Introduction to Cancer and Therapies

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  • Created by: LBCW0502
  • Created on: 27-01-20 09:27
What are the current treatment modalities of cancer? (1)
Surgery (remove visible tumour mass). Radiotherapy (destroys fast dividing cancer cells and those in adjacent tissues). Chemotherapy (destroys fast proliferating cancer cells). Hormone therapy (inhibits growth/survival of hormone dependent cancers)
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What are the current treatment modalities of cancer? (2)
Targeted therapy (blocks specific biochemical pathways on which cancer cell growth is dependent). Immunotherapy (restore/enhance immune system's natural ability to fight cancer)
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Give examples of small molecules used as anti-cancer drugs (1)
Antimetabolites (5-FU, MTX), nucleic acid based therapies (cisplatin, adriamycin, antisense, RNAi). Tubulin inhibitors (taxanes, ixabepilone, vinblastine). Molecularly targeted agents (kinase inhibitors)
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Give examples of small molecules used as anti-cancer drugs (2)
Hormonal therapies (tamoxifen, anastrozole, abiraterone)
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Give examples of large molecules used as anti-cancer drugs
Antibody based therapies (antibodies, ADCs, Kadcyla, Adcetris). Immunotherapies (cancer vaccines, immune modulators, IO agents). Biological agents (biological response modifiers, enzymes, gene/cell based therapies, CAR-T)
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What is cancer? (1)
A disease in which control of growth is lost in cells, leading to a solid mass being formed (tumour - malignant or benign). Death is most caused by spread of the primary tumour to other sites (metastasis), which makes surgical intervention impossible
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What is cancer? (2)
Other cancers can affect white cells in the blood e.g. leukaemia (haematological cancers). Various terminology for cancers. Histology (irregular nuclear border, large nucleus visible)
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Outline features of tumour growth (1)
Cancer cells resemble original cells. Cells lose function/appearance. Normal tissue/bone marrow (steady number of cells, rate of cell division = rate of cell loss)
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Outline features of tumour growth (2)
Cancer cell forms primary tumour, metastasis (cells break off/move to other sites), growth of secondary tumour
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Describe features of metastasis
Ability of solid tumours to spread to new sites in the body to form secondary tumours. Tumours cells can penetrate lymphatic vessels, invade blood vessels (capillaries). Tumours can also spread to organs. Nerve endings also affected/pain
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Describe features of cancer stem cells (1)
Within a tumour, there are multipotent, tumorigenic cancer stem cells capable of reconstituting the heterogeneity of the primary tumour by both self-renewal and differentiation
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Describe features of cancer stem cells (2)
Cancer stem cells - role in treatment resistance/disease relapse (due to slow proliferation rate). Target of cancer stem cells/bulk tumour cells have the potential to induce tumour regression and prevent local recurrence/distant disease
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Which organ in the body is not affected by cancer?
The heart (evolved to resist cancer for evolutionary purposes)
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What are the most commonly diagnosed cancers in the UK?
Breast cancer, prostate cancer, lung cancer and bowel cancer
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What are the most common causes of death from cancer in the UK?
Lung cancer, bowel cancer, prostate cancer and pancreatic cancer
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What are the possible causes of cancer?
Age (increasing damage to DNA, 65-70% of all new cancers are diagnosed in people aged 60+ years). Exposure to chemicals in the environment/diet (carcinogens). Occupational factors/lifestyle. Genetics
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What are the recommended changes to social behaviour as a result of recognising possible causes of cancer?
Overall reduction in cigarette consumption. Curbing of smoking in public places and in cars transporting children. Healthier diets. More exercise. More restrictive health and safety rules in working environments
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What are the risk factors for cancer?
Tobacco, overweight/obesity, UV radiation etc
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What are the challenges of treating cancer?
Over 200 different diseases. Late diagnosis. Metastasis. Tumour cells evolve to become more aggressive and treatment avoiding. Tumour cells originate from human cells/similar to healthy cells. Most drug targets are also prevent in healthy cells
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What are the aspirations for the future?
Effective orally-available low-toxicity agents (such as penicillins). Treat cancer as a chronic disease. Inhibit metastasis. Use body's own immune system to treat cancer. Develop vaccines to provoke the body's own immune system/stop cancer developing
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What are the important drug targets for cancer therapies? (1)
Growth factors, growth factor receptors, adaptor proteins, docking proteins/binding proteins, guanine nucleotide exchange factors, phosphatases and phospholipases, signalling kinases, ribosomes, transcription factors, histones, DNA, microtubules
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What are the important drug targets for cancer therapies? (2)
Antigens for antibody targeting, hormonal pathways, metabolic pathways, targets for biological agents
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Why is early diagnosis important?
Treat cancer early before a metastasis of the primary tumour develops
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Give examples of cancer screening in the UK
Cervical and breast cancer screening in women (routine). Bowel cancer screening for everyone ?50 and prostate screening for men being introduced. Analytical techniques to detect tumour markers. Detect circulating cancer cells. Genetic testing (BRCA)
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What is the multi-hit theory of carcinogens and metastasis?
Most genes require two mutations to cause a phenotypic change. Experimental evidence in mice (initiation, promotion, progression)
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Describe features of tumour growth and Darwinian evolution
Observations of human cancers/animal models suggest that tumour development is analogous to Darwinian evolution, with succession in genetic changes, growth conversion, leads to progressive conversion of normal cells to cancer cells
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What are the hallmarks of cancer? (1)
Sustaining proliferative signalling. Evading growth suppressors. Avoid immune destruction. Enable replicative immortality. Tumour promoting inflammation. Activating invasion and metastasis. Induce angiogenesis. Genome instability/mutation
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What are the hallmarks of cancer? (2)
Resist cell death. Deregulating cellular energetics
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What are the hallmarks of cancer? (3)
Self-sufficiency in growth signals. Insensitivity to anti-growth signals. Tissue invasion and metastasis. Limitless replicative potential. Sustained angiogenesis. Evading apoptosis
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What are the emerging hallmarks and enabling characteristics?
Avoiding immune destruction (tumour promoting inflammation). Deregulating cellular energetics (genome instability and mutation)
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Give examples of therapeutics based on the hallmarks of cancer (1)
Cyclin-dependent kinase inhibitors. Immune activating anti-CTLA4 mAb. Telomerase inhibitors. Selective anti-inflammatory drugs. Inhibitors of HGF/c-Met. Inhibitors of VEGF signalling. PARP inhibitors. Prapoptotic BH3 mimetics. Aerobic glycolysis.
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Give examples of therapeutics based on the hallmarks of cancer (2)
EGFR inhibitors
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Why is cancer relatively rare during a human lifetime?
Due to new developments in preventing cancer (e.g. chemoprevention). Early diagnosis (able to treat). Better analysis of human cancers at genetic/biochemical level
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Which types of factors contribute to the mechanisms of genomic damage?
Internal factors. External factors. Hereditary factors. (Cancer is a genetic disease)
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Give examples of internal factors
Addition/loss of genetic material (DNA bases can be added/deleted, alters codon/protein). Changes gene expression (uncontrolled expression/amplification, tumour-genesis due to involvement of growth factors/receptor formation)
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Describe features of mutations (1)
Point mutation (one base altered, frame-shift mutation, new codon, changes protein, can affect proliferation of tumour suppressor protein)
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Describe features of mutations (2)
Translocation mutation (entire segment of DNA moves from one part of gene to another, loss of proteins/new protein, tumour-genesis). Proto-oncogenes (genes will not cause cancer unless activated - oncogenes e.g. CML)
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Give examples of external factors
Carcinogens, lifestyle factors, infective agents, heat, EM radiation, radioactivity, direct transmission
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What is the DNA damage response?
p53 gene determines whether DNA repair is feasible or whether the cell should be allowed to die via apoptosis
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Give examples of chemical carcinogens in food and the environment
2-Naphthylamine. Aflatoxin B1. Pyrene (Polycyclic Aromatic Hydrocarbon - PAH). 4-Dimethylaminoazobenzene
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Describe features of carcinogens in the environment and food (1)
Certain chemicals in diet/lifestyle/occupation can lead to tumourigenesis. Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are formed when red meat is overcooked (frying/BBQ) and can lead to colon cancers
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Describe features of carcinogens in the environment and food (2)
Carcinogenic amines formed in stomach due to bacterial degradation of nitrates used as preservatives in meat and fish
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Describe features of carcinogens in the environment and food (3)
Potent carcinogens (aflatoxins) can be present in peanut butter due to production as secondary metabolites by a fungus infecting peanuts during growth (strict manufacturing controls)
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Give examples of occupational carcinogens (1)
Vinyl chloride used in plastics (associated with angiosarcoma of the liver). Poor hygiene for chimney sweepers (tarry deposits from coal fires were in contact with the thin and sensitive skin)
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Give examples of occupational carcinogens (2)
Inhalation of particles in furniture industry (nasopharyngeal malignancies). Carcinogens work by covalently modifying DNA before/after metabolism. Hair dyes contain aromatic amines (reaction of hydrogen peroxide). Tattoo ink (skin cancers)
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Give examples of physical carcinogens in the environment
Dusts and minerals. Link between asbestos and pleural and peritoneal tumours (particularly mesothelioma). Physical damage of chromosomes, asbestos penetrate cellular/nuclear membranes. Link between talc and higher risk of ovarian cancer
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Give examples of infective agents
Viruses (HPV - cervical cancer). Bacteria (H. pylori, linked to stomach cancer). Parasitic worms (Clonorchis sinensis – association with cholangiocarcinoma)
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Viruses are linked to which cancers? (1)
Epstein-Barr virus (EBV) is linked to Burkitt's lymphoma. Human Papilloma Virus (HPV) linked to cervical cancer (vaccine developed)
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Viruses are linked to which cancers? (2)
Human T-cell leukaemia virus (HTLV-1, RNA retrovirus). RNA viruses contain DNA polymerase (facilitate production of double-stranded viral DNA). Cause production of oncogene, damage tumour suppressor gene or insert new gene
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Viruses are linked to which cancers? (3)
Hepatocellular carinoma is linked to hepatitis B virus (HBV). HIV - kaposis sarcoma
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State features of bacterial infections
H. pylori colonises in stomach, associated with stomach ulcers. Infection can lead to stomach tumours (precise mechanism is still unclear)
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State features of worm infections (1)
Certain parasitic worms are carcinogenic e.g. Clonorchis sinensis (Clonorchiasis), Opisthorchis viverrini (Opisthorchiasis), associated with cholangiocarcinoma. Schistosoma is associated with bladder cancers.
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State features of worm infections (2)
Schistosoma haematobium has a highly prevalent blood fluke and human parasite has proven link to malignant bladder cancer
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Give examples of other factors in the environment which may cause cancer
Heat, EM energy and radiation, X-rays, nuclear radiation (exposure to a/b particles, DNA damage via fragmentation), radon gas (radiation to all tissues, leukaemia), power lines/mobile phones
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State features of hereditary factors
BRCA1/2 genes identified with close association with breast cancer (high risk, some choose to have radical surgery/prophylactic). Other genes linked to colon/bowel tumours are inherited. Leads to diagnostic screening and genetic counselling
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Give examples of genes associated with specific tumour types (1)
Burkitt's lymphoma (Myc), colon (MSH), lung (EGFR (ErbB-1), Her 2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4), EML4-ALK-1). CML (BCR-ABL, use Gleevec). Malignant melanoma (CDKN2, BCL-2, B-RAF). Endothelial (VEGFR, VEGFR2)
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Give examples of genes associated with specific tumour types (2)
Various tumours (P53 Tumour Suppressor Protein). Presence/over-expression used as bio-markers
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Which animal can cause a direct transmission of cancer?
The Tasmanian Devil
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Which lifestyle factors should be considered/modified to prevent cancer?
Tobacco (smoke, snuff, chew). Alcohol. Other recreational drugs. Diet. Avoid hot drinks. Obesity. Lack of exercise. Stress. Pregnancy/children
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Which two factors are considered chemopreventive agents? (1)
Drugs (Tamoxifen for breast cancers, aspirin prevents GI cancers, low-dose aspirin reduces ovarian cancer risk, statins/conflicting evidence for breast cancer, oral contraceptives, warfarin, vitamin D, vitamin C)
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Which two factors are considered chemopreventive agents? (2)
Diet (fruit/veg contain L-Sulforaphane, Mediterranean diet). (Also importance of gut microbiome linked to gut cancer therapies)
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What are the main treatments in current use for cancer?
Surgery (for small defined tumour). Radiotherapy (x-rays/focused beam to kill/shrink tumour). Radiopharmaceuticals. SACT (systemic anti-cancer therapy). Biologicals. Others (e.g. PDT - photodynamic therapy)
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Give an example of using technology to improve outcomes and reduce side effects
IMRT – multi-leaf collimator, use beam of radiation to focus onto patient’s tumour (beam directly on the area), could also follow breathing of the patient (e.g. tumour in the lung)
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Which radiopharmaceuticals are used in the treatment of cancer? (1)
Cobalt-60, Gold-198 (concentrates in liver) and Iodine-131 (for thyroid cancers). Some tumour cells less sensitive to damage due to being hypoxic (oxygen sensitises tumour cells). Metronidazole used to improve outcome
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Which radiopharmaceuticals are used in the treatment of cancer? (2)
High linear energy transfer used on hypoxic cells
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Describe features of chemotherapy
Use of small molecular drugs. Nitrogen mustards (first agents used). Cisplatin (discovered serendipitously, treats testicular/ovarian carinomas)
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Give examples of small molecule drugs used in chemotherapy
Antimetabolites (MTX), anti-tubulin agents (Taxol), DNA-interactive agents (Cisplatin)
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Which drug is used for hormonal therapy?
Tamoxifen
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Which drug is used in small molecular targeted therapy?
Imatinib (Gleevec)
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Describe features of biological agents - immunotherapy, antibody targeting, cell based therapy and vaccines (1)
Herceptin (monoclonal antibodies specific to breast cancer tumour). T-DM1 combines two strategies: anti-HER2 activity and targeted intracellular delivery of the potent anti-microtubule agent, DM1
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Describe features of biological agents - immunotherapy, antibody targeting, cell based therapy and vaccines (2)
Check point inhibitors - Nivolumab (blocks the “off-switch” on white blood cells called PD-1). Research is ongoing into the development of vaccines. CAR-T therapy for ALL - tisagenlecleucel (Kymriah)
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Describe features of biological agents - immunotherapy, antibody targeting, cell based therapy and vaccines (3)
Yervoy® (Ipilimumab) for the Treatment of Skin Cancer
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Give examples of approved antibody-drug conjugates
Brentuximab vedotin. Trastuzumab emtansine. Gemtuzumab ozogomicin. Inotuzumab ozogomicin. Moxetumoma b pasduotox
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Describe features of photodynamic therapy (1)
Involves the initial systemic administration of a photosensitizer such as the porphyrin derivative PhotofrinTM which is selectively retained by malignant cells
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Describe features of photodynamic therapy (2)
Tumour is irradiated with an intense light source of an appropriate wavelength which excites the Photofrin. Upon decay, oxygen is transformed into singlet form (cytotoxic/damages tumour cells)
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Describe features of photodynamic therapy (3)
Also, by damaging endothelial cells, PDT restricts blood flow to the tumour. Temoporfin (Foscan) used as agent for PDT
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Give examples of factors which can affect cancer therapies
Circadian rhythms. Diet. Gut microbiome
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Where do anti-cancer drugs come from? (1)
Natural products (majority, link to cell cycle, e.g. Trabectidin, Taxol)). Serendipity (cisplatin), Clinical observation (rapamycin, aminoglutethimide, nitrogen mustards)
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Where do anti-cancer drugs come from? (2)
Synthesis and screening (e.g. Temodal). Structural biology/rational drug design/synthesis/screening (molecularly targeted drugs e.g. Imatinib mesylate/Gleevec, Vemurafenib, Crixotinib, Alectinib). Shift towards targeted drugs (high cost of drugs)
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What are the issues with the cost of new types of agents to society?
Health service (NHS) funded by taxpayers. Insurance system. Charitable funding. Pay privately. Drug pension pot arrangement
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State features of evaluating novel anticancer agents (1)
New agents are nearly always evaluated initially in in vitro tumour cell lines (measures cytotoxicity).
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State features of evaluating novel anticancer agents (2)
To date, Human Tumour Xenograft assays represent the most successful animal model in which human tumour fragments are transplanted into immunosuppressed rodents. Effect on tumour growth is observed after administration of novel agent
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Outline the steps for in vitro cytotoxicity evaluation
Obtain cells from humour tumour. Grow in plastic dishes and treat with new drug. Drug kills cells. Count remaining cells
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Give examples of in vivo imaging in animal models
Syngeneic mouse models. Human tumour Xenograft models (CDx, cell line derived vs PDx models, patient derived). Integrated comparative approach to drug development (dogs with cancers in clinical trials, link to human cancers)
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Why is caution required with models? (1)
Sometimes, drugs that are active in humans show no effect in animal models e.g. hexamethylmelamine[2,4,6-tris-(dimethylamino)-1,3,5-triazine] - minimal activity in rodent models but works in humans (in carcinomas of bronchus/ovary/breast)
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Why is caution required with models? (2)
Different metabolic pathways between rodents and humans
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What are the problems associated with treatments? (1)
Accessibility of drugs to tumour cells (e.g. leukaemia). Small tumours more susceptible to drug action, large tumours have poor capillary access (hypoxic/necrotic). Variation in sensitivity of chemotherapeutic agents
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What are the problems associated with treatments? (2)
Brain tumours are resistant to chemotherapy (few drugs can cross BBB). Lipinski's RO5 (not all anticancer drugs follow this)
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What are the problems associated with treatments? (3)
Limiting toxicity of chemotherapeutic agents. Competition between cells within tumours favours those that continuously progress through cell cycle, many healthy cells affected (S/E). Chemotherapeutic agents penetrating BBB are not tolerated by CNS
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What are the problems associated with treatments? (4)
Both chemotherapy and radiotherapy treatments can cause fertility problems in both males and females of child-bearing age. Issue with DNA-interactive agents (cisplatin, damages genome of germ line ells in testes/ovaries)
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What are the problems associated with treatments? (5)
Possible solutions - sperm storage, store, ovarian tissue prior to radio/chemotherapy
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What are the problems associated with treatments? (6)
Follow-on cancers. Chemotherapeutic agents and radiation given to children with cancer can raise their risk of later developing soft tissue sarcoma, a cancer involving tissues such as fat and muscle (ethical dilemma - treat children with cytotoxics)
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What are the other toxicities associated with cancer treatment?
Nausea, vomiting, GI disturbances, hair loss, nail changes, stomatitis. S/E can be limited by use of adjuvant therapies e.g. ondansetron
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State features of the DigniCap device
Placed on the head to cool the scalp, reduce blood flow to the hair follicles to reduce hair loss during/after chemotherapy. Works by circulating cooling fluid through embedded cooling channels under the control of a software based control station
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State features of adjuvant therapies (1)
Sometimes necessary to co-administer other agents that can either enhance the activity of the anticancer drug or counteract any side-effects produced
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State features of adjuvant therapies (2)
E.g. co-administration of 6-alkylguanine transferase inhibitor Patrin with temozolomide to enhance efficacy by slowing removal of DNA adducts formed
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State features of adjuvant therapies (3)
Reduce S/E by co-administrating anti-emetics to counteract nausea (commonly associated with chemotherapeutic treatments). Use of antibiotic/antifungal in myelosuppression treatment (infection)
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State features of adjuvant therapies (4)
Steroids (prednisolone) used with anticancer agents to reduce severity of S/E (may also have anticancer effect through anti-inflammatory activity)
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Give examples of mechanisms contributing to development of resistance (1)
Decreased intracellular drug levels (e.g. vinca alkaloids). Increased drug inactivation (alkylating agents). Decreased conversion of drug to active form (anti-metabolites). Altered amount of target enzyme/receptor, gene amplification (MTX)
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Give examples of mechanisms contributing to development of resistance (2)
Decreased affinity of target enzyme/receptor for drug (e.g. antimetabolites, hydroxyurea). Switch on/off biochemical pathways (re-routing signals)
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Give examples of mechanisms contributing to development of resistance (3)
Enhanced repair of drug-induced defect. Decreased activity of enzyme required for killing effect. Multi-drug resistance (most important mechanism, gene encodes ATP-dependent efflux pump, p-glycoprotein, amplified in drug resistant tumours)
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Describe features of combination chemotherapy (1)
As a rule, each drug included in a particular combination should be active as a single agent and have different toxic (dose-limiting) side-effects compared to the others
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Describe features of combination chemotherapy (2)
Enables the simultaneous attack of different biological targets thus enhancing the effectiveness of treatment. E.g. prednisone, vincristine, daunorubicin increases chances of remission in ALL
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Describe features of precision medicine in oncology (1)
Biomarkers used to design targeted drugs. Use pharmacogenetics and biomarkers to predict risk of disease/re-occurrence/early intervention, use safer/more effective agents, indicate best drug for patient
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Describe features of precision medicine in oncology (2)
monitor/optimise drug therapy/maximise efficacy, minimise S/E. Potential roles of genomics in cancer
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What are the oncology biomarkers? (1)
Physiologic (patient performance status). Images (mammograms). Biochemical (PSA, Her-2). Cell-based markers (circulating tumour cells). Discrete genetic alterations (BRCA mutations, SNPs). Genomic profiling (transcriptone analysis)
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What are the oncology biomarkers? (2)
Protein expression profiles (proteome analysis). Increase in gene testing/use of biomarkers in anticancer drug discovery and treatment strategies. MammaPrint - for breast cancer prognosis. Irinotecan (test for UGT1A1 gene). Prolaris test kit
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What are the future treatments for cancer? (1)
Immune checkpoint inhibitors (CTLA-4, PD-1) - CTLA-4 binds to CD80 to inhibit response, up-regulation, transported to surface of cell (similar process with PD-1), block inhibitory response by targeting CTLA-4, PD-1, or ligand PD-L1
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What are the future treatments for cancer? (2)
E.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab. Keytruda treatment - for lung cancer
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What are the most common ADRs for check point inhibitors? (1)
Dermatological (rash, use corticosteroids). Endocrine (hypothyroidism, use levothyroxine). Hepatic (elevated markers, use corticosteroids). GI (colitis, diarrhoea, pain, manage with loperamide/corticosteroids)
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What are the most common ADRs for check point inhibitors? (2)
Respiratory (pneumonitis, SOB, cough, manage with corticosteroids)
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Outline the steps for CAR-T cell therapy (1)
Collection of T-cells from patient. Cells accepted by GMP facility. Viral gene transfer of TCR or CAR into patient's cells. Genetically modified TCR T-cell formed. Propagated genetically modified tumour reactive T cells
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Outline the steps for CAR-T cell therapy (2)
Cell product released by GMP facility. Transfer cells from manufacturing centre to patient. Precondition patient (chemotherapy) and transfuse T-cell therapy
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State features of cancer prophylactic and treatment vaccines
Prophylactic vaccines (HPV vaccine, hepatitis B vaccine). Treatment vaccines (Provenge for prostate, TICE® BCG for bladder and Imlygic® for melanoma)
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What are tissue agnostic anticancer agents?
Designed against cancer types originating in specific tissues within the body. (RNAi therapies also being developed)
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