New and Emerging Cancer Treatments

Question 1

Need for targeted therapies

Answer 1

• Traditional chemotherapies = number of SFx
• Ways to maximise localised delivery of drugs are therefore required
• Some cancers don’t have effective clinical regimens; e.g. advanced, metastatic cancers, those that have developed resistance
• Need more targeted treatments

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Question 2

Prodrugs

Answer 2

• Derivative of an active drug that has no intrinsic activity but is converted to the active drug in vivo at the appropriate time or place

Question 3

How are prodrugs activated?

Answer 3

• over-expression of a specific enzyme that activates the prodrug
• modification of the target cell to express the enzyme required for the drug release.

Question 4

What does ‘ADEPT’ refer to?

Answer 4

Antibody-directed enzyme prodrug

(1) Design of an mAb developed against a tumour associated antigen
(2) Antibody-enzyme complex generated and administered
(3) Specificity of the antibody for the antigen allows the antibody-enzyme conjugate to be selectively delivered to the tumour cells.
(4) Prodrug administered
(5) Once enzyme is bound to tumour cell –> prodrug activated = kill tumour cells

Question 5

What are some advantages of ADEPT?

Answer 5

• Reduced systemic toxicity
• Opportunity to overcome drug resistance
• Opportunity to revisit drugs that have shown excellent profiles in vitro, or in early clinical trials, but that have not been pursued due to toxicity profiles.
• Amplification of the drug effect

Question 6

What are some challenges of ADEPT?

Answer 6

• immune responses to antibody-enzyme complexes
• identification of appropriate cancer antigen targets
• cost

Question 7

What does ‘GDEPT’ refer to?

Answer 7

Gene-Directed Enzyme Prodrug Therapy
- Mirrors ADEPT but gene therapy
- Therapy involves introducing a gene into the tumor cells that produces an enzyme specific to tumour cells
- Prodrugs are administered and activated same as ADEPT
- + and - (see ADEPT)
- No GDEPT product currently marketed as a drug

Question 8

What does ‘PDEPT’ refer to?

Answer 8

• Polymer-Directed Enzyme Prodrug Therapy
  1. Polymeric prodrug + polymer-enzyme conjugate administered
  2. Both localise in the tumour due to EPR effect
  3. Enzyme which activates the drug is delivered separately to the tumour
  4. Pro drug activated
  3. Generate cytotoxic drug selectively at the tumour site

Question 9

What does ‘MDEPT’ refer to?

Answer 9

Melanocyte-Directed Enzyme Prodrug Therapy
- Malignant melanoma; most serious form of skin cancer as metastasis can occur early and it causes a number of deaths even in young people.
- Metastasis: target the lung, liver and colon.

Question 10

ABCDE

Answer 10

General guideline for symptoms of melanoma
1. Assymmetrical
2. Border
3. Colour
4. Diameter
5. Elevation and enlargement

Question 11

Breslow Thickness Scale

Answer 11

Scale used to classify the thickness of the tumour

Question 12

Clark’s Level

Answer 12

Scale used to classify the depth of the tumour

Question 13

Targeted therapy - Carbohydrate Biosynthesis

Answer 13

• Carbohydrates are synthesised in nature by a series of enzymes
• In some cases the balance and activity of enzymes required for carbohydrate synthesis is disrupted
• Unusual carbs are synthesised and generated on the cell surface
• Confers unusual and often undesirable properties to the cell
• Believed that such processes are responsible for cancer metastasis

Question 14

How does cancer metastasis occur due to carbohydrate bioynthesis?

Answer 14

• By allowing cell surface carbohydrates to interact with lectins in blood vessels
• Alowing migration of the tumour from one site to another

Question 15

Chemical modification of biopolymers in vivo

Answer 15

• Utilise the biosynthetic production of sialic acid on cancer cells for targeted treatment
• Through ‘biochemical engineering’.
• Uses the enzymatic machinery of cells to achieve chemical synthesis of novel biomolecules in the cells

Question 16

Benefits of engineered biomolecules

Answer 16

• May have novel properties
• Provide insight into the importance of certain molecules/functional groups in biological processes
• Provided useful tooks in: Drug discovery, delivery, gene therapy, bioseparation or diagnostics

Question 17

Biosynthesis of Sialic Acid

Answer 17

1. Introduction of ketone groups onto molecules on cell surfaces allows selective reaction of those cells with nitrogen nucleophiles such as aminooxy- or hydrazidefunctional molecules
2. Permits **covalent attachment **of a wide range of structures to the cancer cell surface
3. Under physiological conditions
4. This offers the possibility to bind drugs, dyes or magentic resonance imaging reagents selectively to the cancer cells

Question 18

Impact of modified sialic acid biosynthesis

Answer 18

• Chemicall remodelling of cell surfaces in living animals.
• Immunotargeting of tumour cells by creating vaccines based on cancer specific cell
• Surface glycoconjugate antigens has long been proposed, but many tumour cells dail to express unique markers

Question 19

Sialic acid and ManNProp

Answer 19

• ManNProp: a modified derivative of a precursor to sialic acid
• Can use it to generate carbohydrates on tumour surfaces that contain modified sialic acid, specifically N-propionylneuraminic acid.
• MAbs available for this, allow antibody-mediated cell killing.
• In an in vivo study this antibody effectively controlled metastasis of solid tumour model in mice which had been given ManNProp