Precision Medicine in Cancer Flashcards
What are the multiple benefits of using combination therapy to treat cancer?
- Targets multiple cellular pathways to treat cancer -> synergistic or additive therapeutic effect
- Reduce dose of each drug -> reduced side effects + reduce risk of drug resistance
- Repurpose drugs used elsewhere -> sustainable, faster development and clinical validation
How does genetics underpin the process of precision medicine?
Use of Next generation sequencing - allow analysis of genetics of the cancer cells -> can use to match to the most appropriate treatment.
Screen DNA panel - identifies the presence/lack of only certain genes that would be useful.
What are the most common types of lung cancer by histology?
Small cell = 15%
Adenocarcinoma = 40%
Squamous cell = 30%
Large cell carcinoma = 10%
What are the most targetable mutations in lung cancer?
EGFR
KRAS
What mutations are most common in non-small cell lung cancer?
Early stage - KRAS, EGFR, BRAF
Metastatic - EGFR, KRAS, BRAF
How does smoking history affect the mutations present in lung cancer?
EGFR more common in never smoked (50-60% cases)
KRAS more common in people who have smoked (35% cases)
What is the relationship between air pollution and lung cancer?
Leads to EGFR mutated lung adenocarcinoma
PM2.5 in inhaled air causes IL-1beta secretion, this increases the progenitor function of T2 alveolar cells that already have EGFR mutation -> exaggerates pre-existing cancerous states
How is Necitumumab (portrazza) used clinically to help treat lung cancer?
Approved for advanced sqaoumous NSCLC not previously treated.
Must be combined with chemotherapy - gemcitabine and cisplatin
By what mechanism does Necitumumab (Portrazza) help treat lung cancer)?
Is a monoclonal antibody, binds to FcR on T cells
Antigen binding site outcompetes EGF for EGFR receptor on surface of cancer cell
Brings T cell and cancer cell in closer proximity -> inc probability of immune recongition (antibody-dependent cell-mediated cytotoxicity)
Also blocks EGFR signalling -> leads to reduce cell proliferation and survival.
What small molecules can be used to target EGFR mutated lung cancer?
How is this method different to used immunological agents?
Use Tyrosine Kinase Inhibitors - eriotinib, gefitinib, osmiertinib etc
Blocks the tyrosine kinase intracellular function - receptor not activating signalling
Does NOT affect the binding of the ligand to the receptor
What is the main problem with the use of anti-EGFR treatment in mutant lung cancer?
Therapy resistance
Examples include: EGFR amplification, on-target mutations, upregulation
What is the role of KRAS in NSCLC?
Is a protooncogene
Involved in RTK signalling pathway, norm bound to GDP = inactive
GEF swaps GDP for GTP = active KRAS
Allows progression through signalling cascade = cell proliferation.
GAP turns back to GDP = inactive
Mutation hinders GTPase activity - KRAS more likely in GTP bound state leading to increased cell proliferation
What is the role of Sotorasib or adagrasib in treating NSCLC?
Treats KRAS mutation
Binds irreversibly to and inhibits G12C KRAS
Promotes hydrolysis to GDP bound form = inactive -> prevents progression through the cell cycle.
How has resistance to KRAS inhibitors arisen?
Cell differentiation - different cell type less susceptible to drug
Molecular activation (alternative pathways or drug neutralising methods
Gene mutation - KRAS no longer a suitable target
What are some strategies to overcome therapy resistance?
- Regular treatment follow up
- Timing therapy to have best responses
- Use of combination therapies with non overlapping mechanism of action or checkpoint blockade immunotherapy
- Mapping cancer dependencies - allows synthetic lethality
- Offer palliative therapy
What are some reasons why cancers are resistant to treatment?
- Tumour heterogenicity -> temporal and spatial differences in mutation
- Growth kinetics - slower growing tend to have poorer response
- Genetic mutation is undrugable target
- Selective therapeutic pressure -> drives mutation against treatment
- Immune system and tumour microenvironment
What is the triad of tumour heterogeneity?
- Clonal evolution - stem cell model -> stepwise acquisition of mutations.
- Tumour microenvironment and metastasis - treatment resistant
- Genomic and epigenetics - genetic instability and mutation
How does the variation in a tumours genetics aid its survival?
Multiple genetic fingerprints within one cancer -> small percentage may be slower growing and resistant to treatment -> become the dominant genetic as other cells are killed
Stem cell model of tumour growth = some cells retain stem cell property -> if remain after treatment can continue propagating into new tumour.
What is intertumour heterogeneity?
Genetic and phenotypic variation between tumours of different tissues/cell types as well as between different individuals with the same tumour type
What is intratumour heterogeneity?
Within a single tumour - subclonal diversity (different genetic fingerprints)
Subclones may be spatially seperated (often reflect phsycial barriers such as TME or BV changes) or are intermingled.
What are the different factors regulating the growth of cancer cells?
Patient exposure/lifestyle (aetiology)
Patients/cancers existing genetics
System regulators - hormones, growth factors, immune signallling
Local regulates - space, stroma, oxygen, metabolites
Architectural - physical compartments, basement membranes, restricted niches.
How does mutational burden cause a problem in precision oncology?
High number of mutations = harder to treat, many different pathways that may decrease drug efficacy or inc cancerous potential of the cell
Although may also cause increased sensitivity to synthetic lethality treatment.
Inc chance of activating the immune system
Lower mutation burden -typically in paediatric cancer - clearer targeted treatment - tends to more successful
Less likely to have antigens that will activate the immune system
What strategy tends to be used to treat more advanced cancers with high mutational burden?
Whack a mole
Disease management as goal -> unlikely to find drug what will effectively eradicate all colonies of the tumour.
More likely to develop/show resistance to conventional therapies.
Should try to target driver mutations if possible
What is an example treatment that targets metabolism pathways in cancer cells?
Some cancers lack argininosuccinate synthetase (ASS1), so they are unable to produce own intracellular arginine, relies on extra-cellular sources
Therapy = ADI (arginine degradging enzyme) leads to decreased EC arginine.
Cancer cells die as no arginine
None cancerous cells are not affected as still able to produce argininge.
What are some different approaches used in precision medicine to treat cancer?
- Synthetic lethality
- Targeted oncoprotein destruction
- Epigenetic reprogramming - nucleosome remodelling, blocking recruitment of co-repressor complexes
Give an example of a synthetic lethality pathway used in cancer treatment
BRCA proteins = role in NHEJ and HR double stranded DNA breaks repair
PARP = role in BER single stranded repair
Some cancers have mutated BRCA so rely on PARP for DNA repair, when PARP pathway is blocked by drugs, DNA repair unable to occur, DNA replication permanently blocked and the cell dies.
What is targeted oncoprotein destruction as a method of cancer treatment?
Drugs are designed to specifically bind and mark cancer-causing proteins (oncoproteins) for destruction by the cell’s natural protein degradation machinery, effectively eliminating their function and hindering tumor growth
What is the basic function on a Non-steroidal nuclear receptor?
Receptor bound by co-repressor complex
Ligand enters the nucleus and binds to heterodimeric nuclear receptor
Of the two:
RXR is one -> required retinoic acid binding
Many different choices for second -> ligand dependent on receptor
When both bound by ligand heterodimerise,
Co-repressor complex exchanged for co-activator complex
and activate response element on DNA leading to regulation of target-gene transcription.
Give an example of a cancer that can be treated by targeted oncoprotein destruction?
APL -> a subtype of AML
Has reciprocal translocations between RARalpha (dimer for NSNR) and PML gene -> fusion protein leads to oncogenic function (does not require RXR) of non-steroidal nuclear receptors
Decreases expression of genes needed for cellular differentiation = inc blast cell = leukaemia.
What vitamin is needed to produce the ligand for RXR components of non-steroidal nuclear receptors?
Vitamin A
How does retinoic acid/ATRA treatment relate to the treatment of APL? RARalpha-PML mutation
High conc retinoic acid/ATRA (medical RA) -> causes exchange of co-repressor to co-activator on RARalpha-PML Non-steroidal nuclear receptor -> this turns gene expression back on allowing for differentiation of blast cells into lymphocytes.
What combination therapy can be used to treat APL?
ATRA - turns on differentiation genes for blast -> mature lymphocyte -> binds to RARalpha part of fusion protein.
ATO -> marks cancer cells for apoptosis, causes ubiquitination of fusion protein -> binds to PML part of fusion protein
What are PROTACs in the treatment of cancer?
Proteolysis Targeting Chimeras -> aim to mark cancer specific proteins for ubiquitination
Uses E3 ligase (designed to bind to target protein) to bind to target protein, carries along a ubiquitin protein to cause degradation of target -> in theory should result in death of cancer cell
Why are PROTACs not always a successful method of treating cancer?
- PROTACs = have low bioavailability -> to low conc to be therapeutic
- Selection of E3 ligase - needs to be specific to target and not other human protein -> this can be expensive and complicated to develop
What is a nucleosome?
DNA segment wrapped around histone proteins - regulates gene expression
How can targeted nucleosome remodelling be used to treat APL?
Target the RARalpha gene
Found to be greatly over-expressed compared to normal cells -> due to decreased association with histones
Can give LSD1 inhibitor drug to inhibit the removal of methyl groups -> increase expression of gene
Reactivates the ATRA differentiation pathway in AML.
How is the PF1(PHF-12)-Sin3 protein interaction being utilised to treat triple negative breast cancer?
Sin-3 is a co-repressor in gene expression
Reduces expression of CHD1 -> leads to less e-cadherin = making tumours more likely to metastasise
In order to work Sin-3 must interact with PF1(PHF12)
Stopping this interaction may help stop the progression of breast cancer by increases e-cadherin expression
Uses a protein to mimic SID peptide motif to stop interaction i.e ivermectin.
