Cancer Therapies 1

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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. 4 e.g., Normal B Cellse.g., NHL Cells

Figure (part 1 of 2) Essential Cell Biology (© Garland Science 2010) 5

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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. Some tumors that have not yet advanced to the point of invasiveness can be removed surgically and require no additional treatment. 9

General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics Immunotherapy Stem Cell therapy 10

General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 11

12 Surgery Open or minimally invasive Remove tumor + adjacent healthy tissue +/- regional lymph tissue Limited to solid tumors To remove tumor completely To “debulk”  Relieve symptoms  Can increase effectiveness of other treatment(s) Potential pain Potential infection Potential death Cost What? Why? Downsides:

General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 13

Radiation Therapy External Beam Radiation Internal (Brachytherapy)  Permanent  Cyclic Systemic Adjuvant vs Neoadjuvant What? 14

Radiation Therapy External Beam Radiation Internal (Brachytherapy)  Permanent  Cyclic Systemic Adjuvant vs Neoadjuvant What? 15

16 Radiation Therapy To induce DNA double-strand breaks To generate “free radicals”  To kill cells Why?

17 Radiation Therapy 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 Downsides

General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 18

19 Chemicals given orally, IV, IM, IP, IT, topically—depending upon the drug What? Chemotherapy

20 Chemotherapy Why? To eradicate/cure To control tumor growth To ease symptoms

21 Chemotherapy Alkylating agents (directly damage DNA) Anti-metabolites (interfere with biosynthesis reactions) Agents that interfere with DNA replication Agents that interfere with mitosis How?

22 Chemotherapy

23 Chemotherapy

24 Chemotherapy agents that interfere with DNA replication

25 Chemotherapy agents that interfere with mitosis

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27 Chemotherapy Fatigue Nausea Potential infection Bleeding Many other local/regional/systemic effects More cancer Develop resistance Downsides

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General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 29

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 What? Targeted Therapy

31 Targeted Therapy  To kill cancer cells Selectively and Specifically!Why?

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35 Targeted Therapy Often not orally-available (must be infused) Expensive Not many; few side effects Develop resistance Downsides

General Categories of Cancer Treatments: Surgery Radiation Chemotherapy Targeted therapy Biologics 36

37 Biologic Therapy To inhibit cancer-benefitting biologic processes To alleviate side effects of other therapies (e.g., depressed immunity, bleeding) Why?

38 Biologic Therapy— Anti-angiogenics

39 Biologic Therapy— Anti-metastasis drugs

40 Biologic Therapy— Other drug targets Differentiation promoters Immune system stimulators Epigenetic modifiers Coagulation promoters

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42 High throughput assay Testing new treatments

43 Effective at therapeutic doses No/minimal off-target effects

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46 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.

47 Phase II: 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

48 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)

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50 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