Pharmacology – Oncology lecture 2 Flashcards
(33 cards)
Key Point
- Genes controlling the hallmarks are potential drug targets.
- The “drivers” need to be identified and the drugs developed
Genetic change
• DNA mutations – germline mutations » inherited – every diploid cell in body » “predisposition” to cancer » 50% of these regulate apoptosis or DNA damage repair! – somatic cell » initially “individual cell”, maybe passed on by cell division (natural selection) » sporadic cancer • Genes affected – Oncogenes – Tumour suppressors • 90% of cancer genes are “dominant” – mutation in one allele sufficient • 10% are recessive – mutation of both alleles required • Knudson 2 hit hypothesis: – Sporadic cancer » For a recessive gene, 2 somatic mutations required in same cell – Family history of cancer » one copy already (may be) inactivated in germline » only one somatic mutation required to inactivate other copy
Targeted therapies: inhibition of growth/survival pathways - CML & BcrAbl
• Chronic myeloid leukemia
• 99% patients have chromosomal translocation resulting
in a fusion of two genes, Bcr and Abl.
• Abl = a tyrosine kinase, constitutively active in BcrAbl
• drives proliferation of leukemic cells
Imatinib (Gleevec, Glivec)
– first kinase inhibitor to show efficacy in any cancer
– substantially increased survival
– also found to inhibit KIT and effective in GIST
– however, mutation leads to resistance
Desatinib (Sprycel), nilotinib (Tasigna)
– “2nd generation” compunds
– desatinib – binds active and inactive conformation of BcrAbl
– nilotinib – 30 x more potent than imatinib
– efficacy in resistant disease, although activity against T315I still diminished
Imatinib, nilotinib desatinib
• Indications
– CML
– Imatinib also for GIST
• PK
– Imatinib, nilotinib: metabolism by Cyp 3A4
• ADR
– imatinib, nilotinib: myelosuppresion: neutropenia,
thrombocytopenia, anaemia
– nilotinib, desatinib – prolong QT interval
• Cautions
– hepatic impairment
• Interactions
– imatinib inhibit glucorinidation of paracetamol
– nilotinib/desatinib & drugs which prolong QT/ anti-arrhythmics
– desatinib – exposure reduced by drugs causing ↑gastric pH (H2 antagonists, PPIs antacids)
Which targets next?
• CML
– primarily “driven” by BcrAbl
– solid tumours have more drivers! – target selection harder
• Proto-oncogenes
– regulate critical cancer-relevant pathways:
» cell proliferation
» cell survival
– Usually activated by somatic mutation or amplification
– Activation contributes to a “cancerous phenotype”
» eg growth factor independence, evade apoptosis
• Tumour suppressors
– Inactivated in cancer
– Normal function (wild type):
» inhibition of proliferation
» apoptosis
– Inactivation contributes to “cancerous phenotype”
– Mutations may be inherited (see 2 hit hypothesis!)
Inhibition of growth/survival pathways: EGF-R family
• EGF receptor family members – EGF-R (Her1) – ErbB2 (Her2) – Her3 – Her4 • Monoclonal antibodies – Cetuximab (Erbitux) recognises EGF-R – Trastazumab (Herceptin) recognises HER2 – only works in HER2 positive tumours • Kinase inhibitors – Erlotinib (Tarceva), gefitinib (Iressa) inhibit EGF-R kinase – Lapatinib (Tyverb) inhibits EGF-R and Her2 – Several others!
Erlotinib, Gefitinib, Lapatinib
• Indications – Erlotinib » NSCLC maintenance monotherapy » Pancreatic cancer – Gefitinib » NSCLC with EGF-R activating mutation • PK – Metabolism by Cyp then eliminated in faeces – glucoronidation of erlotinib by Ugt1A1 – substrates PgP • ADR – Rash, diahorrea – interstitial lung disease (ILD) – cardiotoxicity lapatinib – decreased LVEF • Cautions – hepatic impairment – smoking →↓ exposure ~50%: advise stop smoking! – discontinue if develop significant ILD – discontinue lapatinib if significant effect on LVEF • Interactions – Cyp relevant drugs – drugs increasing gastric pH: PPIs, H2 antagonists, antacids – UGT1A1 substrates ? – PgP inhibitors?
Cetuximab, trastuzumab
• Indications
– Cetuximab
» colorectal cancer with wild type K-Ras see diagram
» SCCHN
– Trastuzumab
» Breast and gastric cancer – must be HER2 positive
• PK
– cetuximab: t½ ~100hr ; iv infusion weekly
– herceptin t½ ~ 4 weeks (herceptin); i.v. infusion 3 weekly
– eliminated by proteolysis to peptide
• ADR
– Cetuximab
» Rash & hypomagnesemia
» ILD
– trastuzumab
» cardiotoxicity ( heart failure, arrhythmia, altered bp)
» pulmonary toxicity - wheezing
» neutropenia
• Cautions
– discontinue if develop significant ILD
– trastuzumab – discontinue if significant effect on LVEF
– avoid herceptin if signficant dyspnoea
• Interactions
– trastumumab & anthracyclins: “additive cardiotoxicity”
Interaction destainib,
erlotinib, gefitinib & gastric pH
PPI, H2 antagonist etc –> ↑ gastric pH –> ↓erlotinib, gefitinib solubility –> ↓absorption
so if you alter the pH of the gastric, the gastric contents make it more alkaline perhaps using a proton pump inhibitor or a histamine antagonist h2 antagonist and that causes an increase in gastric pH in other words it becomes more alkaline and as it becomes more alkaline erlotinib and gefitinib are protonated less so they become less charged and therefore their solubility decreases and because the solubility decreases the absorption will also decrease
Inhibition of growth/survival pathways:
Cytosolic kinases 1 – Raf inhibitors
Sorafenib • Indications – Hepatocellular carcinoma – Renal Cancer • Mechanism – inhibits several kinases » Raf - cytosolic serine/threonine kinase – V600E mutation in melanoma » VEGF receptor (primary target?) – receptor tyrosine kinase • ADR – Rash, Hand-foot syndrome – N&V, diarrhoea • Metabolism – Cyp 3A4 • Interactions – Cyp P450 relevant drugs – inhibits PgP so may interact with drugs the are PgP
Vemurafenib, Dabrafenib
• Inhibits V600E Raf
• Melanoma
Inhibition of growth/survival pathways: Cytosolic kinases 2 - everolimus (Afinitor)
• Indications
– Renal Cancer
• Mechanism
– inhibits mTORC1 which regulates protein translation
– includes inhibition of VEGF expression, hence inhibits angiogenesis
• ADR
– Rash
– ↓ lymphocytes & neutrophils – infections common
• PK
– Cyp 3A4 & PgP substrate
• Interactions
– Cyp P450 relevant drugs
– PgP substrate so PgP inhibitors may increase bioavailability
Cell cycle inhibition
• Palbociclib – Cdk4/6 inhibitor – Breast cancer –increases PFS 10 months – Approved but rejected by NICE • Other drugs in phase 3/regulatory review
Bevacizumab, sunitinib, sorafenib
• Bevacizumab (Avastin)
– monoclonal antibody that binds VEGF
• Sunitinib (Sutent), Sorafenib (Nexavar)
– multi-targeted tyrosine kinase inhibitors
– inhibit PDGF and VEGF receptor kinase domain
– because multi-targeted – have other mechanisms of action too
• Deprive tumour of nutrients by inhibiting angiogenesis
Bevacizumab
• Indications
– colorectal, breast, renal cancer, NSCLC
• Mechanism
– sequesters VEGF
• PK
– infusion every 2 weeks, t½ ~ 20 days
• ADR
– GI perforation,
– inhibit wound healing
– hypertension
• Caution
– caution if GI inflammation – increases risk of GI perforation
– delay after surgery 4 weeks (wound healing)
– anti-hypertensives may be appropriate to control ADR
Sunitinib
• Indications – GIST, renal cancer • Mechanism – inhibits VEGF receptor tyrosine kinase and several other tyrosine kinases (Kit, Fms, Ret, CSF1R, PDGF) • PK – metabolised by Cyp 3A4 • ADR – yellow skin discolouration – diarrhoea – pulmonary embolism – thrombocytopoenia – heart failure (↓LVEF), ↑QT interval, hypertension • Caution – monitor patients with history of cardiovascular issues • Interactions – Cyp relevant drugs
Proteosome inhibitors
• Ubiquitinated proteins targeted for degradation by
proteasome
• For reasons that are currently unclear, cancer cells are
more sensitive to proteasome inhibition
• Bortezomib (Velcade)
Bortezomib
• Indications – multiple myeloma • Mechanism • PK – metabolised by several Cyps • ADR – GI effects (N&V, diarrhoea) very common – myelosuppression – peripheral neuropathy – muscle weakness – hypotension • Caution – seek advice if dizziness, light-headed – consider dose-reduction in cases of hepatic impairment • Interactions – Cyp relevant drugs
DNA damage repair inhibitors
• Olaparib – PARP inhibitor
• Synthetic lethality – when two factors on own have no
effect but when combined are lethal
• Olaparib preferentially kills BRCA-null cells
Epigenetic regulation 1
- Covalent modification of histones & DNA that alter gene expression
- Can change dynamically
- Altered in cancer through mutation, amplification, deletion or translocation of genes which regulate epigenetic modifications
- Alternative way to alter activity of genes by altering their expression rather than direct inhibition of gene product
HDAC inhibitors
• HDAC = Histone deacetylase – several isoforms • HAT = Histone acetyltransferase • HDACi – Vorinostat – approved in US, not EU – Panobinostat – approved for multiple myeloma
Demethylating agents
• Actually work by inhibiting methylation of cytosines
• Decitabine
– analogue of cytidine
– Inhibits DNA methyl transferases so cause hypomethylation, altering gene expression
Hedgehog pathway
• Vismodegib
• Teratogenic (Preclinical data- severe birth defects)
– Check for pregnancy
– Women – 2 contraceptive methods
– Men – condom during and after treatment
