Anti-Neoplastic Drugs, Pt. 4

Question 1

What is personalized/precision medicine? How is diagnostic testing employed?

Answer 1

separates patients into different groups with medical decisions, practices, and interventions tailored to the individual patient based on their predicted response or risk for disease

selecting appropriate or optimal therapies based on the context of a patient’s genetic content or other molecular or cellular analysis (proteins, enzymes) and to identify certain drugs that may be dangerous/toxic or completely ineffective

Question 2

What is used to identify mutations liked to certain diseases?

Answer 2

genome-wide association study - sequencing genome of many patients in the particular disease

Question 3

What is pharmacogenetics? Pharmacogenomics? What are their long-term goals?

Answer 3

study of genetic causes of individual variations in drug responses

study of the role of the multiple mutations in the genome that determine differences in drug response

help doctors select drugs and doses best suited for each person

Question 4

What is targeted therapy?

Answer 4

targeting specific molecules and/or signaling pathways

Question 5

What were the 2 main observations made by the Human Genome Project (1990-2003) and International HapMap Project (2002-2010)?

Answer 5

1. certain drugs are more effective in some patients than others
2. in response to certain drugs, some patients experience unusually severe side effects

Question 6

What are the 4 challenges of pharmacogenetics and pharmacogenomics?

Answer 6

1. > 10^6 variations of gene mutations
2. multiple discipline analyses
3. geographic and breed differences
4. ethical problems

Question 7

What is the primary cause of interpatient variability in drug response?

Answer 7

genetically determined differences in drug metabolism, distribution, and target proteins

Question 8

What group is focusing on personalized medicine to unlock new treatment methods in veterinary medicine?

Answer 8

AKC Canine Health Foundation

Question 9

What has been used to reveal what targeted therapies would work best in animals?

Answer 9

genetic testing and tumor type identification helps identify possible cancer-causing mutations

Question 10

What is the single most Very Important Pharmacogene (VIP) in dogs? What does mutations in this gene result in?

Answer 10

MDR1 gene

non-functional P-glycoprotein transporter, which alters the safety and efficacy of drugs in affected patients

Question 11

An MDR1 gene mutation makes affected dogs extremely sensitive to what 2 drugs?

Answer 11

1. Vincristine
2. Doxorubicin

Question 12

What 3 neoplastic diseases are associated with KIT oncogenic receptor tyrosine kinase mutation? What drug is used to control this?

Answer 12

1. cutaneous mast cell tumors**
2. canine GI stromal tumors
3. canine oral melanomas

Palladia (Toceranib) targets mutated c-KIT

Question 13

What is the difference between hormone therapy, targeted therapy, immunotherapy, and cancer vaccines?

Answer 13

sex hormones, or hormone-like drugs, used to slow the growth of mammary gland, prostate, and endometrial cancers by making cancer cells unable to use the hormone they need to grow or preventing the body from making the hormone

more specific than chemotherapy and used as a part of the treatment or after treatment to keep cancer under control

helps immune system to recognize and attack cancer cells

activates immune system to recognize and kill cancer cells

Question 14

Types of cancer therapy:

Answer 14

Question 15

How does hormone therapy work? What are their 2 major mechanisms of action?

Answer 15

steroidal or nonsteroidal hormone-like drugs used to slow the growth of breast and prostate cancers

1. prevent the body from making hormones
2. prevent cancer cells from using hormone for growth

Question 16

What is the main strategy for hormone therapies? In what 2 ways do they do this?

Answer 16

antagonizing effects of estrogens/androgens

1. hormone deprivation - aromatase inhibitors (prevent estrogen production); gonadotropin-releasing hormone analogs (prevent androgen production)
2. hormone receptor antagonism - antiestrogens, antiandrogens

Question 17

What are SERMs used to treat? SARs?

Answer 17

breast cancer
- antiestrogens: Tamozifen, Raloxifene, Toremifene
- aromatase inhibitors

prostate cancer
- antiandrogens: Flutamide, Enzalutamide
- LHRH analogs: Finasteride

Question 18

What is an interesting characteristic of SERMs?

Answer 18

can be estrogenic in some tissues and antiestrogenic in others

Question 19

In what dogs is benign prostatic hypertrophy (BPH) common? What are 3 common signs? What is it commonly accompanied by?

Answer 19

> 80% male dogs over 5 years old

1. increased urination
2. constipation
3. blood in urine

prostatic infection, cysts, or neoplasia

Question 20

What is the pathogenesis of benign prostatic hypertrophy (BPH)? What are 2 common treatments? Potential side effect?

Answer 20

• leydig cells in intact testes release testosterone
• 5α-reductase converts testosterone into active 5α-dihydrotestosterone, increasing androgenic effects
• prostate becomes enlarged and increases urination

1. FINASTERIDE, a 5α-reductase inhibitor
2. FLUTAMIDE, nonsteroidal AR antagonist

impotence

Question 21

How do Flutamide and Enzalutamide work? What are they approved for use in?

Answer 21

blocks intracellular androgen receptors, keeping 5α-dihydrotestosterone from binding and blocking DNA transcription

metastatic castrate-resistance prostatic cancer

Question 22

How does chemotherapy affect tumors? What adverse effect do some treatments have?

Answer 22

reduces size by killing fast-dividing cells

• considerable damage to normal cells
• increased incidence of second-site cancers

Question 23

What make chemotherapy unique compared to other treatments?

Answer 23

traditional predictors, like age, tumor size, LN involvement, pathological grade, and hormone receptor status, do not predict outcome

Question 24

What does targeted therapy allow? How does it compare to chemotherapy?

Answer 24

use molecular targets that enable oncologists to distinguish between indolent and aggressive tumors and develop drugs that interact with specific targets and cancer pathways

chosen carefully with great precision to cause little or not damage to normal cells

Question 25

Targeted therapy vs. chemotherapy:

Answer 25

Question 26

What are the 5 mechanisms of action of targeted therapy?

Answer 26

1. block or turn off chemical signals that tell cancer cells to grow and divide 2. change proteins within the cancer cells so they die 3. stop making new blood vessels to feed cancer cells 4. trigger the immune system to kill cancer cells 5. carry toxins to the cancer cells to kill them, but not normal cells

Question 27

What are the best 2 targets for targeted therapy? What are the 2 types of targets?

Answer 27

1. molecular signaling pathways present in cancer cells and absent in normal cells 2. molecule present more frequently in cancer cells than in normal cells (allows for dose adjustment) - DRUGGABLE: vulnerable to attack and inhibition by low MW compounds - UNDRUGGABLE: transcription factors and protein-protein interactions more difficult to target

Question 28

What is a common type of druggable targets for targeted therapy? What major exceptions to types of undruggable targets?

Answer 28

enzymes with catalytic domains, like kinases that have well-defined catalytic clefts that can specifically bind small organic molecules nuclear hormone receptors (ER, AR) with hormone-binding domains

Question 29

What are the 3 types of target drugs?

Answer 29

1. small molecules (peptides) 2. antibodies 3. vaccines - therapeutic, preventative

Question 30

How do small molecule target drugs work?

Answer 30

travel across cell membrane to bind proteins inside of the cell and interact with specific areas

Question 31

What are 3 ways that antibody target drugs work?

Answer 31

1. interfere with receptor binding and signaling pathways outside of the cell 2. delivery vehicles of toxins or radioactive molecules to cancer cells 3. trigger immune response by reactivating T or B cells

Question 32

What are the 4 signaling pathways of cancer cells that targeted therapies block?

Answer 32

1. cell growth 2. apoptosis 3. angiogenesis 4. metastasis

Question 33

What is the growth signaling pathway in normal cells?

Answer 33

- growth factors and inhibitors bind receptors on the membranes of cells and activate downstream signaling - receptors interact with one another or dimerize - activated receptors process signaling pathways inside cells to nucleus and DNA

Question 34

In what 4 ways does the growth signaling pathway differ in cancer cells?

Answer 34

1. cancer cells produce their own growth factors that travel outside of the cell and activate its own receptors 2. cancer cells have a greater number of growth hormone receptors (overexpressed) 3. genes that encode for growth factors are mutated and stay on without ligand - constitutively active 4. able to bypass normal growth regulations because they lack inhibitors

Question 35

What is the goal of targeting growth signaling in targeted therapy? What are the main 3 ways drugs do this?

Answer 35

block any part of dysregulated growth signaling pathway 1. bind to growth factor receptors and prevent their interaction with other receptors and dimerization 2. keep growth factor receptors in the off position 3. kinase inhibitors - prevent phosphorylation pathway that activate receptors

Question 36

What kind of anticancer drug is Erlotinib (Tarceva)? What does it target? What cancer is its target associated with?

Answer 36

small molecule inhibitor - targeted therapy epidermal growth factor receptor (EGFR) with tyrosine kinase catalytic activity EGFR is mutated and overactivated in metastatic non-small cell lung cancer and pancreatic cancer

Question 37

How does Erlotinib (Tarceva) work?

Answer 37

fits itself in a key-in-lock fashion into a specific pocket of epidermal growth factor receptor (EGFR)

Question 38

What kind of anticancer drug is Herceptin (Trastuzumab)? What does it target? What cancer is its target associated with?

Answer 38

monoclonal antibody - targeted therapy oncogenic growth factor cell-surface receptor (HER2), an EGFR with tyrosine kinase catalytic activity overexpressed in breast cancer - more aggressive type, but easily controlled by Herceptin

Question 39

What are the 2 actions of canine anti-EGFR?

Answer 39

1. decreases canine mammary carcinoma cell proliferation 2. mediated tumor cell killing by macrophage phagocytosis in vitro

Question 40

Overexpression of what receptor has been identified in spontaneous feline mammary carcinomas?

Answer 40

HER2

Question 41

What has been especially implicated in the pathogenesis of canine cutaneous mast cell tumors? What 2 drugs are used to treat this? How do they work?

Answer 41

genetic defect causing constitutive activation of KIT oncogene receptor kinase tyrosine kinase, resulting in uninhibited mast cell proliferation 1. Toceranib (Palladia) - competitively blocks ATP binding site of several tyrosine kinase receptors 2. Masitinib - impairs phosphorylation and downstream signaling

Question 42

What 2 feline cancers commonly use Toceranib as treatment?

Answer 42

1. mast cell tumors 2. squamous cell carcinomas

Question 43

What small molecule (peptide) inhibitor is not approved for use in cats? What is recommended as an addition in treatment with this drug?

Answer 43

Masitinib supportive (antacids) and combination (glucocorticoids) therapies