Applied pharmacology: brain cancer

Question 1

Cancer Definition

Answer 1

According to the World Health Organization, cancer is a broad term describing diseases where abnormal cells rapidly multiply, surpassing their usual boundaries, invading nearby tissues, and potentially spreading to other organs.

Question 2

Introduction to Cancer Neuroscience

Answer 2

Cancer neuroscience is an emerging field focused on understanding the nervous system’s involvement in cancer development and progression.

Question 3

Clinically Approved Drug Criteria for cancer drugs = 4

Answer 3

1. Known safety profile.
2. Well-understood pharmacokinetics in humans (absorption, distribution, metabolism, excretion).
3. Reduced time for repurposing from 10-17 years to 3-12 years.
4. Cost-effectiveness, saving money on early development.

Question 4

Ion Channel Target in Cancer Neuroscience

Answer 4

Ion channels serve as potential targets in cancer neuroscience research.

Question 5

Re-purposing Drugs in Cancer Neuroscience

Answer 5

Re-purposing clinically approved drugs offers benefits including known safety profiles, well-understood pharmacokinetics, reduced time for repurposing, and cost-effectiveness.

Question 6

Hallmarks of cancer = 10

Answer 6

1. Avoiding immune destruction
2. tumor-promoting inflammation
3. genome instability and mutation
4. enabling replicative immortality
5. resisting cell death
6. activating invasion and metastasis
7. inducing angiogenesis
8. evading growth suppressors
9. sustained proliferative signalling
10. deregulating cellular energetics

Question 7

TREATMENT OF CANCER AND EXPLAIN THEM = 5

Answer 7

1.Chemotherapy – use of drugs to kill cancer cells

2. Radiotherapy – high energy particles or x-rays kill cancer cells
3. Surgery – is the removal of tumour and the surrounding tissue

4.Immunotherapy – boosts the body’s natural defenses to kill cancer

5. Targeted therapy – based on the unique genetics of tumour

Question 8

5 CANCER Treatment disadvantages:

Answer 8

1. Chemotherapy – toxic
2. Radiotherapy – limited reach, side-effects
3. Surgery – invasive, inaccessible
4. Immunotherapy – inconclusive data
5. Targeted therapy – drug resistance, limited targets

Question 9

Ion Channels

Families… STRUCTURE.. FUNCTION… ROLES..

Answer 9

1. Families: There are 31 families of ion channels.
2. Structure: Ion channels are transmembrane domain proteins.
3. Function: They facilitate the permeation of charged ions across cellular membranes.
4. Roles: Ion channels are involved in numerous cellular processes.

Question 10

Ligand vs Voltaged - gated ion channels…

Answer 10

1. LIGAND-GATED
   - neurotransmitter binds to channel
   - channels opne, letting ions in
2. VOLTAGE-GATED
   - Channels open, in response to a change in voltage across the membrane, letting ions in

Question 11

Understanding Chemical synapse

types
duration
function

Answer 11

• Types: Chemical synapses can be categorized into two main types:
  1. EXCITATORY Synapses: These synapsesINCREASES LIKLIHOOD of a postsynaptic NEURON FIRING AN ACTION POTENTIAL
     .
     2.INHIBITORY : These synapses DECREASE LIKLIHOOD of a postsynaptic neuron firing an action potential.
• Duration: Chemical synapses typically last for MILISECONDS
• Mechanism:
  1. • When an action potential arrives at the presynaptic terminal, it triggers the opening of ‘voltage-gated calcium channels.’
  2. • Calcium influx into the presynaptic terminal causes SYNAPTIC VESICLES CONTAINING NEUROTRANSMITTERS to fuse with the presynaptic membrane, releasing neurotransmitters into the SYNAPTIC CLEFT
  3. • Neurotransmitters diffuse across the synaptic cleft and BIND TO RECEPTORS on the POSTSYNAPTIC MEMBRANE

4. BINDING of neurotransmitters to receptors results in CHANGES in the postsynaptic membrane POTENTIAL,
5. either DEPOLARIZING (excitatory) or HYPERPOLARIZING (inhibitory) the postsynaptic neuron.
6. • The postsynaptic neuron integrates excitatory and inhibitory signals, and if the NET EFFECT REACHES THE THRESHOLD FOR FIRING ACTION POTENTIAL = GENERATE ONE

Question 12

How do drugs act on ion channels? = 3

Answer 12

1. • ORTHOSTERICALLY: binding to the channel protein itself, to
     the ligand-binding site of ligand-gated channels.
2. • ALLOSTERICALLY: bind to other sites on the channel.
3. • Physically block the pore.

Question 13

ORTHOSTERICALLY

Answer 13

binding to the channel protein itself, to the ligand-binding site of ligand-gated channels.

Question 14

ALLOSTERICALLY

Answer 14

: bind to other sites on the channel.

Question 15

ION CHANNELS …BLOCKERS VS MODULATORS

Answer 15

BLOCKERS = Permeation blocked

MODULATORS = INCREASED OR DECREASED OPENING PROBABILITY

Question 16

What does the patch clamp method measure, and how does it work? = 5

Answer 16

1. The patch clamp method measures the flow of ions across the cell membrane
2. It involves using a pipette to create a seal with the cell membrane, forming a high resistance seal (gigaohm seal).
3. By applying voltage changes, such as ‘depolarization’,
4. the method can study the activation and behavior of ion channels, such as ‘Na+ channels.’
5. This allows researchers to observe phenomena like Na+ influx during action potential generation.

Question 17

Why are ion channels a good target to treat
brain cancer? = 2

Answer 17

1. Tight association with ion channels and ‘cancer hallmarks.’
2. Ion channels are essential for ‘neuron-brain cancer cell’
   interactions (which drives brain tumour cancer growth).

Question 18

How do ion channels contribute to cell proliferation and the cell cycle?

Answer 18

Ion channels regulate cell volume, intracellular signaling, membrane potential, cell migration, and cell adhesion, all of which are essential for cell growth, division, and tissue development.

• Dysregulation of ion channels can impact these processes and contribute to diseases like cancer.

Question 19

What role do ion channels play in processes like migration, invasion, and metastasis?

Answer 19

Ion channels are involved in regulating cell migration, invasion of surrounding tissues, and the formation of metastases.

They influence cell motility, cytoskeletal dynamics, and interactions with the extracellular environment, contributing to cancer progression and spread.

Question 20

What role do ion channels play in processes like migration, invasion, and metastasis?

Answer 20

Ion channels are involved in regulating cell migration, invasion of surrounding tissues, and the formation of metastases.

They influence cell motility, cytoskeletal dynamics, and interactions with the extracellular environment, contributing to cancer progression and spread.

Question 21

How are ion channels related to cancer progression?

Answer 21

Ion channels participate in cell migration, invasion of neighboring tissues, and the formation of metastases in cancer.

They influence cell motility and interactions with the surrounding environment, contributing to the spread of cancer cells.

Question 22

How do ion channels contribute to tumor angiogenesis?

Answer 22

Ion channels play a role in regulating processes involved in tumor angiogenesis, such as endothelial cell proliferation, migration, and vessel formation.

They can influence the release of angiogenic factors and signaling pathways involved in blood vessel growth, impacting the development and progression of tumors.

Question 23

Challenges in Targeting Ion Channels

Answer 23

While there are numerous targets among ion channels, there are relatively few drugs available for their modulation.

Question 24

Challenges in Targeting Ion Channels = 5

Answer 24

1. • Structural Similarity: Achieving selectivity is challenging in ion channel families with similar structures.
2. • Conformational Changes: Ion channels undergo significant structural changes during gating, complicating drug design.
3. • Complex Structure: Ion channels are large, multi-subunit membrane proteins, making them difficult drug targets.
4. • Technical Demands: Screening assays for ion channel drugs are technically demanding and require expertise in electrophysiology.
5. • Blood-Brain Barrier: Drugs targeting brain cancer must cross the blood-brain barrier, which adds another layer of complexity to drug delivery.

Question 25

Need for Improvement in Brain Cancer Treatment

Answer 25

Survival Rates: While survival rates for many cancers are improving, those for brain tumors remain stagnant.

Complexity of Brain Cancer: Brain tumors present unique challenges due to the delicate nature of the brain and the difficulty in accessing and treating tumors within it.

Limited Treatment Options: Current treatments for brain cancer are often limited in efficacy, leading to poor outcomes for many patients.

Urgency for Advancements: There is an urgent need to develop better treatments for brain cancer to improve survival rates and quality of life for patients.

Question 25

What are the primary and secondary types of brain tumors? = 10

Answer 25

1. Primary brain tumors include
   - gliomas (astrocytic, oligodendroglial, or mixed),
   - meningioma,
   - medulloblastoma,
   - central nervous system lymphoma,
   - germ cells.
2. They are classified by WHO grade, ranging from benign (grade I) to most malignant (grade IV).
3. Secondary brain tumors, also known as metastasis, originate from cancers in other parts of the body and spread to the brain.

Question 26

Glioblastoma …characteristics…population?…symptoms?

Answer 26

1. Characteristics:
   - Glioblastoma is the most aggressive
   - common brain cancer in adults,
   - a poor prognosis.
   - Majority of patients die within two years of diagnosis.
2. Affected Population:
   - Predominantly affects adults aged 45 to 70,
   - with males being 1.6 times more likely to be affected than females.
   - Incidence is relatively consistent worldwide.

Symptoms:
- Patients typically develop edema
- bleeding in the brain.

Question 27

Mutations in glioblastoma =

Answer 27

1. • Proto-oncogenes
     - Epidermal growth factor receptor (EGFR), Platelet-derived growth factor receptor (PDGFR)
2. • Tumour suppressor genes
     -Tumour protein p53

Question 28

Mutations in Glioblastoma

Proto-oncogenes: 4

Answer 28

1. examples = Epidermal growth factor receptor (EGFR), Platelet-derived growth factor receptor (PDGFR)
2. • Involved in normal cell growth
3. • Becomes ‘oncogenes’ upon mutation, which can induce cellular transformation
4. • Some do not need to be mutated but only to be over-expressed/activated via
     mutations in the promoter region

Question 29

Mutations in glioblastoma …Tumour suppressor genes = 5

Answer 29

1. Example : Tumour protein p53
2. • Protect cells from transformation
3. • Mutations prevent these genes from performing adequately
4. • This helps cancer progression, usually in combination with genetic changes in oncogenes
5. • Can be activated in other ways than through mutation

Question 30

What factors contribute to the complexity of the genetic profile of glioblastoma? = 4

Answer 30

Glioblastoma genetics are complex due to factors such as

1. gene expression profiles,
2. chromosomal abnormalities,
3. dysregulation of oncogenic growth factors
4. dysregulation of tumor suppressor genes.

Question 31

HOW Xenograft mouse models FOR CANCER RESEARCH = 3

Answer 31

1. Modify Cancer Cells:
   - Cancer cells are modified, for example, using ‘lentivirus systems’, where a gene of interest (e.g., GFP) is inserted next to the gene of interest in the cancer cell’s genome.
2. Inject Modified Cancer Cells into Mouse:
   - The modified cancer cells are then injected into a mouse model.
3. Study Cancer Within Mouse:
   - Researchers study the behaviour and progression of the cancer cells within the mouse model, providing insights into tumor growth, response to treatments, and potential therapeutic targets.

Question 32

What are the treatment options for glioblastoma (GBM)? =3

Answer 32

1. Surgical Resection: While possible, complete resection is unlikely due to the infiltrative nature of GBM.
2. Radiotherapy: Prolongs life by approximately 12 months.
3. Chemotherapy (Temozolomide): Prolongs life by approximately 15 months when used in conjunction with radiotherapy.

Question 33

Electrical Activity in Brain Cancer.. 4

Answer 33

1. Explanation: Brain cancer cells exhibit increased electrical activity compared to normal brain cells.
2. Significance: This heightened electrical activity is due to alterations in ion channel function and signaling pathways within the cancer cells.
3. Consequences: The increased electrical activity can promote tumor growth, invasion, and resistance to therapies.
4. Study Importance: Understanding and targeting this electrical activity may provide novel approaches for brain cancer treatment.

Question 34

The Missing Piece: Electrical Activity?

for cancer in the brain = 3

Answer 34

1. Healthy Brain: Exhibits normal electrical activity, regulated by ion channels and neural networks.
2. Tumor: Brain tumors, such as glioblastoma, display aberrant electrical activity due to dysregulation of ion channels and altered signaling pathways.
3. Significance: Understanding and targeting this electrical activity could provide insights into tumor behavior and potential therapeutic strategies.

Question 35

Synapses Between Neurons and Glioma Cells

Answer 35

1. Neurons and Glioma Cells: Can form synapses, allowing communication between the two cell types.
2. Significance: This synaptic communication may influence tumor growth, invasion, and response to therapies.
3. Understanding: Studying these synapses could provide insights into the interactions between neurons and glioma cells, potentially identifying new therapeutic targets.

Question 36

Glutamatergic Neuron-Glioma Synapses…

description..Glioma Cell Excitatory Post-Synaptic Current…experimental setup…significance

Answer 36

1. ***Description: Synapses formed between glutamatergic neurons and glioma cells.
2. ***Glioma Cell Excitatory Post-Synaptic Current: Activation of glutamate receptors on glioma cells generates excitatory post-synaptic currents (EPSCs), influencing glioma cell activity.
3. Experimental Setup: In xenografted glioma models, recording electrodes monitor EPSCs in glioma cells, while stimulating electrodes activate glutamatergic neurons, such as those from the shaffer collaterals.
4. Significance: Studying these synapses helps understand the role of neuronal activity in glioma progression and may reveal potential therapeutic targets.

Question 37

Blocking Synaptic Signaling in Glioma Growth…

CNQX, EXPERIMENTAL SETUP, EFFECT, SIGNIFICANCE

Answer 37

1. CNQX: Blocks glutamate receptors, specifically AMPA receptors, which are ligand-gated ion channels.
2. Experimental Setup: In a “co-culture,” neurons and glioma cells are grown together in a petri dish.
3. Effect: Blocking synaptic signaling using CNQX inhibits glioma growth, suggesting a role for neuronal activity in tumor progression.
4. Significance: This finding highlights the potential of targeting synaptic signaling pathways as a therapeutic approach for glioma treatment.

Question 38

Optogenetics in Glioblastoma = 4

Answer 38

1. Process: Cancer cells are modified to express optogenetic tools, such as channelrhodopsin (ChR2), which depolarizes the cells upon exposure to light.
2. Experimental Setup: Modified cancer cells are injected into the mouse brain.
3. Light Stimulation: The cancer cells are stimulated with 470nm light, activating ChR2 and inducing depolarization.
4. Purpose: Optogenetic techniques allow precise control over the activity of cancer cells, facilitating the study of their behavior and response to stimulation.

Question 39

Glioma Membrane Depolarization and Tumor Growth = 4

Answer 39

Finding: Glioma membrane depolarization drives tumor growth.

Method: Glioma cells expressing ChR2, which depolarizes cells upon exposure to blue light.

Effect: Blue light induces depolarization of glioma cells expressing ChR2.

Significance: This finding suggests that controlling membrane potential through optogenetic techniques may impact glioma growth, providing potential therapeutic avenues for glioblastoma treatment.

Question 40

Which combination therapy is effective?… GLIOBLASTOMA

Answer 40

IMMUNOTHERAPY AND NEUROLOGICAL DRUGS

Question 41

Possible targets for ion channel drugs to treat brain cancer:

Answer 41

1. ‘Targets of Ion Channel Inhibition:’ Ion channels critical for tumor cell function can be targeted for inhibition.
2. ‘Neuronal Excitability:’ Modulating ion channels involved in neuronal excitability may impact tumour cell behaviour.
3. ‘Synaptic/Presynaptic Transmission:’ Targeting ion channels involved in synaptic transmission can disrupt communication between neurons and tumour cells.
4. ‘Synaptogenesis’: Inhibiting ion channels involved in synaptogenesis may impair the formation of synapses between neurons and tumour cells.
5. ‘Network Effects’: Ion channels contribute to network effects in the brain, altering the tumour microenvironment.
6. ‘Downstream Effects’: Targeting ion channels can influence downstream signalling pathways crucial for tumour cell proliferation and invasion.
7. ‘Rewiring of Signalling Pathways’ : Tumour cells may rewire signalling pathways in response to therapy, making them potential targets for ion channel drugs.

Question 42

What is the significance of ion channels in cancer pathogenesis?

Answer 42

Ion channels are integral to cancer pathogenesis, serving as potential targets for drug therapy.

Question 43

What is the status of drugs targeting ion channels?

Answer 43

There are already several drugs on the market targeting ion channels.

Question 44

How are scientists and clinicians working to expedite future treatments?

Answer 44

To fast-track future treatments, scientists and clinicians are exploring the re-purposing of already approved drugs.

Question 45

What potential role do ion channels play in stopping glioma growth?

Answer 45

Targeting ion channels may hold the key to stopping glioma growth by disrupting neuron-glioma interactions.

Question 46

How might re-purposed ion channel drugs be utilized in cancer treatment?

Answer 46

Re-purposed ion channel drugs could be combined with other treatments, such as immunotherapy, to effectively treat malignant brain cancers like glioblastoma.