Lecture 15 – Targeted therapies and drug development strategies (FINISH)

Growth of normal mammary epithelium is dependent upon which hormone?

Oestrogen

• Affects signalling pathways which control growth 

In pre-menopausal women with breast cancer, oestrogen seems to come mainly from….

Ovaries and adrenal glands 

In post-menopausal women with breast cancer, oestrogen seems to come mainly from…

The cancer itself 

Why is oestrogen a good target for breast cancer treatment?

Many cancers retain oestrogen dependency for growth

• Targeting oestrogen could therefore allow for control over tumour growth

What are the two options for removal of oestrogen sources?

Surgery 

• Removal of adrenal gland and ovaries 

Drug to inhibit synthesis of oestrogen 

• E.g. aromatase inhibitors  

  • Androgens turned into oestrogen by aromatase  

What type of receptor is the oestrogen receptor?

Intracellular receptor

What prevents the oestrogen receptor from aberrantly activating gene transcription?

HSP90 complex.

What does Tamoxifen target?

Binds the oestrogen receptor but doesn’t activate all its transcription factor activities

• This reduces tumour growth signalling 

What type of breast cancers is Tamoxifen good at treating?

Oestrogen receptor positive tumours generally respond better than oestrogen receptor negative tumours.

What is the Philadelphia chromosome?

Result of translocation between chromosome 9 and 22 which is found in nearly all CML patients.

• Results in a minute chromosome 22 

How is BCR/ABL produced?

Translocation of chromosome 9 and 22 which forms a fusion gene.

What is produced by the BCR/ABL gene?

P210 BCR-ABL fusion protein.

• Mutant ABL tyrosine kinase

ABL is normally what kind of protein in cells?

Tightly regulated tyrosine kinase as it can regulate many pathways involved in cell function.

What does aberrant ABL activation caused by BCR/ABL cause?

Overall promotes cell proliferation, inhibits cell death and altered adhesion 

• Promotes leukaemia transformation

Imatinib targets what?

Designed to act as an ATP binding site inhibitor of ABL kinase  

• No phosphorylation of tyrosine residues  

• No activation of signal pathways necessary for cancer growth 

Imatinib’s phase III trial was cut short. Why?

Results were so good, it was deemed unethical to continue using standard treatment 

Why was Imatinib deemed ‘better’ than standard treatment at the time?

• Better response rates 

• Better tolerability and quality of life 

• Longer survival 

ADD HER2 AND HERCEPTIN

How can monoclonal antibodies directly target the cancer?

• Often via ADCC and complement dependent cytotoxicity (CDC) 

• Can also be conjugated to drug/toxin/radiochemical 

How can monoclonal antibodies indirectly target the cancer?

• Alter host response to cancer 

• Target angiogenesis 

• Retarget T-cells towards cancer 

What is Myelotarg and what is it used to treat?

Used to treat acute myeloid leukaemia  

• Monoclonal antibody with a toxic drug attached to it 

  • Allows concentration of the toxic drug at the cancer

How are CAR-T cells made?

• Patients T-cells are taken

• T-cells are the engineered to transform them into CAR-T cells

• CAR-T cells are then reinfused back into the patient

• CAR-T cells then attach the cancer

What do CAR-T cells target?

All CD19+ cells in the body.

• This means it doesn’t only target cancer cells as some other cells display CD19 

What are some disadvantages of CAR-T cell therapy?

• Activation and proliferation when they contact large tumour burden  

  • Can be too toxic 

• Long term depletion of normal cells displaying CD19 

• Produced individually for each patient 

  • Very expensive 

What are the three ways of finding new potential drug candidates?

• Screening approach

  • Screen large number of test compounds to find possible candidates

• Rational drug design

  • Use computational methods to discover, design and develop candidates 

• Structure-Based Drug Design

  • Use 3D geometrical proteins

  • Can then precisely examine interactions between the atoms of target and drug