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PHCY320 ON7 Targeted Therapies Exam Latest Update
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PHCY320 ON7 Targeted TherapiesExam Latest Update
Targeted therapies differ from standard cancer therapies in that - Answer Act on
specific molecular target(proteins that control how cancer cells grow, divide & spread),
generally cytostatic and are products of rational drug design.
Cytostatic - Answer Inhibits cell growth and proliferation.
Targeted therapies are the cornerstone of precision medicines where using - Answer
Information about genes & proteins can help diagnose and treat. This helps target
survival and growth pathways and improve outcomes/minimise adverse effects.
Normal tumour-suppressor gene acts as - Answer Brake for cell growth.
Normal proto-oncogene acts as - Answer Accelerator for cell growth.
Abnormal cell cycle (cancer cells) caused by - Answer Mutated tumour-suppressor gene
-> loss of function &/or mutated proto-oncogene -> gain of function.
Oncogenic pathways - Answer Spontaneous undesired mutations -> activate
proto-oncogenes -> inactivate tumour-suppressing & DNA repair genes.
Can also overexpression of growth factors & enzymes -> gain of function -> increased
cell proliferation.
Tumour associated antigens (TAIs) are - Answer Molecules involved in oncogenic
pathways (optimal blocking targets to prevent cancer cell proliferation).
Receptor tyrosine kinase (RTK) mediates - Answer Cell-cell communication, regulates
eg. growth, motility, differentiation. All 58 known RTKs in humans have inherent tyrosine
kinase activity & can auto-phosphorylate -> activation & promotion of cell growth.
Dysregulation of RTK signalling leads to - Answer Many human diseases especially
cancer.
Three examples of RTKs - Answer VEGF Rs (vascular endothelium-derived growth
factor), HE Rs (human epidermal growth factor), PDGF Rs (platelet-derived growth
factor).
Under normal physiological conditions, RTK activity is tightly balanced. - Answer
Growth factor ligand binds -> dimerisation -> auto-phosphorylation -> R activated.
When oncogenes are activated -> RTK production -> - Answer Auto-phosphorylation ->
always on -> stimulates proliferation & blocks apoptosis.
, -tinib drug means - Answer A small molecule inhibitor of the RTK.
Tyrosin kinase inhibitors (eg. gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib) MoA
- Answer Competitive inhibition of ATP binding at RTK catalytic site BUT each have
different spectrum of targeted kinases.
Sunitinib inhibits signals from several Rs including - Answer VEGF and PDGFR families.
Rare SE: osteonecrosis of the jaw esp w radiation or bisphosphonates.
Fusion genes are potential therapeutic targets based on rationale of - Answer
Chromosomal abnormalities in cancer cells but not normal cells. Fusion genes -> fusion
proteins -> drive cancer development.
Fusion gene is when - Answer The gene incorporates parts of two different genes.
Chronic myeloid leukaemia is associated with - Answer Philadelphia chromosomes ->
BCR-ABL mutation -> BCR-ABL fusion protein -> constitutively active tyrosine kinase
activity.
Imatinib (Gleevec) is the first NIB approved by FDA MoA - Answer Small molecule
intracellular inhibitor selective for BCR-ABL TK fusion protein, used in chronic myeloid
leukaemia. It competes with ATP for binding site -> inhibits phosphorylation -> turn off
constitutive activation of TK -> prevents cell proliferation.
RTK inhibitor (-nibs) Side effects - Answer Usually well tolerated, myelosuppression,
rash, GI upset, fatigue, arthralgia, myalgia; (rare) cumulative cardiotoxicity,
osteonecrosis(sunitinib)
Pt taking nibs Monitoring - Answer Cardiovascular functions.
RTK inhibitor (-nibs) Interactions - Answer CYP3A4 substrates eg. rifampicin(inducer)
increase clearance of nibs, fluconazole(inhibitor) decreases clearance by 30%
(clinically sig).
Rifampicin induces/inhibits CYP3A4? - Answer Induces.
Fluconazole induces/inhibits CYP3A4? - Answer Inhibits.
-ciclib (newer ibs) means - Answer Cyclin-dependent kinase inhibitor.
-mab means - Answer Monoclonal antibodies which binds to specific antigen epitopes
(historically used to assess molecular phenotype).
Standard nomenclature of MABs - Answer Preceding the -mab is animal source:
o(murine), i(primate), xi(chimeric), zu(humanised), u(human).
MABs MoA - Answer Targets angiogenesis especially VEGF-A and VEGFR2 (keys in
angiogenesis).
Angiogenesis - Answer New blood vessel formation(normally tightly controlled). It is
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