Cancer: Targeted Biological Therapy Flashcards
What is the limitation of conventional cytotoxic chemotherapy?
Toxicitiy to normal cells
Lack of individualisation and specificity to patient’s specific tumour characteristics
Lack of effectiveness
What are the classifications of breast cancer?
ER positive/negative
PR positive/negative
HER2 positive/negative
What is HER2?
Human Epidermal growth factor Receptor 2, a tyrosine kinase oncogene that promotes cellular proliferation and can become mutated in breast cancer, due to an issue with the ERRB2 gene.
What is a triple negative breast cancer?
Negative for ER or PR receptors and no abnormality in HER2. Caused by mutation of BRCA1
pIK3/AKT Pathway
Phosphoinotiside 3-kinase pathway which controls apoptosis, cell proliferation. This is regulated by pten protein.
What is GATA-3?
Transcription factor which is responsible for oestrogen receptor expression anddifferentiation. Mutation leads to uncontrolled cell division and metastasis.
What are the features of breast cancer?
Derived from epithelium lining the ducts or tubules, classified as ductal or lobilar breast carcinoma.
What is a ductal carcinoma?
Earliest form of breast cancer which is most common and found in the milk duct lining. They can progress to become invasive if they break off and spread into surrounding tissue.
What is an ER positive cancer?
Tumour growth is driven by high oestrogen levels that are highly expressed. It is the most common cause of breast cancers that leads to luminal carcinomas, and has a better prognosis which is more common in white women.
What is an ER negative cancer?
Tumour expresses very few oestrogen receptors
What is a PR positive cancer?
Tumour which expresses progesterone receptors and drives its growth. It is a hormone positive cancer.
What is a HER2 positive cancer?
Tumours which have overexpression of the protooncogene human epidermal growth factor. Metastasis occurs more, grows faster and spreads and recurs more often and a worse prognosis. It can be treated with HER2 inhibitors.
How does HER act?
Human epidermal growth factor receptor with no ligand and once activated, induce tyrosine kinase and PKC for cell proliferation and differentiation. Expressed in many organs and is a fast spreading cancer that typically targets the bone and lungs.
What is a triple negative breast cancer?
Most common cause of breast cancer in younger women below 40 and causes basal-like carcinomas with the worst prognosis and higher chance of metastasis and recurrence.
It is ER, HER2 negative and PR negative and more common in African women.
This typically occurs due to a mutation in the BRCA1 gene for double strand DNA repair.
How is breast cancer treated?
Chemotherapeutic agent paclitaxel and tamoxifen.
What are the classes of cancer therapies?
Classed based on their target:
Cell cycle signalling
Immune checkpoint inhibitors
Epigenetic modifiers
Angiogenesis
How do targeted therapies work?
Acts on specific molecular targets associated with cancer designed to interact with target which are cytostatic (block cancer cell growth).
What are the cell signalling therapies?
Control of cell cycle progression and ligands involved such as EGFR.
What is CDK2?
Cyclin-dependent kinase 2 which is a cell cycle inhibitor that controls rate of cell proliferation for G1->S phase.
What are the D type cyclins?
Cell cycle components which increase progression through G1.
What is EGFR?
Epidermal growth factor receptor which responds to the binding of EGF which is important in regulation of cell proliferation.
How does Epidermal growth factor work?
Binding to EGFR causes activation of the heterodimer by EGFR pairing with aother extracellular protein ligand.
This causes activation of tyrosine kinase which autophosphorylates the C-terminal of the heterodimer using ATP, causing activation of downstream signalling cascades for DNA proliferation
How is EGFR implicated in cancer?
Somatic mutations of EGFR leads to constant overactivity for DNA proliferation, associated with:
Anal cancer
Glioblastoma (brain glial cell cancer)
Squamous cell carcinoma
Epithelial cancer tumour of the head and neck
How does testing for EGFR mutation occur?
Tissue test for DNA shed from the tumour which is found in the bloodstream which means treatment can be tailored and increase responsiveness of treatment
How is cancer caused by EGFR mutation treated?
Immunotherapies that inhibit EGFR ATP autophosphorylation, such as Monoclonal antibody inhibitors and small molecule kinase inhibitors that block the receptor to prevent downstream signalling.
Patients with a T790M mutation may be resistant to EGFR inhibitors.
What is a small molecule antibody inhibitor?
Drugs which target and bind to extracellular proteins or kinases on cancer cells to prevent downstream signalling of the oncogenes and limit cellular proliferation. Generally more stable than monoclonal antibodies.
What are the cancer immunotherapies?
Drugs which stimulate the immune system to destroy the cancer cells which include:
—>Immune checkpoint inhibitors which target CTL-4 and PDL-1 that are overexpressed in cancer cells which deactivate T cells
—>Monoclonal antibodies
—>Small molecule antibodies
What is a monoclonal antibody?
Singular antibody clone which are injected to target a specific receptor, typically oncogenes on cancer cells to prevent cellular proliferation.
How do monoclonal antibodies work as a cell signalling therapy in EGFR?
Antibody binds to the EGFR extracellular signal binding domain to prevent activation of tyrosine kinase. Includes centuximubab and pentuximubab
What is a small molecule antibody?
Antibody treatment which targets receptors and kinases.
What distinguishes a small molecule antibody from a monoclonal antibody?
Small molecule antibodies can cross the blood-brain barrier and have a shorter half life.
What is a small molecule kinase inhibitor?
Immunotherapy modulator which inhibits the autophosphorylation of tyrosine kinase by blocking ATP binding site on the EGFR receptor
What are the cell cycle signalling side effects?
EGFR inhibitors cause a papule-pustular rash across face and torso. Commonly, GI symptoms like diarrhoea and vomiting are common. T980M mutation or MET oncogene mutation occurs.
What is the effect of cell cycle inhibitor?
Neutropenia, nausea, vomiting and bone marrow depression.
What is the MET pro-oncogene?
Encodes for the tyrosine kianse receptor in EGFR for hepatocyte growth factor and increase proliferation
What are immune checkpoint inhibitors?
They target proteins involved in regulation of the immune system such as:
—>PD-1 on surface of T cells (programmed cell death protein 1)
—>Ligand PD-L1, typically found on cancer cells
—>CTLA-4
What is PD-1?
Programmed cell death protein which is found on the surface of B and T cells which downregulates immune response and suppresses T cell activity when interacting with PD-L1 receptors on cells
What is CTLA-4?
Protein receptor found on regulated T cells which causes the suppression of the immune response, found in malignant tumours to prevent T cell attack
What ligands are overexpressed in tumour cells?
PDL-1 that suppresses T cell response
How can malignant tumours with CTLA-4 be treated?
Monoclonal antibodies
What is a hallmark of a tumour going from benign -> malignant?
Inducing angiogenesis
What is the side effects of immune checkpoint inhibitors?
Causes immunosuppression. Fatigue, itching, nausea, loss of appetite and skin rash
What is angiogenesis?
New Blood vessels emerge from pre-existing vessels which allows tumour a supply of nutrient rich blood to sustain excessive cell proliferation. This usually occurs after environmental conditions called the angiogenic switch
What is the angiogenic switch?
Factors which induce tumour angiogenesis. Capillaries sprout following this:
Hypoxia, inflammation, oncogenic mutations and mechanical stress. This induces the release of pro-angiogenic factors.
What are the pro-angiogenic factors?
Vascular endothelial growth factor: anti-apoptotic factor for blood vessels
Fibroblast growth factor: cellular proliferation
Angiogenin: promotes blood vessel formation
Downregulation of transforming growth factor: induces apoptosis of vascular endothelial cells
Stem cell factor
How do angiogenesis inhibitors work?
Blocking FGF, VEGF, SCF and PDGF receptors and endothelial receptors on blood vessels
How is angiogenesis of tumours inhibited?
Transforming growth factor
What are the side effects of angiogenic inhibitors?
Mucositis (mouth sores) Bleeding, increased blood pressure due to vasoconstriction, rash, , diarrhoea, fatigue and low blood count.
What is driver mutation?
Mutations that provide a selective advantage for growth
What is passenger mutation?
Mutations that occur to cells during cancer which do not contribute to cancer.
How does metastasis occur?
Combination of driver and passenger mutations.