lec 24 - targeted therapies

cancer has been traditionally treated with

radiation therapy

surgery

chemotherapy - targeting proliferating cells

gardasil

vaccine that targets HPV 6,11,16,18

HPV16 and 18 cause 70% of cervical cancer and 6 and 11 cause 90% of genital warts

virus-like particle vaccine - contains purified inactive HPV proteins made in yeast cells using recombinant viral material, non-infectious

elicit strong T and B cell response - development of antibodies against HPV 6,11,16,18

herceptin 

targets HER2 proteins 

also erB2 - receptor tyrosine kinase, erBs are receptors for neurogulins 

found on normal cells but more receptors on tumour cells as a result of gene amplification 

erB2 is a monoclonal antibody stopping normal ligand so cant get growth factor and will die 

normal process that RTKs and growth factors involved in 

growth factors bind to the receptor tyrosine kinase intracellular domain 

signal transducing proteins go to nuclear transcription factors 

entry to cell cycle 

growth receptor specific antibodies 

many receptors expressed by cells 

different antibodies can target each receotor and stop the normal ligand from binding stopping the normal signaling pathway from happening 

targeted therapy for ER+ breast cancer

tamoxifen is a selective estrogen receptor (ER) modulator

it blocks the action of estrogen

binds ERs and prevents estrogen from binding

breast cancer cells that require estrogen (ER+) are therefore not able to grow

tyrosine kinase inhibitors

normally RTKs trigger downstream signalling cascades which act on cell processes such as proliferation, apoptosis, invasion and angiogenesis

many places to block

other tyrosine kinase inhibitors

MET TKIs

EGFR TKIs
IGF1R TKIs 

VEGF receptor inhibitors - inhibit angiogenesis

specific pathway inhibitors

all of these steps have specific inhibitors that are there to target them but in NZ most of these are not funded - stops increased specificity of treatments

ideally would be able to target the most ideal treatment based on the patient and their specific mutation

vascular endothelial growth factor inhibitors

targeting VEGF and VEGF-receptor which are upregulated in cancer

bevacizumab, sunitinib, sorafenib

resistance

after long term therapy cells become resistent to anti-angiogenic (VEGF) treatments 

change in metabolism, highsurivialsignal, increase in invasion 

problems with telomerase inhibitors

stem cells have continual expression of telomerase and could theoretically be adversely affected by treatment with telomerase inhibitors

chronic myeloid leukaemia

due to translocation

encodes a constituatively expressed BCR-ABL tyrosine kinase

this leads to a creation of a fusion protein which is active in RAS, STAT and AKT pathways, all of which lead to growth factor independant proliferation and survival

medication for BCR-ABL gene

gleevec

in trials 31/31 patients showed complete remission (note as this was extended the rate dropped from 100% but still very high)

now being tested on other cancers such as melanoma

oncotype Dx breast cancer recurrence score

PCR based quantification of tumour mRNA (21 genes)

look at markers for proliferation, invasion, HER2, estrogen, reference and other to provide a score

<18 is low recurrent risk >25 is high recurrence risk

pietenpol TNBC subtyping

for cancers that dont have known receptors etc to help with clinical decisions 

broader impacts of profiling cancer genomes 

Idea that if we can profile tumours we can make really informed decisions about treatment and a care plan

genomic profile from tumor indicates a known vulnerability that we can target

immunotherapy

immune system DOES recognise own cancer cells 

imune response is normally suppressed by cytokines secreted by the tumour

research into boosting the immune response

goal is to use this as an adjuvant therapy 

the cancer immunity cycle

the development of immunity to cancer is a cyclic event

1. release of cancer antigens by dying cells 

2. presentation of antigen by APCs

3. priming and activation of APCs and T-cells 

4. trafficking of cytotoxic T lymphocytes

5. infiltration of tumour cells

6. recognition of cancer cells by T cells

7. killing of cancer cells

what are immune checkpoints

inhibitory pathways that maintain self tolerance

A way that a cancer cell will evade immune recognition

Cell expresses antigen that binds to TCR and also expresses ligand that will bind to CD1 on T cell

This makes T cell think it is a good cell so lets it proliferate

programmed death ligand 1 (PD-L1)

CTLA4 

mechanism of PD-1/PD-L1 therapies

tumour cells upregulate PD-L1 (ligand) that binds to PD-1 and turns T cells offso that they do not see tumour cells as non-self 

anti PD therapies blocks the PD-L1/PD-1 interaction so that T cells are now able to see tumour cells as non self 

pembrolizumab - plus can now treat other cancers 

strategies for development of new checkpoint blockade therapies

identification of neo-antigens on tumour cells - personalised neovaccines

adoptive immunotherapy - modification of patient-derived CTLs to express chimeric antigen receptors (CARs) that bind to tumour antigens

production of CAR T-cells

drugs targeting the cancer immunity cycle

concept that drugs have been developed to target each one of the steps for the cancer immunity cycle 

so lots of options to treat different cancers 

epigenetics - what 

modification of gene expression without altering genetic code 

DNA methylation by DNA methyl transferases → gene silencing - normally CpG islands (a C followed by G at TSS 5’) are unmethylated 

hypermethylation of CpG islands occurs in many cancers → gene silencing - ESR1 (estrogen response gene), BRCA1 (DNA repair genes) 

histone acetylation by histone acetyltransferases 

miRNA binding 

types of epigenetic therapies

HDAC inhibitors

DNMT inhibitors

combination with other therapies - ESR-1 (endocrine therapy), HER2 (antibody), chemotherapy

miRNA

malignant pleural mesothelioma

80-90% of people diagnoses with MPM have been exposed to asbestos

• mechanics working with brake linings

• insulators

• builders

20-40 year latency following inhalation

miRNA therapy for MPM

miRNAs target pathways that are known to be involved in MPM - miR-185 targets DNMT1/PTEN/Akt pathway that is normally activated in MPM (suppresses inflammation) 

miR-15b is downregulated in MPM

miR-126 targets include VEGF-A which is involved in angiogenesis 

hallmarks of cancer

inducing angiogenesis

resisting cell death

deregulating cellular energetics

sustaining proliferative signalling

avoiding immune destruction

evading growth suppression

enabling replicative immortality

tumour promoting inflammation

activating invasion and metastasis

genome instability and mutation