Molecular targeted Therapy Flashcards
Alkylating agents
Cyclophosphamide
Melphalan
Chlorambucil
Antimetabolites
Methotrexate
Plant alkaloids
Taxanes
Vinca alkaloids
Hormones + antagonists
Anti-oestrogens
Anti-androgens
Targeted therapy
Monoclonal antibodies
Small TKIs
Breast cancer genetics
13-20% overexpress HER2
- HR2 Gene amplification
Breast cancer treatment
Trastuzumab
Lapantanib
Colorectal cancer genetics
35-50% overexpress EGFR
Polysomy or EGFR gene amplification + wild-type RAS only
Metastatic cancer in liver
Colorectal cancer
Combination of Cetuximab with Oxaliplatin-containing chemo
Lung cancer genetics
15% EGFR-positive- somatic mutations
some in TK domain
usually late diagnosis, poor prognosis
Lung cancer treatment
Afatinib (EGFR/HER2)
Erlotinib
Gefitinib
Bevacizumab
Melanoma genetics
> 50% with unresectable or metastatic melanoma have a mutation in the BRAF
20% patients don’t initially respond
Melanoma treatment
Vemurafenib
Dabrafenib
Trametinib
Antibody inhibitors of growth receptors
Bind to growth factor receptors and prevent growth signals
Antibody-drug conjugates
Antibody targets drug to tumour cells
TKI of growth receptors
Bind to growth receptors + prevent growth signals
Alemtuzumab (CLL)
Naked antibody
Activate immune system
Pembrolizumab (melanoma)
Naked antibody
Target immune system checkpoints
Herceptin (breast cancer)
Naked antibody
Inhibiting activity of antigen + prevent growth
MOA monoclonal antibodies
Kill tumour directly
Kill tumour via an immune-mediated mechanism
Vascular or stromal ablation
VEGF
Required for formation of nascent blood vessels
Protects endothelial cells from death via activation of PKC pathways + upregulation of anti-apoptotic proteins such as Bcl-2
Activity modified by TK receptors- VEGFR1 + VEGFR2
Most upregulated genes in cancer- survival of tumour cells
Targetting VEGFR
Antibody target
Angiogenesis inhibited
Deprives tumours of nutrient-providing blood vessels
TKI inhibitors targets
Inhibit intracellular TK enzymes to inhibit ATP binding
Target oncogene product
Inhibit signalling at key steps
Safer than chemo
Side effects of targeted therapy
Rash- EGFR Hand foot syndrome- VEGF High BP- VEGF Slow wound healing/clotting- EGFR Congestive HF- HER2
-tinib
TKI
-zomib
proteasome inhibitor
-ciclib
cyclin-dependent kinase inhibitor
-parib
poly ADP-ribose polymerase inhibitor
EGFR Family TKRIs
Extracellular + Intracellular AAs
Extra- 630
Intra- 560
target EGFR
Cetuximab
target HER2
Trastuxumab
target HER2/3
Pertuzumab
target VEGFR
Bevacizumab
Trastuzumab
Bind to domain IV on HER2
Suppresses ligand-independent HER2 signalling
Pertuzumab
Binds to domain II on HER2
Supresses ligand-dependent HER2 signalling
Fab in monoclonal antibody
selective monoclonal antibody targets tumour specific or tumour associated antigens
Fc in monoclonal antibody
Has potent cytotoxic payload
Tyrosine Kinases nomenclature
-tinib
Mutations in TK domain of EGFR in lung cancer
exon 18,19,20,21
Drug resistance
70% women don’t respond/resistant to trastuzumab
Most develop resistacne to TKI
Trastuzamab
Cardiotoxicity
Decline in LV cardiac function
