Biological basis of cancer therapy Flashcards
What are the 5 most common cancers worldwide?
Lung Breast Bowel Prostate Stomach
What is expected to happen to the incidence of cancer?
It is expected to increase- 27 million cases in 2030
What is expected to happen to distribution in terms of infection-based and western cancers?
Greater westernisation in developing countries will reduce infection based cancers (cervical, stomach etc) and increase western cancers such as breast, colorectal, lung and prostate
What are the 4 main anti-cancer modalities?
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
What types of genetic mutation are there that cause cancer?
Chromosome translocation
Gene amplification
Point mutations within promoter or enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression
Inherited
What types of cytotoxic chemotherapy are there?
Alkylating agents Antimetabolite Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
What targeted therapies are there?
Small molecule inhibitors
Monoclonal antiboides
How is cytotoxic chemotherapy normally given?
IV or occasionally orally
What cells does cytotoxic chemotherapy target?
It is non-targeted - it targets all rapidly dividing cells in the body e.g. hair and intestinal epitherlium
What does adjuvant chemotherapy mean?
Given post op
How do alkylating agents work?
These add alkyl groups to guanine residues in DNA which cross-links DNA strands and prevents DNA from uncoiling at replication and then triggers apoptosis
How do pseudo-alkylating agents work?
These add platinum to guanine residues in DNA which triggers the same mechanism of death as alkylating agents
Give some examples of alkylating agents?
Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide
Give some examples of pseudo-alkylating agents?
Carboplatin
Cisplatin
Oxaliplatin
What are the side effects of alkylating and pseudo-alkylating agents?
Hair loss Nephrotoxicity Neurotoxicity Ototoxicity Nausea Vomiting Diarrhoea Immunosuppression Tiredness
How do anti-metabolites work?
These masquerade as purine or pyrimidine residues leading to inhibition of DNA synthesis, breaking the double strand of DNA and apoptosis- they block DNA replication and transcription
What can anti-metabolites be?
Purine analogues
Pyrimidine analogues
Folate antagonists- directly inhibit folate reductase which is required to make folic acid- important building block for all nucleic acids especially thymine
Give some examples of anti-metabolites?
Methotrexate 6-mercaptopurine Fludarabine 5-fluorouracil Capecitabine Gemcitabine
What are the side effects of anti-metabolites?
Hair loss Bone marrow suppression Increased risk of neutropenic sepsis or bleeding Nausea and vomiting Mucositis and diarrhoea Palmar-plantar erythrodysesthesia Fatigue
For which anti-metabolites is hair loss not a side effect?
5-fluorouracil or capecitabine
What does bone marrow suppression cause?
Anaemia, neutropenia and thrombocytopenia
What do anthracyclines do?
Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand and block DNA repair- they create DNA damaging and cell membrane damaging oxygen free radicals
Give some examples of anthracyclines?
Doxorubin
Epirubicin
What are the side effects of anthracyclines?
Cardiac toxicity Alopecia Neutropenia Nausea Vomiting Fatigue Skin changes Red urine (doxorubicin- red devil)
What do vinca alkaloids and taxanes do?
Inhibit the assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest
What are the side effects of microtubule targeting drugs (VAs and Texans)?
Nerve damage- peripheral neuropathy and autonomic neuropathy Hair loss Nausea Vomiting Bone marrow suppression Arthralgia Allergy
What are topoisomerase responsible for?
Uncoiling of DNA- prevent DNA torsional strain during DNA replication and transcription
How do topoisomerase work?
They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA and protect the free ends of DNA from aberrant recombination events
How do topoisomerase inhibitors work?
Some alter the binding of the DNA to the complex and allow permanent DNA breaks
Give some examples of topoisomerase inhibitors?
Topotecan (topo 1)
Irinotecan (topo 1)
Etoposide (topo 2)
What are the side effects of topoisomerase inhibitors?
Irinotecan- acute cholinergic type syndrome- diarrhoea, abdominal cramps and diaphoresis (sweating)- given atropine Hair loss Nausea Vomiting Fatigue Bone marrow suppression
How can cells survive despite chemotherapy?
There are resistance mechanisms:
DNA repair mechanisms unregulated
DNA adducts replaced by base excision repair
Drug effluxed from cell by ATP-binding cassette transporters
What to targeted/non-cytotoxic therapies mainly involve?
Monoclonal antibodies and small molecule inhibitors
What are the 6 hallmarks of cancer?
SPINAP: Self sufficient Pro-invasive and metastatic Insensitive to anti-growth signals Non-senescent Anti-apoptotic Pro-angiogenic
What are the 4 hallmarks that have been added to the previous 6?
DIE U Dysregulated metabolism Inflammation Evades the immune system Unstable DNA
In terms of growth signals what is the difference between normal cells and cancer cells?
Normal cells require growth signals to move from quiescent state to an active proliferating state which are transmitted via growth factors by signalling pathways
Cancer cells are self sufficient in growth signals (tyrosine kinase receptor is associated with >50% of malignancies)
Which receptors are overexpressed in certain types cancer?
HER2- amplified and over expressed in 25% of breast cancers
EGFR- over expressed in breast and colorectal cancer
PDGFR- Glioma (brain cancer
All growth factor receptors so lead to up regulation of kinase cascade and signal amplification
What ligand is over expressed in prostate, kidney and breast cancer?
VEGF- leads to up regulation of kinase cascade and signal amplification
What receptors is there constitutive (ligand independent) receptor activation of?
EGFR- lung cancer
FGFR- head and neck cancers, myeloma
If a monoclonal antibody ends in momab, where is it derived from?
Mouse antibodies
If a monoclonal antibody ends in ximab, where is it from?
Chimeric
If a monoclonal antibody ends in mumab, where is it from?
Fully human
What part of the receptor do monoclonal antibodies target?
Extracellular component
What do monoclonal antibodies do?
Neutralise the ligand
Prevent receptor dimerisation
Cause internalisation of the receptor
Activate Fcy receptor dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody dependent cellular cytotoxicity
Give some examples of monoclonal antibodies in oncology and what they do?
Bevacizumab binds and neutralises VEGF- improves survival in colorectal cancer
Cetuximab targets EGFR
What do small molecule inhibitors do?
Bind to the kinase domain within the cytoplasm and block autophosphorylation and downstream signalling
What was the first targeted therapy?
Glivec- small molecule inhibitor that targets ATP binding region within kinase domain- inhibits the kinase activity of ABL1
What do small molecule inhibitors act on?
Receptor protein tyrosine kinases and intracellular kinases- therefore affect cell signalling pathways
Give some small molecule inhibitors that inhibit receptors
Erlotinib (EGFR)
Gefitinib (EGFR)
Lapatinib (EGFR/HER2)
Sorafenib (VEGFR)
Give some small molecule inhibitors that inhibit intracellular kinases
Sorafenib (Raf kinase)
Dasatinib (Src kinase)
Torcinib (mTOR inhibitors)
What are the advantages of monoclonal antibodies?
High target specificity Cause ADCC, complement mediated cytotoxicity and apoptosis induction Can be radio labelled Cause target receptor internalisation Long half life Good for haematological malignancies
What are the disadvantages of monoclonal antibodies?
Large and complex structure Less useful against bulky tumours Only useful against targets with extracellular domains Not useful for constitutively activated receptors Cause immunogenicity Parenteral administration Risky! Expensive
What are the advantages of small molecules?
Can target TKs without an extracellular domain or which are constitutively activated Pleiotropic targets Oral administration Good tissue penetration Cheap
What are the disadvantages of small molecules?
Shorter half life- more frequent administration
Pleiotropic targets
What is the big problem with targeted therapies?
Resistance
What resistance mechanisms to targeted therapies are there?
Mutations in ATP-binding domain
Intrinsic resistance
Intragenic mutations
Upregulation of downstream or parallel pathways
What are anti-sense oligonucleotides?
Single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
What do anti-sense oligonucleotides do?
Hybridise to the complementary gene and hinders translation of specific mRNA- it recruits RNaseH to cleave target mRNA
What is RNA interference?
Single stranded complementary RNA- lagged behind anti-sense technology
What is another major obstacle to the targeted approach?
Tumour heterogeneity
What are the new therapeutic avenues for cancer treatment?
Nanotherapies- delivering cytotoxic more effectively
Virtual screening technologies to identify undruggable targets
Immunotherapies using antigen presenting cells to present artificial antigens
Targeting cancer metabolism
