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Cancer > 6.6 Wk 5 New & emerging therapies > Flashcards

6.6 Wk 5 New & emerging therapies Flashcards

1
Q

What is the role of targeted therapies?

A

Targeted therapies help to optimise efficacy and minimise side effects

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2
Q

What is the aetiology of cancer?

A

Aeitology Not fully understood, best guess?

  • 80% environmental factors
  • 20% hereditary
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3
Q

What is the mechanism of resistance for the following drugs?

A

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

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4
Q

What is a pro drug?

A

A derivative of an active drug with no intrinsic activity, which is converted into the a**ctive drug **at the appropriate time and place.

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5
Q

What are 3 approaches which can be undertaken to develop a pro drug which is highly specific for a specific cancer?

A

Antibody directed enzyme pro drug therapy (ADEPT)

Gene directed enzyme pro drug therapy (GDEPT)

Polymer directed enzyme pro drug therapy (PDEPT)

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6
Q

What do we want to do?

A

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…

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7
Q

So, How can you get the enzyme into the cell?

A

Antibody Directed Enzyme Pro Drug Therapy (ADEPT) is one potential option to get the enzyme and the pro drug into the cancer cell.

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8
Q

How can you get the pro drug into the cell? (ADEPT)

A

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.

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9
Q

What are the advantages of ADEPT?

A

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.

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10
Q

What are the challenges of ADEPT?

A
  • 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
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11
Q

Where is the ADEPT approach currently being investigated ?

A

Animal models for breast cancer and colon cancer

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12
Q

Identify another approach for getting the enzyme and pro drug into the cell?

A

Gene Directed Enzyme Pro Drug Therapy (GDEPT)

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13
Q

How does the GDEPT approach work?

A

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.

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14
Q

What is an alternative approach to get the enzyme and pro drug into the cell, other than ADEPT & GDEPT

A

Polymer directed enzyme prodrug therapy (PDEPT)

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15
Q

What approach is used with PDEPT

A

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

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16
Q

ow is the Melanocyte Directed Enzyme Pro drug therapy (MDEPT) approach different to ADEPT, GDEPT and PDEPT?

Osbournes pet project !

A
  • 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
17
Q

Why is MDEPT of interest for Melanoma?

A

Melanoma is highly malignant and can be fatal.

18
Q

How is melanoma diagnosed?

A

Normal mole, maybe a melanoma, diagnosis can be difficult

ABCDE system in melanoma
* Asymmetry
* Irregular Border
* Colour more than one
* Diameter - > 6mm
* Mole – Evolution

19
Q

What is she looking at…

A

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,

20
Q

What is the importance of carbohydrates in bioynthesis and thereafter targeted therapy - Key points.

A

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.

21
Q

What percentage of the human genome are focused on glycan production and modification?

A

1%

22
Q

Which two enzymes involved in the construction of glycans are commonly encoded by the genes?

A
  • Glycosyltransferase enzymes
  • Glycosidase enzymes
23
Q

What is one of the ways you can use CHO biosynthesis to develop targeted therapy?

A
  • Chemical modification of biopolymers in Vivo
24
Q

Identify an acid which is overexpressed on cancer cells

A

Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone

25
Q

How could you develop Sialic acid as a targeted therapy?

A

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.

26
Q

So what could you do?

A
27
Q

What are the potential opportunities?

A

Cancer (37 decks)

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