Cancer therapy - depends on tumour type, location, grade + stage of the disease and general health of the patient What is cancer therapy? - purposes: 1) prolong survival time 2) improve quality of life - goals: 1) cure 2) control 3) palliative care (can’t be cured => alleviate symptoms + improve life qual.) => eliminate cancer cells & reduce chance of recurrence - 5 pillars of cancer treatment => most common 1st treatments : surgery (45%) > chemotherapy (28%) > radiotherapy (27%) - example of treatment: Key terminology - adjuvant therapy = treatment given in addition to the primary treatment- neoadjuvant therapy = treatment given to shrink the tumour before primary treatment- cancer grade = appearance of tumour compared to original normal cells- cancer stage = size of tumour & how far it has spread from the original site - complete remission = treatment has eliminated cancer as measured by medical tests BUT not cure Surgery - functions: prevention - diagnosis - staging - primary treatment - debulking - relieve symptoms
- often 1st line of treatment for localised solid tumours/ at an early stage dvlp => NOT if systemic cancer (leukaemia, lymphatic cancer), metastasised cancer or near a risky area - aim: remove the tumour mass/ whole organ (with or without surrounding lymphatic systems) => margin of healthy tissue also removed => reduce chance of recurrence - often used in combination => before chemo/ radiotherapy (adjuvant treatment)=> radiation given before surgery to reduce the tumour size (neoadjuvant treatment) 1) debulking => remove as much of the tumour as possible but not all of it => better chances of successful chemo- or radiotherapy => ex: advanced cancer of the ovary 2) laparoscopic surgery => less invasive: a laparoscope inserted into small incisions => relays images of the inside of the abdomen/ pelvis 3) radical surgery => remove all nerby tissue including lymph nodes, muscles, nerves => lower change of recurrence=> ex: radical mastectomy removes breast & associated lymph nodes 4) preventive (prophylactic) surgery => remove non-cancerous areas of tissue in patients at high risk => ex: family history of breast cancer or adenomatous polyposis (large intestine) - risks: => bleeding=> blood clots => damage to nearby tissues, nerves, other organs => adverse reactions to drugs => pain => infections=> slow recovery of other body functions
Radiotherapy - 40 % of patients at some pt in their treatment - ionising radiation (IR) delivered by a linear accelerator to match the 3D shape of the tumour => cause DNA damage + kill malignant cells w/ less exposure to healthy tissue => curative when tumour is localised & can be used instead of surgery (or (neo)adjuvant)=> not suitable for metastatic cancers + some radio-resistant cancers (renal cell carcinoma...) - given as doses over days => time for normal cells exposed to IR to repair & recover - 3DCRT (3-dimensional conformal radiotherapy) => most commonly used - computer programmes match exact tumour shape - IMRT (intensity-modulated radiation therapy) => deliver different intensities of radiation to ≠ segments of the 3D shape of the tumour - IGRT (image guided radiotherapy) => treat tumours in areas that move (lungs...)/ close to critical organs => frequent imaging before & during radiotherapy - SBRT (stereotactic body radiation therapy) => consolidative SBRT (after cancer has disappeared) => imaging & computer programmes to deliver at high dose => single/ small number of treatments=> alternative to surgery for small to moderately-sized cancers - brachytherapy => place a radioisotope source (in a capsule) in or near the tumour => ex: for prostate cancer - ionising radiation = particles, X-rays or gamma rays w/ sufficient E to cause ionisation => remove tightly bound electrons from the orbit of the atom => damage DNA directly => or indirectly (via H2O which become free radicals) => sensor p recruit transducer p which recruit mediator p => effector proteins give the cellular outcome: apoptosis here 1) permanent seed brachytherapy 2) temporary brachytherapy (tubes inserted) => no sexual dysfunction risk BUT decline technique
- cells can repair DNA damage BUT cancer cells are often overwhelmed => double-stranded DNA breaks trigger cell death via: => apoptosis=> mitotic catastrophe (cell death during mitosis because of premature/ inappropriate entry)=> necrosis=> IR-induced senescence (cells cease to divide + grow) followed by apoptosis=> IR-induced autophagy (cells self-degrade their cellular components) followed by apoptosis main - adjacent cells/ cells in the path of radiation are exposed to IR => BUT proliferate more slowly => time to repair + repair more effectively => BUT damage can happen => side-effects => sore, red skin=> feeling tired (low RBCs (bone marrow affected) + body uses E to repair healthy tissue)=> hair loss in area treated (proliferate at fast rate)=> feeling sick, sore mouth, loss appetite=> diarrhoea=> lymphoedema (swelling of limbs due to lymphatic system damage) Chemotherapy - history of chemotherapy: - genetic mutations causing cancer => chr translocation=> gene amplification => pt mutation within promoter/ enhancer region of gene=> deletion/ insertion => epigenetic alterations to gene expression => germline mutations
- chemotherapy: cytotoxic drugs to kill cancer cells => systemic treatment (travel through blood stream & affect cells all over the body)=> administered intravenously or by mouth & given in cycles, w/ a recovery period of months - targets rapidly dividing cells => affect cells in mouth, digestive tract, reproductive system - cells in bone marrow - hair follicles => nasty side effects - given alone (often several in combination) or as an adjuvant/ neoadjuvant or w/ steroids... => MIC (non-small cell lung cancer & oesophageal cancer): mitomycin/ ifosfamide/ cisplatin=> CHOP (non-Hodgkin lymphoma...): cyclophosphamide/ doxorubicin/ vincristine/ prednisolone Alkylating agents: => nitrogen mustards: they add alkyl groups to guanine residues in DNA => strands cross-linking => replication arrest => apoptosis => pseudo-alkylating agents add platinum to guanine residues => replication arrest => apoptosis => most are also carcinogenic: encourage mispairing during repair => toxic to cells that divide frequently (GI tract, bone marrow, testicles + ovaries) => side effects => hair loss => nephrotoxicity (kidneys)=> ototoxicity (platinum toxic to ear)=> nausea, vomiting, diarrhoea=> immunosuppression=> tiredness Antimetabolites: => interfere with enzymes necessary for DNA synthesis=> purine (A, G) + pyrimidine (T, U, C) analogues/ folate antagonists => cell death during S phase reduce inflammation, reduce sickness of chemo...
=> side effects => fatigue=> hair loss=> bone marrow suppression => anaemia, low WBCs & platelet count=> risk of neutropenic sepsis (inflammatory response to infection)/ bleeding => nausea, vomiting=> mucositis + diarrhoea=> palmar-plantar erythrodysesthesia (PPE): reddening, peeling... of hand palms + soles of feet Anti-microtubule agents: => inhibit cell proliferation by binding microtubules & suppressing their dynamics => cell death => also antiangiogenic => from natural sources => vinca alkaloids inhibit assembly of mitotic microtubules=> taxanes: inhibit disassembly of mitotic microtubules => side effects => peripheral neuropathy (nerve damage), autonomic neuropathy (autonomic sys. nerve damage)=> hair loss=> nausea, vomiting, bone marrow suppression (myelosuppression)=> arthralgia (pain in joints)=> allergy Topoisomerase inhibitors: => topoisomerases regulate DNA unwinding => temporary single-strand break (topoisomerase 1) // double-strand break (topoisomerase 2) => then re-ligate DNA segments => bind enzyme + prevent re-ligation => repair mechanisms BUT overwhelmed => apoptosis=> side effects => acute cholinergic type syndrome (diarrhoea...) => give atropine to counteract side effects => hair loss=> nausea, vomiting=> fatigue=> bone marrow suppression interfere w/ axonal microtubule function + cause axonal degeneration
Cytotoxic antibiotics: => naturally-occurring drugs that interrupt cell division => 2 main groups: anthracyclins (doxorubicin, daunorubicin...) & bleomycins=> intercalate DNA to prevent transcription & synthesis, inhibit TOP II, produce ROS (bleomycin)=> side effects => cardiac toxicity (free radicals)=> hair loss (alopecia)=> neutropaenia (low neutrophils conc)=> nausea, vomiting=> fatigue => skin changes=> red urine (dyes in doxorubicin) risk with chemotherapy is that cells not killed can mutate => resistance development via: => increased clearing of drug=> inhibition/ loss apoptosis => increased DNA repair Targeted therapy - target specific cancer signalling pathways to avoid side effects of chemotherapeutic agents => selectively kill cancer cells - 4 types => cancer growth blockers => monoclonal antibodies (MAOs/ mAbs)=> anti-angiogenics => PARP inhibitors (PARPi) - cancer growth blockers: target growth signals of cancer => tyrosine kinase inhibitors (ex: Gleevec): stop cell growing & dividing (stop phosphate transfer)=> proteasome inhibitors: inhibit proteasome that breaks down unwanted cellular p (w/ proteases)=> mTOR inhibitors: inhibit protein kinase mTOR activated by growth factors (insulin...) => produce new p + control cytoskeletal reorganisation => increase cell size + proliferation trastuzumab: prevent dimerisation HER2 receptor ibrutinib: block early signalling
=> P13K inhibitors: target P13K family of enzymes involved in growth, proliferation, survival... (often altered in cancer) => histone deacetylase inhibitors: enzymes controlling coiling & uncoiling of DNA around histones=> hedgehog pathway blockers: target embryonic signalling pathway involved in cell differentiation => is reactivated in some cancers, including brain + skin cancer - 9;22 chr translocation (Philadelphia chr): creates its own unique fusion p Bcr-Abl (oncogene) => continuous tyrosine kinase activity => over-production of WBCs => chronic myeloid leukaemia (‘oncogene addiction’: a unique hyperactive gene drives a tumour) => Gleevec specifically target ATP binding site of Bcr-Abl => prevent binding to ATP => fantastic clinical results (83.3% survival rate) BUT resistance + unspecific binding - tyrosine kinase signalling pathway: => receptor tyrosine kinases (RTK): EGFR for ex => bind an external GF: EGF for ex => signal transduction via P13K & MAPK pathways => pathway contains most oncoproteins => therapy targets RTK signalling - monoclonal antibodies: target antigens on the surface of tumour cells (TAAs, TSAs) => can cause allergic reactions1) naked monoclonal antibodies: work by themselves => most common => trigger antibody-dependent cell-mediated cytotoxicity (ADCC)/ block cancer GF receptors... interact w/ interleukin 3 beta receptor (CML) epigenetically reprogramme gene expression in cancer cells => differentiation, apoptosis... => no resistance HDACi
2) conjugated monoclonal antibodies: joined by a chemotherapy drug/ radioactive particle => take the substance directly to cancer cells 3) bispecific monoclonal antibodies: parts of 2 ≠ antibodies => attach to 2 ≠ p at same time => brings cancer cells & immune cells together => attack cancer cells - anti-angiogenic: => tumours release pro-angiogenic factors (VEGF...) => acts on endothelial cells lining blood vessels => vessels grow towards & supply blood 1) block vessel GF (ex: prevent VEGF from binding to receptor): bevacizumab2) block signalling within cell (tyrosine kinase inhibitors) What is synthetic lethality? - normal cells: loss of cellular viability when 2 genes are disrupted // survive when 1 is disrupted => ideal for cancer treatment because they often have 1 gene mutated with loss of function => PARP inhibitor if BRCA1/ BRAC2 deleted/ mutated cancer => PARP enzymes: activated by DNA damage => facilitate DNA repair of SSBs & BER => inhibitor => stalling replication fork (accumulation SSBs) => degrade into DSBs => normally repaired by homologous recombination (HR)=> BRCA-mutated cells can’t use HR => cell death (cancer arises if 2 copies lost) 1 copy lost in healthy cells
ex: Olaparib: PARPi w/ clinical benefits in 63% cases, especially w/ chemo => myelosuppression + central nervous system side effects=> approved for ovarian, fallopian, peritoneal & BRCA-mutated HER2- metastatic breast cancers=> BUT not w/ triple negative breast cancer TNBC patients + resistance occurs (restoration HR)=> future: => combine w/ targeted agents (ex: ATR inhibitor: p involved in cell cycle arrest for DNA repair)=> combine w/ immunotherapies (ab...)=> combine w/ stratified/ personalised medicine: mutations that predispose patients to benefit - oligoprogression = after an initially successful treatment, progression of a few sites of metastasis- definitive therapy = only optimal treatment plan for a patient after all options have been considered - targeted therapy, hormone therapy, immunotherapy: selectively kill cancer => fewer side-effects - other emerging therapies: => cryotherapy: extreme cold to kill cancer cells locally=> DNA cages: modified nanostructures that can carry drug cargo to particular DNA sequence=> cannabis: induce apoptosis & inhibit proliferation of cancer cells => ZIKA virus of oncolytic therapy: target glioblastoma cells in brain => PROTACs: target & degrade specific p => high intensity focused ultrasound (HIFU): high frequency sound waves kill cancer cells - remark: aromatherapy uses essential oils to help with well-being, anxiety, cancer side-effects...