Diagnosis and Treatment Flashcards
(29 cards)
What is the golden rule of a successful cancer therapy?
The benefit : side effect ratio.
*Must be able to cause enough damage to cancer cells to regress tumour
*Must be specific enough to allow tolerance of treatment
What are the associated problems with MMP inhibitors?
MMPIs have been trialled but so far unsuccessful.
- Some MMPs appear to have anti-tumour effects (e.g. MMP8 regulates collagen and inflammation in breast cancer), therefore broad MMPIs can in fact progress tumours.
- Side effects severe (e.g. fever, pain, muscoskeletal syndrome)
- May be design of trial - MMPs mainly have effect early in cancer development but trials in stage IV patients (where MMPs less involved anyway).
Why might the poor set up of clinical trials prevent the advancement of useful drugs?
*Trial in a group of patients with different mutation profile
*Trial in group at wrong stage (e.g. MMPIs)
Why might MMPIs still be a viable treatment despite poor clinical trial outcomes?
Main be design of trial - MMPs mainly have effect early in cancer development but trials in stage IV patients (where MMPs less involved anyway).
MMPIs can be specialised to ensure they do not target anti-cancer MMPs. Has two effects:
*Increasing efficacy per unit drug to reduce cancer burden
*Allows lower dose to be used (which may decrease side effects)
Can ion channels be targeted in treatment?
20% of all drugs target ion channels but yet to be a cancer drug developed.
Oncochannels proposed:
* Kv10.1 channel regulates transmitter release. Expression causes loss of contact inhibition (invasive cancer in immunodeficient mice).
* Antibody inhibition of Kv10.1 effectve in controlling cancer in mouse xenograft model
* Kv10.2 enables successful mitosis and medulloblastoma growth
* Knockdown of Kv10.2 leads to mitotic catastrophy. Reduces tumour burden and increases survival
* Designer peptide to target channel (based on a known psychotic drug) was successful in a glioblastoma patient.
What are immune checkpoints? Why is inhibiting them useful in cancer?
‘Off switches’ to the immune system. Prevents overactivation which can cause damage to healthy tissues (e.g. autoimmunity).
Immune cells are capable of selectively killing cancer cells. Tumour microenvironment is immunosuppressive which allows immune evasion. ICIs block these off-switches, upregulating the immune system to overcome this immunosuppression and kill the cancer cells.
Major breakthrough and very effective in some cancers.
What are the main classes of immunotheraputic treatments? Give an example of each.
- Monoclonal antibodies (mAbs): target specific proteins on cancer cells to induce a selective immune response (e.g. Bevacizumab against VEGF, α-LGR5 mAb for HCC where 90% cells express it).
- ICIs (also mAbs): block regulatory immune receptors (e.g. nivolumab against PD-1) or increase co-stimulatory activaiton (e.g. anti-CTLA-4) to increase immune attack on cancer cells
- Immune system modulators (e.g. cytokines IL-2)
- CAR-T cell therapy: modifying patients own immune cells and re-introducing them.
- Cancer vaccines: priming immune system against tumour specific antigens to increase efficacy.
- BiTEs (bispecific engagers): bring together tumour and T-cells
What are the general advantages and disadvantages of ICIs?
Advantages:
* No direct collateral damage (i.e. damage from drug itself)
* Easy to manufacture and administer
* Evidence for long lasting immunity
Disadvantages:
* Resistance can occur (mutation to get around inhibitor)
* Autoimmune responses are common (and very serious) (IrAEs)
What are CAR-T cells? What are the advantages and disadvantages?
Chimeric antigen receptor T cell therapy: GE cells with receptors specific for tumour antigen (expand the patient population and re-infuse)
Advantages:
* Very effective for blood cancer (e.g. B cells leukaemias)
* Approved for specific cancers e.g. melanoma
* Long lasting
* Reduce relapse risk
Limitations:
* Cytokine release syndrome (‘cytokine storm’) requires CAR-T cells reduction and IL-6 infusion
* Can struggle to ener solid tumours
* On-target-off-tumour toxicities: e.g. circuiating B cells
* Off-target toxicities (e.g. some engineered cells became cross-reactive with titan protein in heart muscle causing heart failure.
Provide an example of an off-target effect of CAR-T cells.
How could these effects be mitigated?
Some engineered cells became cross-reactive with titan protein in heart muscle causing heart failure.
Mitigation:
* Logic gated CAR: express both activating and inhibiting receptors, healthy tissues can silence cells.
* Inclusion of selective ‘suicide genes’ which are activated in healthy tissues
What are the advantages and disadvantages of BiTEs?
BiTEs are a onjoined anti-TSA and anti-CD3 to bring together cancer cells and T cells.
Advantages:
* Effective against solid tumours
* Easy to manufacture (‘off the shelf’) and fast to administer
* Can have multiple target antigens
* MHC independent killing (overcomes reduction in presentation)
Limitations:
* Short-half life (compared to CAR-T with potential for relapse) - requires continuous administration
* Cytokine release syndrome
* Neurotoxicity observed
Give an example of a mAb use:
Belvacizumab against VEGF:
* Inhibits angiogenesis
* Used for RCC
α-LGR5 mAb for hepatocellular carcinoma:
* LGR5 (for Wnt, catenin and stem cell signalling) is overexpressed in >90% HCCs (correlated with poor prognosis)
* internalisation occurs robustly and quickly
* Efficacy for tumour regression high in mouse models
Outline traditional cancer treatments (non-immunotheraputic). Provide examples.
Surgery:
* Resectable tumours (brain, breast) - not all are
* Can slow but very difficult to remove all tumour (need to be combined with other treatments)
Chemotherapy:
* Premise: cancer cells are more sensitive to chemotherapy (reduced ability to repair)
* Alkylating agents (e.g. cisplatin to transfer alkyl group to G); antipyrimidines (e.g. 5-fluorouracil), topoisomerase inhibitors
* Can be given as primary, neo-adjuvant (i.e. pre-surgery to shrink mass), adjuvant or palliative.
* High associated toxicity in both short and long term
Radiotherapy:
* Premise: cancer cells are more sensitive to radiation (reduced ability to repair)
* Ionising radiation induce signal and double stand breaks (until cell overwhelmed) and die
* Can be external (image guided tech, confocal) or internal (i.e. catheter placed in target cancer)
How can metabolites be used to diagnose cancer?
Changes to metabolism are a hallmark of cancer:
* Warburg effect common: tumours have different metabolic profile
* Labelling metabolites for diagnosis e.g. 18F-FDG and PET scan can show up unknown metastasis (build up TCA intermediates)
* 13C tracing glucose
How can differences in metabolism be used to treat cancer growth and metastasis? (General and specific example)
Profiling patients by metabolism can allow personalised treatment (i.e. targeting specific metabolism difference seen).
Exploit pathways tumour is using to get energy:
* Ferraro et al: FFA synthesis necessary for breast cancer metastasis in brain to survive (therefore target FFA synthesis)
* IDH mutant glioma: use IDH1 or 2 inhibitor (doubled progression free survival time).
What are TSAs and how are they useful for treatment?
Tumour specific antigens - i.e. molecules expressed on tumour cells
* Can be used for recognition by immune cells (increase efficacy of ICIs)
* Are relatively safe since expression localised to tumour
* Reduced killing of healthy bystander cells
What are some immune evasion strategies used by cancer?
- Downregulation of antigen presentation (MHCI reduction)
- Causing immune exhaustion (PD-1 expression, CTLA-4 activation, TGF-β expression)
- Immunosuppression through Treg, TAM, CAF, TAN activation
- Immune privilege: e.g. vessels from tumour angiogenesis may not present correct selectins (P&E) for extravasation.
Describe the potential side effects from CBT. Give stats on neurological side-effects.
Since CBT takes the ‘brakes off’ the immune system, autoimmunity can result - i.e. irAEs.
Example is neurological complications:
* Rossi et al 2024
* 1-3% incidence rate of irAEs of which where is a ~2% mortality rate
* Mostly from cardiac (cardiomyositis) or myasthenic crisis causing respiratory failure.
Unfortunately, there is a correlation between those who show strong tumour response to treatment and develop irAEs…
Name the main types of ICI and give examples:
PD-1 inhibitor (binds to antigen on immune cells (CD8))
* Nivolumab, pembrolizumab
PD-L1 inhibitor (prevents binding of PD-1 to silence T-cell)
* Durvalumab
CTLA-4 inhibitor (CTLA-4 is a competitive inhibitor of CD28 co-stimulatory molecule on T-cells)
* Ipilimumab
Provide a specific example of CBT success:
- Melanoma study, CTLA-4 inhibitor providede 22% of patients with additional >3 years of life (Queirolo)
- Success in head and neck cancers (which are very difficult ot treat surgically)
Give an example of hormone therapy for cancer treatment.
Treatment of breast cancer using tamoxifen
* Blocks oestrogen receptors (reducing stimulation of ER+ cancer cells)
* Since these ER+ cells support the ER- cells, this reduces both populations
What are the different strategies to target TAMs that have been tried?
- TAM Depletion (particularly of senescent cells)
- TAM Re-education (i.e. try to revert tumour progressing TAMs to suppressing)
- TAM Reprogramming (i.e. change gene expression to be suppressing) e.g. block Clever-1 (switch more towards M1 phenotype and decrease PD-L1 expression)
- Recruit inflammatory TAMs
- Inhibit (anti-recruitment) of immunosuppressive TAMs
(Don’t run rough races angry)
How do mRNA based DC cancer vaccines work? Give an example for indication of success.
- Mononuclear cells are taken fron blood
- These are used to generate immature DC cells
- Ex vivo maturation occurs (using mRNA ‘vaccination’ into DC cells)
- DCs now present TSAs
In a melanoma study (Kyte et al), patients had significantly improved survival time (14 vs. 6 months). Seem to have few side-effects (no significant autoimmunity)
Why are the pros of anti-body drug conjugates?
Allow targeted delivery of drug to cancer cells.
* Reduces off-target effects
* Can promote immune recognition (e.g. anti-body binding activates phagocytosis and complement)
* Long half-life
* Off the shelf
BUT: relies on there being a unique and significant TSA
