Targets for cancer therapy Flashcards
What is the use of biologics in cancer therapy?
Block the action of the cell surface protein by preventing proteins binding to them (ligand binding / dimerization).
Bind to proteins to prevent them binding to cell surface proteins (i.e. act as neutralising antibodies).
Delivering targeted radiotherapy (radioimmunotherapy) or chemotherapy as conjugated antibodies.
Immunotherapy:
Cytotoxic response (ADCC).
Complement activation (CDCC).
Blocking inhibition of the immune response.
Linking cancer and cytotoxic T cells (bi-specific antibodies).
How do receptor tyrosine kinase inhibitors work?
Biologics prevent ligand binding to the extracellular
domain of the receptor.
Small molecule inhibitors bind to ATP binding site of
the receptor tyrosine kinase domain or those of
intracellular kinases.
Target the receptor:
Used when there is overexpression of the receptor.
Cetuximab is a chimeric (mouse/human) Mab that
binds to and inhibits EGFR (HER1).
Trastuzumab is a humanised Mab targeting HER2.
Target the growth factor:
Bevacizumab binds to vascular endothelial growth
factor (VEGF-a) preventing it from binding to its
receptor.
Both approached block the signalling pathway.
Only useful in tumours that do not have downstream mutations.
How does trastuzumab work?
HER2 can forms a dimer with other EGFRs.
Forms an active conformation without ligand binding.
Forms homodimers in the absence of ligand.
Mechanism of action:
Inhibition of tumour cell proliferation – cytostatic
activity:
Binding of Trastuzumab to HER2 prevents it dimerising
and signalling.
Stimulates HER2 receptor downregulation by promoting
its endocytosis and proteolysis limiting the signal for
further cell growth.
Facilitation of immune function (cytotoxic):
Trastuzumab binding promotes antibody-dependent cellular cytotoxicity (ADCC) by activating
natural killer cells and macrophages.
Prevention of constitutive activation:
Prevents shedding of the extracellular portion of the receptor by inhibiting the action of metalloproteinases.
What is the mechanism of resistance to
receptor tyrosine kinase targeting antibodies?
Mutations in downstream signalling proteins bypass the
receptor inhibition.
Masking of the MAb binding epitope of the receptor by
membrane-associated glycoprotein.
Impairment of MAb-induced receptor endocytic
downregulation.
Overexpression of receptor ligands.
Neutralising antibodies to the MAb (anti drug antibodies).
What are some examples of HER1 receptor tyrosine kinase inhibitors?
Gefitinib - 1st generation reversible binding to wildtype and mutated receptors.
Afatinib - 2nd generation irreversible binding to wildtype and mutated receptors.
Osimertinib - 3rd generation irreversible binding to receptors with the resistance mutation T790M.
What are some examples of kinase inhibitors?
Vemurafenib:
B-RAF kinase inhibitor with selectivity for the
ATP binding site with the V600E mutation (constitutively active) inhibiting the kinase activity.
CYP1A2 inhibitor; CYP3A4 inducer.
Trametinib:
Reversible MEK1 and MEK2 kinase inhibitor.
Binds to S218 in the activation loop of the enzyme preventing phosphorylation by RAF at this residue.
What happens during the G1/S transition entry into the cell cycle?
Retinoblastoma protein inhibits the E2F family of
transcription factors when hypo-phosphorylated.
Mitogens bind to cell surface receptors and activate
downstream signalling pathways.
Expression of cyclin D and activation of CDK4 and
CDK6.
CDK4/6 phosphorylates Rb.
Phosphorylated Rb cannot bind to E2F transcription
factor, and E2F is activated.
G1/S genes are transcribed and translated.
Cell passes through G1/S checkpoint – the restriction point.
How do CDK4 / 6 Inhibitors work?
RB is the only target of CDK4/cyclin D1.
RB must be phosphorylated to enable the cell to
pass the restriction point.
Cdk4 is ubiquitous, Cdk6 is tissue specific.
Cdk4 is inhibited by p16 / p21/ p27.
p21 is induced by p53.
Overexpression of Cyclin D1, loss of expression of
p16 or p53 occur in some cancers.
Palbociclib - reversible inhibitor of CDK4 and CDK6.
Cell cycle arrest and a block to cell cycle progression.
How do rituximab (chimeric) and ofatumumab (human) work?
Directed against CD20 expressed on B cells.
Recruits macrophages, natural killer cells, complement
proteins for cell destruction.
How does blinatumomab (human) work?
A bi-specific antibody composed of 2 variable regions which recognise CD19 (B cell) and CD3 (CD8+ T cell).
Tethers the cancerous B cells to cytotoxic T cells promoting their destruction.
How does cancer immunotherapy work?
Checkpoint inhibitors target proteins that normally
downregulate immune cell function.
Ipilimumab (human) binds to CTLA-4.
CTLA-4 is an inhibitory protein expressed on the surface of activated T cells. It binds to C80/86 to downregulate T cell function.
Nivolumab (human) binds to PD-1 preventing PD-1L binding to it.
Atezolizumab (humanised) binds to PD-1L.
PD-1 limits the activation of immune cells. When PD-1L binds to PD-1 it triggers prompt apoptosis of the T cell.
Checkpoint inhibitors act to increase the immune response.
How do poly ADP ribose polymerase (PARP)
inhibitors work?
Poly ADP ribose polymerase (PARP) is involved in the repair of single strand breaks in DNA.
DNA repair pathways are often upregulated in cancer cells (a mechanism of resistance).
Poly ADP ribose polymerase (PARP) inhibitors e.g. olaparib and niraparib.
Inhibit repair of single strand breaks in DNA.
Traps PARP on the DNA causing double strand breaks and stalling of the replication fork during DNA replication.
Uses:
To potentiate the effect of chemotherapy used to induce DNA strand breaks.
As monotherapy in tumours with impaired homologous recombination e.g. BRCA mutation containing tumours.
To extend time between conventional chemotherapy for relapsed cancer.
