Biological Basis of Cancer Therapy Flashcards
What are the main anti-cancer modalities?
surgery, chemotherapy, radiotherapy and immunotherapy
Some cancers may be treatment with endocrine therapy (e.g. breast cancer)
What genetic mutations pre-dispose people to cancer?
- Chromosome translocation
- Gene amplification (copy number variation)
- Point mutations within promoter or enhancer regions of genes
- Deletions or insertions
- Epigenetic alterations to gene expression
What are some cytotoxic chemotherapies?
Alkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitor
What are targeted therapies?
Small molecule inhibitors
Monoclonal antibodies
How do cytotoxics work?
- not that specific (they tend to have other, systemic effects) - affect rapidly dividing cells
- given intravenously or by mouth (occasionally), and works systemically - Any other normal tissues with high turnover will suffer consequences of cytotoxic chemotherapy
- given POST-OPERATIVELY to deliver adjuvant chemotherapy
- can also be given PRE-OPERATIVELY to deliver neoadjuvant chemotherapy
- can be given as a singly agent (monotherapy) or in combination
- can be given with CURATIVE or PALLIATIVE intent
How do alkylating agents work?
e. g Chlorambucil, cyclophosphamide, dacarbazine, temozolomide
- agents add alkyl (CNH2N+1) groups to guanine residues in DNA -> causes cross-linking (intra, inter, DNA-protein) of DNA strands -> prevents DNA from uncoiling at replication -> triggers apoptosis (via checkpoint pathway)
* Occasionally, alkylating agents can lead to secondary cancers (they encourage miss-pairing – oncogenic)
** BENEFITS OF THIS TREATMENT OUTWEIGHS THE RISKS
What are pseudoalkylating agents?
e.g carboplatin, cisplatin, oxaliplatin
- Instead of an alkyl group, these agents add platinum to guanine residues in DNA
- They follow the same mechanism of cell death as alkylating agents
Side effects: cause hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness
What do anti-metabolites do?
- masquerade as purine or pyrimidine residues
- incorporate into the DNA -> inhibition of DNA synthesis, DNA double strand breaks and apoptosis
- At the DNA checkpoint, the cell recognises this as an error -> programmed cell death
- Block DNA replication (DNA-DNA) and transcription (DNA –RNA)
- Can be purine (adenine and guanine), pyrimidine (thymine/uracil and cytosine) or folate antagonists (inhibit dihydrofolate reductase required to make folic acid)
- Folic acid is an important building block for all nucleic acids – especially thymine
Examples: methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
What are the side effects of anti-metabolites?s
- Hair loss (alopecia) – not 5FU or capecitabine
- Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
- Increased risk of neutropenic sepsis (and death) or bleeding
- Nausea and vomiting (dehydration)
- Mucositis and diarrhoea
- Palmar-plantar erythrodysesthesia (PPE)
- Fatigue
What do anthracyclines do?
Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand, also block DNA repair, so can be mutagenic
They create DNA and cell membrane damaging free oxygen radicals
Examples: doxorubicin, epirubicin
What are the side effects of anthracylcines?
- Cardiac toxicity (arrythmias, heart failure) – probably due to damage induced by free radicals
- Alopecia
- Neutropenia
- Nausea and Vomiting
- Fatigue
- Skin changes
- Red urine (doxorubicin “the red devil”)
What do microtubule targetting drugs do?
inhibit assembly (vinca alkaloids) or disassembly ( taxanes) of mitotic tubules -> mitotic arrest of cells
What are the side effects of microtubule targeting drugs?
- Nerve damage: peripheral neuropathy, autonomic neuropathy
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression (neutropenia, anaemia etc.)
- Arthralgia
- Allergy
What do tropoisomerase inhibitors do?
Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription - 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: Topotecan and irinotecan (topo I) and etoposide (topo II) alter binding of the complex to DNA and allow permanent DNA breaks. This causes apoptosis at DNA check points
What are the side effects of tropoisomerase inhibitors?
- (Irinotecan): Acute cholinergic type syndrome
- Diarrhoea, abdominal cramps and diaphoresis (sweating) à therefore given with atropine
- Hair loss
- Nausea, vomiting
- Fatigue
- Bone marrow suppression
What are the hallmarks of cancer cells?
- Self–sufficient
- Insensitive to anti-growth signals – survivals with minimal stimulation and grows regardless of intake
- Anti-apoptotic
- Pro-invasive and metastatic – spreads rapidly into the surrounding area
- Pro-angiogenic
- Non-senescent
What are some examples of over expression of receptors?
- HER2 – amplified and over-expressed in 25% breast cancer
- EGFR – breast and colorectal cancer
- PDGFR – glioma (brain cancer)
- Over-expression -> increased kinase cascade -> increased signal amplification
What is an example of over expression of ligands?
VEGF – prostate cancer, kidney cancer and breast cancer (-> increased kinase cascade -> increased signal amplification)
What do the suffixes of monoclonal antibodies mean?
- momab (derived from mouse antibodies)
- ximab (chimeric) e.g. cetuximab
- zumab (humanised) e.g. Bevacizumab, trastuzumab
- mumab (fully human) e.g. panitumumab
What are some examples of monoclonal antibodies in oncology?
Bevacizumab binds and neutralises VEGF -> improves survival in colorectal cancer
Cetuximab targets EGFR -> also used in colorectal cancers
What do small molecule inhibitors do?
- bind to the kinase domain of the tyrosine kinase within the cytoplasm
- block auto-phosphorylation and downstream signalling
- e.g GLIVEC (imatinib)
What is glivec?
small molecule inhibitor - targets the ATP binding region within the kinase domain
creates its own unique fusion protein (Bcr-abl), an enzyme which drove over-production of white cells
What are some advantages and disadvantages of monoclonal antibodies?
advantages:
- high target specificity
- can be radioblasted
- long half-life
- good for haematological malignancies
disadvantages:
- large and complex structure
- less useful against bulky tumours
- only useful against targets with extracellular domains
- cause allergy
- risky
- expensive
What are some advantages and disadvantages of small molecule inhibitors?
advantages:
- can target TKs without any extracellular domain
- cheap
- good tissue penetration
- oral administration
disadvantages:
- shorter half-life
- pleiotropic targets (more unexpected toxicity)
What are the mechanisms of resistance to targeted therapies?
- Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene targeted by Glivec)
- Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream or parallel pathways
What are anti-sense oligonucleotides?
- Single stranded, chemically modified DNA-like molecules: 17-22 nucleotides in length
- Complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA
- Recruits RNase H to cleave target mRNA
- Good for “undruggable” targets
What is RNA interference?
- Single stranded complementary RNA
- Compounds have to be packaged to prevent degradation – nano-therapeutics
- CALAA-01 targeted to M2 subunit of ribonucleotide reductase
What percentage of melanomas have a B-raf mutation?
60%
What are the side effects of b-raf inhibitors?
arthralgia, skin rash and photosensitivity
What id PD-1? What does it do?
- ligand present on surface of cancer cells
- requirede to maintain t-cell activation
- after binding the ligand PDL1, the body’s T cells can no longer recognise tumour cells as foreign
- if either is blocked, the immune system is stimulated
What is nivolumab?
- anti-PD1 antibody
- good results in lung cancer, melanoma and renal cell carcinoma
- n treatment-refractory melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC)
- overall response rate of 31% in melanoma (compared to the usual 5-15%)
- Median survival of 16 months (incredible for a phase I trial)
