Cancer 4) Principles of treatment Flashcards
What are the types of chemotherapy drugs?
Alkylating agents Antimetabolites Mitotic inhibitors Tumour antibiotics DNA topoisomerase inhibitors All-trans retina acid and HDAC inhibitors Hormone and hormone antagonists Agents inhibiting DNA repair: PARP inhibitors (olaparib) Inhibitors of DNA methylation
What are the classes of alkylating agents?
Nitrogen mustard based
Tetrazines
Non-classic
Platinum
Give examples of nitrogen mustard based alkylating agents
Chlorambucil Mechlorethamine Cyclophosphamide Melphalan Bendamustine
Give examples of tetrazine alkylating agents
Dacarbazine (DTIC)
What is the mechanism of alkylating agents?
Cause DNA alkylation and cross linking
Intra and inter strand cross linking of DNA which stops fork replication and causes mitotic catastrophe
Give an example of a non-classic alkylating agent
Procarbazine
Give examples of platinum-based alkylating agents
Cisplatin
Carboplatin
Oxaliplatin
Give an example of antimetabolites
Methotrexate Pemetrexed 6-mercaptopurine 5-fluorouracil Capecitabine Cytosine arabinoside Gemcitabine
Give the 2 types of mitotic inhibitors and examples of each
Taxans: docetaxel (taxotere), paclitaxel (taxol)
Vinca alkaloids: vinblastine, vincristine
How do vinca alkaloids work?
Disrupt microtubules leading to mitotic arrest
What are the 2 types of tumour antibiotics and give examples?
Anthracyclines: doxorubicin, daunorubicin
Non-anthracyclines: bleomycin, dactinomycin
How do anthracyclines work?
Topoisomerase II dependent DNA cleavage
Inhibits DNA and RNA synthesis by intercalating between bases of DNA and RNA strands which inhibits activity of DNA and RNA polymerase
What are the 2 types of DNA topoisomerase inhibitors and give examples
I (camptothecin): irinotecan, topotecan
II (podophyllotoxins): etoposide, mitoxatrone, teniposide
Give examples of hormone and hormone antagonists chemo drugs
Prednisone
Tamoxifen
Aromatase inhibitors
Abiraterone
Give examples of inhibitors of DNA methylation
Zebularin
Azacytidine
5-aza-2’-deoxycytidine
What are the side effects of chemotherapy?
Pain Neuropathy Hair loss Weakened immune system Trouble breathing Bruising and bleeding Rashes Nausea and vomiting Constipation, diarrhoea Mouth sores
What are the side effects of nitrogen mustard?
BMT
Nausea and vomiting
Leukemogenic
What are the side effects of vincristine?
Neurotoxicity
Constipation
ANS disturbance
What are the side effects of procarbazine?
BMT Nausea and vomiting Leukemogenic Infertility Psychotic reactions Hypertensive crisis with MAOi
What are the side effects of cyclophosphamide?
BMT - thrombocytopenia
SIADH
Nausea and vomiting
Bladder toxicity
What are the side effects of chlorambucil?
BMT - neutropenia and anaemia
Nausea and vomiting
Leukaemia
What are the side effects of vinblastine?
BMT - neutropenia
Mucositis
Hypertension
What are the side effects of doxorubicin?
BMT Alopecia Nausea and vomiting Diarrhoea Cardiac
What are the side effects of bleomycin?
Fever
Skin toxicity
Pulmonary toxicity
What are the side effects of DTIC?
BMT
Flu-like syndrome
Hepatic vein thrombosis
What are the side effects of etoposide?
BMT - leukopenia and neutropenia
Leukaemia
What are the side effects of cisplatin?
Neurotoxicity
Ototoxicity
Nephrotoxicity
Why do most of the chemotherapy agents cause bone marrow toxicity and GI disturbance?
These are sites associated with high levels of normal cell division
Give examples of targeted antibodies
Rituximab
Ofatumumab
Obinutuzumab
Alemtuzumab
What is the mechanism of rituximab?
Binds to CD20 on surface of B cells
Attracts macrophage which engulf tumour B cell
Complement fixation which attracts NK cells that deploy cytotoxic granules to kill the B cell
How does ofatumumab work?
Induces antibody dependent cytotoxicity
How does obinutuzumab work?
Has cytotoxic effects of its own. Binds to CD20 receptor causing antibody to induce an apoptotic programme in the cell
Induces antibody dependent cytotoxicity
What is the standard therapy of diffuse large B cell lymphoma?
CHOP cyclophosphamide doxorubicin vincristine prednisone
Give examples of targeted inhibitors
Ibrutinib
Idelalisib
ABT199
Imatinib
What are the mechanisms of targeted inhibitors?
Growth factor kinase inhibition Apoptosis induction DNA damage, response to inhibition Epigenetic reprogramming Telomerase inhibition Redox modulation Metabolic reprogramming Proteasome inhibition CSC trans-differentiation Immune modulation
Why are most of the new approvals of target agents in the haematology oncology space?
Much easier to access a haemato-oncological tumour using peripheral blood or through lymph node / bone marrow biopsy compared to pancreatic or liver tumour
What is CML?
Cancer of haematopoietic stem cell
What is the molecular pathogenesis of CML?
Monogenic
Philadelphia chromosome 9;22 translocation
Chronic phase of 4 years followed by blast phase
What is Bcr-Abl tyrosine kinase?
Single molecular abnormality causing transformation of a haematopoietic progenitor into a malignant clone in CML
How does imatinib work?
Starves Bcr-Abl tyrosine kinase of energy by binding to ATP binding pocket of aberrant tyrosine kinase. This switches off the activity of this kinase.
Describe the resistance to imatinib
ABL kinase domain mutations prevent or reduce efficacy of binding of imatinib to ATP binding pocket
Increased amplification of BCR-ABL1
Clonal evolution - tumour is reliant on BCR-ABL
Drug efflux mechanisms - imatinib is a p glycoprotein substrate. Overexpression of p-gp on surface of CML blasts reduces bioavailability of imatinib
Give examples of next generation tyrosine kinase inhibitors
Nilotinib
Dasatinib
Bosutinib
Ponatinib
Described targeted therapy in NSCLC
Give gefitinib to those with mutated EGFR
Give crizotinib to those with genetic lesions that activate anapaestic lymphoma kinase
How does gefitinib work?
EGFR kinase inhibitor
How does crizotinib work?
oral anapaestic lymphoma kinase inhibitor
What is vemurafenib used for?
Malignant melanoma
How does vemurafenib work?
Switches off b-raf signal which switches off signalling downstream and interrupts b-raf / MEK / ERK pathway
What is ibrutinib?
Example of targeted inhibitor important in CLL
Novel Bruton’s tyrosine kinase inhibitor
What is ibrutinib used for?
CLL
Mantle cell lymphoma
How does ibrutinib work?
Targets Bruton’s tyrosine kinase which is downstream of the B cell receptor
BTK inhibition switches of NFkB and NFAT and ERK signalling which arrests proliferation and reduces survival of malignant B cell
Why is it important to target angiogenesis in solid tumours?
Solid tumour growth is limited by its ability to extract oxygen and nutrients from its microenvironment due to its vasculature or lack of blood supply
Tumour promotes neovascularisation allowing primary tumour to grow bigger and leading to metastatic disease
Give examples of drugs targeting angiogenesis
Bevacizumab (avastin)
Perception (traztuzumab)
How does bevacizumab work?
Blocks VEGF binding to VEGFR on surface of tumour which inhibits the angiogenic drive in tumour cells
Improves survival in colon, lung and renal cancer
Describe HER-2
Human epidermal growth factor receptor 2
Overexpresed in 25% of breast cancers
Associated with more aggressive course of disease leading to metastases
How does perception work?
Competitively inhibits EGF from binding to EGF receptor which blocks dimerisation of EGFR on surface of tumour cell. This stops signalling cascade downstream of EGF binding to EGFR
What are the general principles of immunotherapy?
Immune system can recognise and react to cancers - immune surveillance hypothesis
Immune response against tumours is often dominated by regulation or tolerance
Some immune responses prompt cancer growth
Describe potential immune cell responses to tumours
Macrophages recognise tumour specific antigens and engulf them leading to tumour eradication
B cells recognise tumour specific antigens via ligation of their B cell receptor leading to plasma cell production, humeral response and tumour specific antibody responses
B cells response requires CD4+ T helper cells
Potential that cytotoxic T-cells recognise tumour specific antigens presented to the on surface of tumour cell or in context of antigen presentation from B cell, macrophage or dendritic cell
What immune responses promote tumour growth?
Tumour causes polarisation of CD4 T cells to produce Th2 cytokines (IL-4, IL-13)
Th2 cytokines cause macrophage polarisation to M2 macrophage which secrete iNOS and arg1 which actively repress cytotoxic T cells
Macrophages secrete VEGF, EGF and TGF beta which drives neoangiogenesis of tumour
Describe neoantigens
Not normally present on non-malignant cells so no tolerance as they aren’t self
Produced by mutated genes that may be involved in oncogenesis or reflect genomic instability
What are the 3 strategies being developed to harness hosts immune system to combat cancer?
Cancer vaccine production
Identify T cells that recognise tumour specific antigens and expand ex-vivo - CAR
Develop checkpoint control inhibitors
Describe the PD-1 ligand in tumour cells
Tumours up regulate PDL-1 on their surface which encourages PDL1 ligation of PD-1 on affected T-cells leading to repressive signal to T cell
This stops T-cell mounting a cytotoxic response
Describe the CTLA-4 molecule in tumour cells
Binds to and competes for co-stimulatory molecule expressed on APC - either CD80 or CD86
Competitive binding prevents CD80 or 86 binding to CD28 on T cell so T-cell won’t mount a cytotoxic response against tumour as it doesn’t have costimulation
What are checkpoint blockade?
Strategies to block these checkpoint molecules and remove the breaks on the immune system
Repress CTLA-4 response using anti-CTLA-4 antibody
Give an example of a anti-CTLA-4 antibody and its use
Ipilimumab for malignant melanoma
Give examples of anti-PD-1 monoclonal antibodies
Pembrolizumab
Nivolumab
What is the challenge of combining inhibitory checkpoints?
May increase toxicity
Describe possible biomarkers of response vs resistance
Nature of cellular infiltrates around tumour
Expression of ligands for inhibitory receptors
Frequency of neoantigens in tumours from different patients
Frequency of tumour-specific exhausted T cells
What are CAR-T?
Autologous T cells isolated from peripheral blood of patient and then expanded ex-vivo using CD3, CD28 Bs in combination with cytokines like IL-2
T-cells are transducer with a CAR then transferred back into patient
Describe 1st generation CARs
Simple chimeric antigen receptors that spliced together a CD3 zeta chain with a single chain variable fragment that recognises the tumour antigen e.g. CD19
Describe 2nd generation CARs
Incorporated co-stimulatory molecules into CAR
Once ligated, the CAR is fully activated so is con stimulated which drives signal to T cell to become cytotoxic
Describe 3rd generation CARs
Incorporate multiple costimulatory molecules
Describe 4th generation Cars
TRUCKS
Transcription factors e.g. NFAT attached to base of CAR.
Once engaged the receptor drives the activation of the transcription factor leading to cytokine release
What are the limitations and challenges of CAR-T therapy?
Cytokine storm
Unclear how well it will work for solid tumours
Will tumour lose target antigen and develop resistance?
Technical challenges of producing genetically modified CAR-T cells for each patient
Exhaustion of transferred T cells
Increased risk of autoimmune reactions from endogenous T cell receptors
Describe the exhaustion of transferred T cells and how this could be solved
Potential impact on longevity of response you might see from CAR-T cell
Patient T cells already show signs of increase immune cell raging
CRISPR editing of PD-1 from T-cells to reverse immune cell ageing or the exhaustion phenotype shown by these cells
