Pharmacological Targets for Cancer Therapy Flashcards
What are the general problems with anti-cancer drugs?
- Selectivity and specificity (avoiding healthy tissue)
- Off-target side effects (= noncompliance)
- Tumour-cell heterogeneity; mixture of cells (multiple targets?)
- Drug resistance; e.g. body develops resistance to anti-VEGF compounds
- Dose intensity; increased to counter resistance?
- Patient-specific factors; e.g. some patients develop hypertension w/anti-VEGF therapy
What is the main goal of anti-cancer drug therapy?
- Preserve ‘normal’ metabolism and cell function
- Shut down ‘abnormal’ processes that drive proliferation and growth
What approaches are there to treatment?
- Surgery
- Radiotherapy (DNA)
- Chemotherapy (DNA/cell cycle/topoisomerases/microtubules)
- Targeted Therapies (interfere w/specific pathway; signalling pathways, mABs, RTK inhibitors, hormones)
What is the purpose, pros and cons of Surgery?
+ Offers best ‘cure’ for solid tumour (particularly when still encapsulated and easy to access, or early)
+ Remove isolated metastatic masses
+ Facilitate further treatment; providing access for chemotherapy delivery (implanted infusion pumps)
+ Can be used for prevention; removal of moles, polyps, other precancerous lesions (catching cells in pre-cancerous state)
+ Debulking; removing bulk of tumour size before chemotherapy initiated
- Invasive
What does radiotherapy entail, what does it do?
- Gold standard
- Effect: Damages DNA
- But normal tissues also affected
External beam RT:
- From outside the body using high energy ionising radiation
- Used in up to 60% of treatment (common)
- Can leave burn marks
Internal brachytherapy:
- Radiotherapy from small radioactive ‘seeds’ placed within the body
What does chemotherapy do, and what part of this does it affect?
- Interferes with the Cell Cycle
- Inhibits cellular events that lead to cell division and replication
- Most chemotherapeutic cytotoxics target either the S or M phase of the cell cycle
What is the S phase of the cell cycle?
DNA Synthesis
What is the M phase of the cell cycle?
Mitosis; division of two daughter cells.
Describe the Cell Cycle and its main phases.
- G1 phase (cell with chromosomes in nucleus); production of RNA proteins/enzymes needed for DNA synthesis
»> S phase (chromosome duplication); DNA synthesis - G2 phase (cells w/duplicated chromosomes); cell prepares for mitosis
»> M phase (chromosome separation); mitosis, division to form 2 daughter cells. DNA condensed into chromosomes. - G0; dormant, resting phase.
Why is the G1 phase not targeted?
- Hard to hit cell at this point
- Cell is ‘relaxed, chilled out’, doesn’t particularly care
Why is the S phase one of two that are mainly targeted?
- The S phase (DNA synthesis) is where cells start to have activity differentiating them from ‘normal’ cells
- Normal cells do not need DNA synthesis, apart from lining in the gut/hair.
What Targeted Therapy approaches are availible?
- Inhibiting the interaction of a growth factor/hormone with its receptor
e. g. Bevacizumab (Avastin) and VEGF (no downstream angiogenesis if VEGF stimulus nullified) - Inhibiting signaling via receptor
e. g. Trastuzumab (Herceptin) and HER-2 - Target hormone signalling pathways
e. g. Tamoxifen and ER.
Why are Targeted Therapies desirable, and what are their issues?
- Targets are more ‘specific’ for cancer cells, and are critical for tumour cell survival
- Therapies aimed specifically at cancer cells, rather than all rapidly proliferating cells (e.g. immune cells like WBCs/ANCs, hair)
But, issues with:
- Are they actually more effective?
- Decreased side effect profile?
- Patient-specific?
- Physical and mental wellbeing
What is the normal VEGF (/EGF/PDGF) cell signalling pathway?
- VEGF binds to receptor
- Autophosphorylation at specific tyrosine residues
- Triggers phosphorylation cascade of RAS-RAF-MEK-ERK
- As well as upregulation of other intracellular tings: MAPK, Ca2+, AKT (as well as ERK)
- This leads to increase DNA transcription and translation
- Which means increased protein synthesis
= Growth, angiogenesis.
Which type of VEGF/corresponding receptor is implicated in angiogenesis and migration?
- VEGFA (not VEGFB/C/D etc.)
- And the receptor VEGFR2 (VEGFR1 is a decoy receptor)
