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Cancer Therapies 1 2 3 DNA microarrays are used to assess the relative expression of thousands of genes simultaneously—relative expression means that two things are being compared relative to one another. e.g., Normal B Cells 4 e.g., NHL Cells 5 Figure 10-33 (part 1 of 2) Essential Cell Biology (© Garland Science 2010) 6 7 8 • Some tumors will never advance. Treating them is a waste of resources. • Some tumors are highly-aggressive and have probably already advanced to the point of metastasis by the time they’re diagnosed. Treating them is a waste of resources; it just delays the inevitable. 9 • Some tumors that have not yet advanced to the point of invasiveness can be removed surgically and require no additional treatment. General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics Immunotherapy 10 Stem Cell therapy General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 11 Surgery What? 12 • Open or minimally invasive • Remove tumor + adjacent healthy tissue +/- regional lymph tissue • Limited to solid tumors Why? • To remove tumor completely • To “debulk” Relieve symptoms Can increase effectiveness of other treatment(s) Downsides: • • • • Potential pain Potential infection Potential death Cost General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 13 Radiation Therapy What? 14 • External Beam Radiation • Internal (Brachytherapy) Permanent Cyclic • Systemic • Adjuvant vs Neoadjuvant Radiation Therapy What? 15 • External Beam Radiation • Internal (Brachytherapy) Permanent Cyclic • Systemic • Adjuvant vs Neoadjuvant Radiation Therapy Why? • To induce DNA double-strand breaks • To generate “free radicals” To kill cells 16 Radiation Therapy Downsides 17 • • • • Effects not immediate (cells die over weeks months) Fatigue Skin irritation Other regional “collateral damage” (e.g., functional loss in salivary glands, bowels, infertility, memory loss) • More cancer General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 18 Chemotherapy What? 19 • Chemicals given orally, IV, IM, IP, IT, topically—depending upon the drug Chemotherapy Why? 20 • To eradicate/cure • To control tumor growth • To ease symptoms Chemotherapy How? 21 • • • • Alkylating agents (directly damage DNA) Anti-metabolites (interfere with biosynthesis reactions) Agents that interfere with DNA replication Agents that interfere with mitosis Chemotherapy 22 Chemotherapy 23 Chemotherapy agents that interfere with DNA replication 24 Chemotherapy agents that interfere with mitosis 25 26 Chemotherapy Downsides 27 • • • • • • • Fatigue Nausea Potential infection Bleeding Many other local/regional/systemic effects More cancer Develop resistance 28 General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 29 Targeted Therapy What? 30 • Small molecules directed to intracellular messengers • Antibodies directed to cell-surface molecules Antibody-dependent cellular death Complement-dependent cytotoxicity “Delivery” mechanisms o Toxins or pro-toxin converting enzymes o Radioactive isotopes Targeted Therapy Why? 31 To kill cancer cells Selectively and Specifically! 32 33 34 Targeted Therapy Downsides 35 • • • • Often not orally-available (must be infused) Expensive Not many; few side effects Develop resistance General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 36 Biologic Therapy Why? 37 • • To inhibit cancer-benefitting biologic processes To alleviate side effects of other therapies (e.g., depressed immunity, bleeding) Biologic Therapy— Anti-angiogenics 38 Biologic Therapy— Anti-metastasis drugs 39 Biologic Therapy— Other drug targets • • • • 40 Differentiation promoters Immune system stimulators Epigenetic modifiers Coagulation promoters 41 Testing new treatments 42 High throughput assay • Effective at therapeutic doses • No/minimal off-target effects 43 44 http://www.cancer.gov/about-cancer/treatment/clinical-trials/search 45 Phase I: • Small numbers of subjects (~20) • Subjects usually have advanced disease • Purposes: gauging toxic effects (maximum tolerated dose) and pharmacokinetics (how long the drug “lasts”—concentration/time) in vivo pharmacodynamics (is drug at functional concentrations) ex vivo, often using a surrogate marker Goal is to generate a "therapeutic window"-dose that is therapeutically effective but below the maximum tolerated dose. 46 Phase II: • • • • 47 Larger numbers of subjects (typically <100) Often low doses of drug (“bottom” of therapeutic window) tested Specific patient population, may/may not have been previously treated Goal is to observe clear signs of efficacy Phase III: • Even larger numbers of subjects (hundreds-thousands) • Some subjects receive the study drug and others serve as controls Randomized Typically, control subjects receive current 'standard of care' • Low bar for FDA approval because participants are already failing other treatments • The drug only as to be better that ‘standard of care’ in only one aspect (e.g., fewer side effects, weight gain, better at shrinking tumor) 48 49 Phase IV: • After FDA approval • “Post-marketing surveillance” • Goal is to: fine-tune the best patient population in which to use the drug (different type of cancer, subtype of the original cancer type tested) to better define effective use in other ways (e.g., other similar uses) To assess long-term effectiveness/safety 50