risk of seizures.
P53 tumour suppressor.
EGFR
Cyclin-dependent kinases (CDKs): Cyclin D1 is a protein that regulates cell cycle progression by forming complexes with cyclin-dependent kinases (CDKs) like CDK4 and CDK6, primarily in the G1 phase of the cell cycle. These complexes phosphorylate and inactivate the retinoblastoma protein (Rb), which then releases E2F transcription factors, ultimately promoting cell cycle progression.
