6.6 Wk 5 New & emerging therapies Flashcards
What is the role of targeted therapies?
Targeted therapies help to optimise efficacy and minimise side effects
What is the aetiology of cancer?
Aeitology Not fully understood, best guess?
- 80% environmental factors
- 20% hereditary
What is the mechanism of resistance for the following drugs?
Drug Mechanism of resistance
Methotrexate
↓ cellular uptake / Bypass biochemical pathways
Doxorubicin
↑ drug efflux
Fluorouracil
↓ intra cellular activation
Cytarabine
↑intra cellular breakdown
Alkylating agents
↓ intra cellular uptake
What is a pro drug?
A derivative of an active drug with no intrinsic activity, which is converted into the a**ctive drug **at the appropriate time and place.
What are 3 approaches which can be undertaken to develop a pro drug which is highly specific for a specific cancer?
Antibody directed enzyme pro drug therapy (ADEPT)
Gene directed enzyme pro drug therapy (GDEPT)
Polymer directed enzyme pro drug therapy (PDEPT)
What do we want to do?
Use an Enzyme to activate the pro drug in the cancer cell
However, the enzyme needed is not always in the cancer cell…
We therefore need to get both the enzyme and the pro drug into the cancer cell…
So, How can you get the enzyme into the cell?
Antibody Directed Enzyme Pro Drug Therapy (ADEPT) is one potential option to get the enzyme and the pro drug into the cancer cell.
How can you get the pro drug into the cell? (ADEPT)
Antibody Directed Enzyme Pro Drug Therapy (ADEPT) is a means of activating a pro drug in the cell.
The monoclonal antibody is designed to target a specific tumour antigen
Step 1
An antibody – enzyme conjugate is developed and administered IV
The specificity of the antibody for the antigen allows the antibody enzyme cojugate to be selectively delivered to tumour cells
Step 2
A pro drug is then typically administered IV
The pro drug is converted to the active drug by the antibody enzyme conjugate, also delivered to the cell.
What are the advantages of ADEPT?
Reduced system toxicity → Allows higher dosing
* May help to knock out the tumour faster, which may help overcome resistance
Opportunity to revisit drugs which have shown excellent profiles in vitro,
* but have not been pursued in clinical trials owing to toxicity
Amplification of drug effect
Bystander effect, the toxic form of the drug diffuses out from one tumour cell and take up by the surrounding cells via active transport.
What are the challenges of ADEPT?
- It can be difficult to identify the antigen which needs to be targeted by the antibody, enzyme conjugate
* - It can be difficult to activate the enzyme/pro drug step
* - An immune response to the monoclonal antibody is possible
Where is the ADEPT approach currently being investigated ?
Animal models for breast cancer and colon cancer
Identify another approach for getting the enzyme and pro drug into the cell?
Gene Directed Enzyme Pro Drug Therapy (GDEPT)
How does the GDEPT approach work?
Step 1
* The Gene encoded enzyme is delivered to the cancer cell
Step 2
* A Pro drug is administered
The gene activates the enzyme in the cancer cell
This enzyme activates the pro drug, releasing its cytotoxic effect
Leading to cell death.
What is an alternative approach to get the enzyme and pro drug into the cell, other than ADEPT & GDEPT
Polymer directed enzyme prodrug therapy (PDEPT)
What approach is used with PDEPT
PDEPT involves a 2 step process
Step 1
The polymer enzyme conjugate is given via parenteral administration
It circulates in the blood and eventually accumulates at the tumour site owing to the enhanced permeability and retention effect, (EPR effect) which allows macromolecules to accumulate at the tumour site.
Step 2
The polymeric pro drug is then administered
The enzyme then converts the prodrug into its active cytotoxic form.
Killing the cancer cells
ow is the Melanocyte Directed Enzyme Pro drug therapy (MDEPT) approach different to ADEPT, GDEPT and PDEPT?
Osbournes pet project !
- ADEPT, GDEPT and PDEPT all deliver the enzyme and pro drug to the cancer cell
- In contrast MDEPT uses enzymes already expressed in tumours to activate the pro drug
Why is MDEPT of interest for Melanoma?
Melanoma is highly malignant and can be fatal.
How is melanoma diagnosed?
Normal mole, maybe a melanoma, diagnosis can be difficult
ABCDE system in melanoma
* Asymmetry
* Irregular Border
* Colour more than one
* Diameter - > 6mm
* Mole – Evolution
What is she looking at…
Tyrosinase is upregulated in melanoma cells
○ This leads to the formation of Melanin ○ Also may breaks down a pro drug into active form.
So can you hijack this pathway,
What is the importance of carbohydrates in bioynthesis and thereafter targeted therapy - Key points.
CHO found on the surface of the cell are produced via enzymes.
Enzymes have to be carefully controlled, if the right CHOs are to be expressed on the surface of the cell
If the enzymes are not carefully controlled…or disrupted…
The wrong CHOs are found in the surface of the cell which can lead to disease or errors in differentiation, interaction and recognition.
It could be that if a cell has the wrong CHOs on the surface they may be more prone to cancer.
What percentage of the human genome are focused on glycan production and modification?
1%
Which two enzymes involved in the construction of glycans are commonly encoded by the genes?
- Glycosyltransferase enzymes
- Glycosidase enzymes
What is one of the ways you can use CHO biosynthesis to develop targeted therapy?
- Chemical modification of biopolymers in Vivo
Identify an acid which is overexpressed on cancer cells
Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone
How could you develop Sialic acid as a targeted therapy?
Identify how it is made – The Biosynthesis Pathway
Then use biochemical engineering to a produce a new form of Sialic Acid
Which has additional probes on the molecule during the biosynthesis process
These probes could be used as tags for targeting by imaging agents or pro drugs for activation
NB: Anything you do to the outside of the cell can alter its properties e.g. could stop it metastasising or act as a drug target.
So what could you do?
What are the potential opportunities?
