Anti-Neoplastic Drugs, Pt. 4 Flashcards
What is personalized/precision medicine? How is diagnostic testing employed?
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
What is used to identify mutations liked to certain diseases?
genome-wide association study - sequencing genome of many patients in the particular disease
What is pharmacogenetics? Pharmacogenomics? What are their long-term goals?
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
What is targeted therapy?
targeting specific molecules and/or signaling pathways
What were the 2 main observations made by the Human Genome Project (1990-2003) and International HapMap Project (2002-2010)?
- certain drugs are more effective in some patients than others
- in response to certain drugs, some patients experience unusually severe side effects
What are the 4 challenges of pharmacogenetics and pharmacogenomics?
- > 10^6 variations of gene mutations
- multiple discipline analyses
- geographic and breed differences
- ethical problems
What is the primary cause of interpatient variability in drug response?
genetically determined differences in drug metabolism, distribution, and target proteins
What group is focusing on personalized medicine to unlock new treatment methods in veterinary medicine?
AKC Canine Health Foundation
What has been used to reveal what targeted therapies would work best in animals?
genetic testing and tumor type identification helps identify possible cancer-causing mutations
What is the single most Very Important Pharmacogene (VIP) in dogs? What does mutations in this gene result in?
MDR1 gene
non-functional P-glycoprotein transporter, which alters the safety and efficacy of drugs in affected patients
An MDR1 gene mutation makes affected dogs extremely sensitive to what 2 drugs?
- Vincristine
- Doxorubicin
What 3 neoplastic diseases are associated with KIT oncogenic receptor tyrosine kinase mutation? What drug is used to control this?
- cutaneous mast cell tumors**
- canine GI stromal tumors
- canine oral melanomas
Palladia (Toceranib) targets mutated c-KIT
What is the difference between hormone therapy, targeted therapy, immunotherapy, and cancer vaccines?
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
Types of cancer therapy:
How does hormone therapy work? What are their 2 major mechanisms of action?
steroidal or nonsteroidal hormone-like drugs used to slow the growth of breast and prostate cancers
- prevent the body from making hormones
- prevent cancer cells from using hormone for growth
What is the main strategy for hormone therapies? In what 2 ways do they do this?
antagonizing effects of estrogens/androgens
- hormone deprivation - aromatase inhibitors (prevent estrogen production); gonadotropin-releasing hormone analogs (prevent androgen production)
- hormone receptor antagonism - antiestrogens, antiandrogens
What are SERMs used to treat? SARs?
breast cancer
- antiestrogens: Tamozifen, Raloxifene, Toremifene
- aromatase inhibitors
prostate cancer
- antiandrogens: Flutamide, Enzalutamide
- LHRH analogs: Finasteride
What is an interesting characteristic of SERMs?
can be estrogenic in some tissues and antiestrogenic in others
In what dogs is benign prostatic hypertrophy (BPH) common? What are 3 common signs? What is it commonly accompanied by?
> 80% male dogs over 5 years old
- increased urination
- constipation
- blood in urine
prostatic infection, cysts, or neoplasia
What is the pathogenesis of benign prostatic hypertrophy (BPH)? What are 2 common treatments? Potential side effect?
- leydig cells in intact testes release testosterone
- 5α-reductase converts testosterone into active 5α-dihydrotestosterone, increasing androgenic effects
- prostate becomes enlarged and increases urination
- FINASTERIDE, a 5α-reductase inhibitor
- FLUTAMIDE, nonsteroidal AR antagonist
impotence
How do Flutamide and Enzalutamide work? What are they approved for use in?
blocks intracellular androgen receptors, keeping 5α-dihydrotestosterone from binding and blocking DNA transcription
metastatic castrate-resistance prostatic cancer
How does chemotherapy affect tumors? What adverse effect do some treatments have?
reduces size by killing fast-dividing cells
- considerable damage to normal cells
- increased incidence of second-site cancers
What make chemotherapy unique compared to other treatments?
traditional predictors, like age, tumor size, LN involvement, pathological grade, and hormone receptor status, do not predict outcome
What does targeted therapy allow? How does it compare to chemotherapy?
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
Targeted therapy vs. chemotherapy:
What are the 5 mechanisms of action of targeted therapy?
- block or turn off chemical signals that tell cancer cells to grow and divide
- change proteins within the cancer cells so they die
- stop making new blood vessels to feed cancer cells
- trigger the immune system to kill cancer cells
- carry toxins to the cancer cells to kill them, but not normal cells
What are the best 2 targets for targeted therapy? What are the 2 types of targets?
- molecular signaling pathways present in cancer cells and absent in normal cells
- 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
What is a common type of druggable targets for targeted therapy? What major exceptions to types of undruggable targets?
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
What are the 3 types of target drugs?
- small molecules (peptides)
- antibodies
- vaccines - therapeutic, preventative
How do small molecule target drugs work?
travel across cell membrane to bind proteins inside of the cell and interact with specific areas
What are 3 ways that antibody target drugs work?
- interfere with receptor binding and signaling pathways outside of the cell
- delivery vehicles of toxins or radioactive molecules to cancer cells
- trigger immune response by reactivating T or B cells
What are the 4 signaling pathways of cancer cells that targeted therapies block?
- cell growth
- apoptosis
- angiogenesis
- metastasis
What is the growth signaling pathway in normal cells?
- 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
In what 4 ways does the growth signaling pathway differ in cancer cells?
- cancer cells produce their own growth factors that travel outside of the cell and activate its own receptors
- cancer cells have a greater number of growth hormone receptors (overexpressed)
- genes that encode for growth factors are mutated and stay on without ligand - constitutively active
- able to bypass normal growth regulations because they lack inhibitors
What is the goal of targeting growth signaling in targeted therapy? What are the main 3 ways drugs do this?
block any part of dysregulated growth signaling pathway
- bind to growth factor receptors and prevent their interaction with other receptors and dimerization
- keep growth factor receptors in the off position
- kinase inhibitors - prevent phosphorylation pathway that activate receptors
What kind of anticancer drug is Erlotinib (Tarceva)? What does it target? What cancer is its target associated with?
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
How does Erlotinib (Tarceva) work?
fits itself in a key-in-lock fashion into a specific pocket of epidermal growth factor receptor (EGFR)
What kind of anticancer drug is Herceptin (Trastuzumab)? What does it target? What cancer is its target associated with?
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
What are the 2 actions of canine anti-EGFR?
- decreases canine mammary carcinoma cell proliferation
- mediated tumor cell killing by macrophage phagocytosis in vitro
Overexpression of what receptor has been identified in spontaneous feline mammary carcinomas?
HER2
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?
genetic defect causing constitutive activation of KIT oncogene receptor kinase tyrosine kinase, resulting in uninhibited mast cell proliferation
- Toceranib (Palladia) - competitively blocks ATP binding site of several tyrosine kinase receptors
- Masitinib - impairs phosphorylation and downstream signaling
What 2 feline cancers commonly use Toceranib as treatment?
- mast cell tumors
- squamous cell carcinomas
What small molecule (peptide) inhibitor is not approved for use in cats? What is recommended as an addition in treatment with this drug?
Masitinib
supportive (antacids) and combination (glucocorticoids) therapies
