Biological Basis of Cancer Therapy Flashcards
Which are the Most Common Cancers Worldwide and what are the predictions for the future:
- Lung
- Breast
- Bowel
- Prostate
- Stomach
- The incidence of cancer is set to increase
Greater westernisation in developing countries will reduce infection-based cancers (e.g. cervical, stomach etc.) and increase western cancers such as breast, colorectal, lung and prostate
Men- Lung
Women- Breast
Which are the Main Anti-Cancer Modalities?
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
What Types of genetic mutation can cause cancer?
- Chromosome translocation
- Gene amplification (copy number variation)
- Point mutations within promoter or enhancer regions of the genes
- Deletions or insertions
- Epigenetic alterations to gene expression
- Can be inherited
What are the different types of a Systemic therapy, where can they be used and how?
Cytotoxic Chemotherapy (several different drugs from different classes to maximize efficiency)
- Alkylating agents
- Antimetabolites
- Anthracyclines
- Vinca alkaloids and taxanes
- Topoisomerase inhibitors
Targeted Therapies
- Small molecule inhibitors
- Monoclonal antibodies
Cytotoxic drugs ‘select’ rapidly dividing cells by targeting their structures (mostly DNA)
Cytotoxic Chemotherapy
- Given IV or orally and function systemically
- It works systemically, they affect all the rapidly dividing cells
- Non-targeted - it affects all rapidly dividing cells in the body e.g. hair and intestinal epithelium, bone marrow suppression.
- Different times at which it can be used:
- Post-operatively = adjuvant (better diagnosis)
- Pre-operatively = neoadjuvant (trying to down stage them during thereapy, avoid complete mastectomy)
- As a monotherapy or in combination
- With curative or palliative intent, it doesn’t mean that the patient will die in a few weeks
Describe the use of Alkylating and Pseudo-alkylating Agents, what are the side effects?
Alkylating Agents
- These add alkyl (CNH2N+1) groups to guanine residues in DNA
- It then cross-links DNA strands and prevents DNA from uncoiling at replication
- It then triggers apoptosis (via a DNA checkpoint pathway)
It encourages mis-pairing
Pseudo-alkylating Agents
- These add platinum to guanine residues in DNA
- It triggers the same mechanism of death as alkylating agents
Alkylating and Pseudo-alkylating Agents
- Alkylating agents:
- Chlorambucil
- Cyclophosphamide
- Dacarbazine
- Temozolomide
- Pseudo-alkylating agents:
- Carboplatin
- Cisplatin
- Oxaliplatin
Side effects:
- Hair loss (not carboplatin)
- Nephrotoxicity
- Neurotoxicity (peripheral neuropathy)
- Ototoxicity (platins)
- Nausea
- Vomiting
- Diarrhoea
- Immunosuppression
- Tiredness
Describe the use of Anti-metabolites and their side effects
- These masquerade as purine or pyrimidine residues leading to the inhibition of DNA synthesis, breaking of the double strand of DNA and apoptosis
- purine analogues (adenine or guanine)
- pyrimidine analogues (thymine/uracil and cytosine)
- folate antagonists (these inhibit dihydrofolate reductase, which is required to make folic acid, an important building block for all nucleic acids (especially thymine))
- They block DNA replication and DNA transcription
Examples of anti-metabolites:
- Methotrexate- Folate
- 6-mercaptopurine- Purine
- 5-fluorouracil- Pyramidine
Side effects of anti-metabolites:
- Hair loss (alopecia) - not 5-fluorouracil or capecitabine
- Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia (increased risk of neutropenicn problem)
- Increased risk of neutropenic sepsis (and death) or bleeding
- Nausea and vomiting (leading to dehydration)
- Mucositis and diarrhoea
- Palmar-plantar erythrodysesthesia (PPE)
- Fatigue
Describe the use of Vinca Alkaloids and Taxanes, what are their side-effects?
- They work by inhibiting the assembly (vinca alkaloids) or disassembly (taxanes) of MITOTIC MICROTUBULES causing dividing cells to undergo mitotic arrest
Side effects of microtubule targeting drugs:
- Nerve damage: peripheral neuropathy, autonomic neuropathy
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression (neutropenia, anaemia etc.)
- Arthralgia (severe pain in a joint without swelling or other signs of arthritis)
- Allergy
Describe the usage of Anthracyclines and state their side effects
- Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand
- They also block DNA repair (mutagenic)
- They create DNA-damaging and cell membrane damaging oxygen free radicals
- Examples of anthracyclines:
- Doxorubicin
- Epirubicin
Side effects of anthracyclines:
- Cardiac toxicity (arrhythmias, heart failure) - probably due to damage induced by free radicals
- Alopecia
- Neutropenia
- Nausea
- Vomiting
- Fatigue
- Skin changes
- Red urine (doxorubicin = ‘the red devil’)
Describe the usage of Topoisomerase Inhibitors and state their function
- Topoisomerases are responsible for the uncoiling of DNA - they prevent DNA torsional strain during DNA replication and transcription
- They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA
- They protect the free ends of DNA from aberrant recombination events
- Drugs, such as anthracyclines, have anti-topoisomerase effects through their action on DNA
- Specific topoisomerase inhibitors alter the binding of the complex to DNA and allow permanent DNA breaks
- Examples of topoisomerase inhibitors:
- Topotecan (topo 1)
- Irinotecan (topo 1)
- Etoposide (topo 2)
Side effects of topoisomerase inhibitors:
- Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis (sweating) - they are therefore given atropine)
- Hair loss
- Nausea
- Vomiting
- Fatigue
- Bone marrow suppression
- Neutrophilic Sepsis; give them IV antibiotics if theu get infected
Summarize the different roots of Apoptosis
- DNA damage at checkpoint
- DNA double strand breaks
There are resistance mechanisms that can allow cells to survive despite the chemotherapy
- The cell can survive the damage by the cytotoxic drugs which may lend to the lower chance of relapse/cure.
- DNA repair mechanisms upregulated
- Base excision repair using PARP.
- DNA efflux by ATP-binding cassettes (ABC) transporters.
What are the Six Hallmarks of Cancer (mention the new additions as well)?
- 6 Hallmarks: SPINAP
- Self-sufficient
- Pro-invasive and metastatic
- Insensitive to anti-growth signals
- Non-senescent
- Anti-apoptotic
- Pro-angiogenic
- In other words:
- Survives with minimal stimulation
- Grows regardless of intake
- Doesn’t take the hint to move out
- Spreads rapidly into the surrounding area
- Refuses to grow up
- The 6 hallmarks have now been extended to become 10 hallmarks:
- In addition to the 6 previously mentioned, these 4 have been added: DIE U
- Dysregulated metabolism
- Evades the immune system
- Unstable DNA
- Inflammation
Cancer cells are self-sufficient in growth signals
- Normal cells need growth signals to move from a quiescent (resting) state to an active proliferating state
- These signals are transmitted to cells via growth factors that bind to transmembrane receptors (tyrosine kinase linked receptors) and activate downstream signalling pathways
- NOTE: refer back to Cancer 3 for the full tyrosine kinase mediated signalling pathway
- Receptor tyrosine kinase are associated with >50% of human malignancies
Describe the use of Modern, targeted (non-cytotoxic) therapies, what are the side effects?
This mainly involved monoclonal antibodies and small molecule inhibitors
These seek to manipulate what we know about cancer cells
- There is a lot of signalling within cancer cells and these signals can be cut in monogenic cancers
- However, for other cancers, parallel pathways and feedback cascades are activated
- We are now in an era of dual kinase inhibitors, which prevent feedback loops but increase toxicities
Describe the different types of Monoclonal Antibodies based from where they’ve divided
Dependent on twhere they derived from
Which receptors are over-expressed and with which cancers do they relate, what else can be over-expressed?
Over-expression of receptors (HER2, EGFR)
- HER2 - amplified and over-expressed in 25% of breast cancers
- EGFR - over-expressed in breast and colorectal cancer
- PDGFR - glioma (brain cancer)
- These are all growth factor receptors so over-expression will lead to an upregulation of the kinase cascade and signal amplification
Over-expression of the ligand
- VEGF - prostate, kidney and breast cancer
- This also leads to upregulation of the kinase cascade and signal amplification
Constitutive (ligand independent) receptor activation
- EGFR - lung cancer
- FGFR - head and neck cancers, myeloma
All of these result in increase in kinase cascade and signal amplification
What is the action of Monoclonal antibodies?
Monoclonal antibodies target the extracellular component of the receptor
- The monoclonal antibodies:
- Neutralise the ligand
- Prevent receptor dimerisation (by binding to one of the receptors)
- Cause internalisation of the receptor, it may lead to an immune response
They also activate:
- Fcg-receptor-dependent phagocytosis
- cytolysis induced complement-dependent cytotoxicity (CDC)
- antibody-dependent cellular cytotoxicity (ADCC)
Examples of monoclonal antibodies in oncology
- Bevacizumab binds and neutralises VEGF - this improved survival in colorectal cancer
- Cetuximab targets EGFR
Small Molecule Inhibitors
- These bind to the kinase domain within the cytoplasm and block autophosphorylation and downstream signalling
- Glivec – first SMI, targets BCR-ABL fusion protein made in CML.
Describe the effect of Bcr-abl translocation in CML
- Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain
- It inhibits the kinase activity of ABL1
- SMIs act on the receptors TKs but also on the intracellular kinases–>affect cell signalling pathways.
- I.E. they bind not just to the TK but also to Raf, MEK, Akt, etc. proteins.
Small molecule inhibitors act on receptor protein tyrosine kinases but also on intracellular kinases - therefore they can affect cell signalling pathways (e.g. kinase cascade)
SMI of:
TK receptors: Intracellular kinases:
Erlotibib – EGFR. Sorafinib – Raf kinase.
Gefitinib – EGFR. Dasatinib – Src kinase.
Lapatinib – EGFR/HER2. Torcinibs – mTOR inhibitors.
Sorafinib – VEGFR.
By acting on receptors (either externally or internally), targeted therapies block cancer hallmarks (e.g. VEGF inhibitors alter blood flow to the tumour, AKT inhibitors block apoptosis resistance mechanisms) without the toxicity observed with cytotoxics
What are the Advantages and Disadvantages of Targeted Therapies?
- However, one big problem is RESISTANCE
Resistance mechanisms to targeted therapies
- Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
- Intrinsic resistance (herceptin is effective in 85% of HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream of parallel pathways (that lead to cell proliferation)
Describe the use of Anti-sense Oligonucleotides
- Single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
- This complementary nucleic acid hybridisation to the target gene hinders translation of specific mRNA
- It recruits RNase H to cleave target mRNA
- This is good for ‘undruggable’ targets
- Mechanism of action of anti-sense oligonucleotides:
RNA Interference
- Single-stranded complementary RNA
- This has lagged behind anti-sense technology - especially in cancer therapy
- Compounds have to be packaged to prevent degradation (nanotherapeutics)
- CALAA-01 targeted to M2 subunit of ribonucleotide reductase (phase 1 clinical trials in cancer at the moment - results are awaited)
NOTE: all these treatments are very expensive for the NHS
Tumour heterogeneity is a major obstacle to the targeted approach
