Cancer - Signal Transduction & Cancer Rx

Front 1

What are the three major classes of receptor signals?

Back 1

1) phosphorylation/ dephosphorylatin… 2) GTP/GDP exchange… 3) Acetylation/deacetylation (Post translational modification not a receptor signal)

Front 2

Illustrate the phosphorylation pathway

Back 2

Dephosphorylated substrate (inactive) --> Protein kinase w/ ATP --> (ADP byproduct) + Phosphorylated substrate (active) --> [interaction with effectors-AND/OR- Protein phosphatase] --> (Pi byproduct) + Dephosphorylated substate (inactive)

Hint 2

None

Front 3

Name the 6 signaling pathways.

Back 3

1) nuclear hormone receptors… 2) ligand-gated ion channels… 3) G protein coupled receptors (with second messenger c-AMP)… 4) Receptor protein tryosine kinase (RAS and MAP Kinase)… 5) cytokines receptor and non-receptor tyrosine kinase… 6) proteolysis regulated signals

Hint 3

None

Front 4

Which of the signaling systems utilizes different domains with various functions as well as a basic plan?

Back 4

Nuclear hormone receptors

Front 5

Which cancers would be good candidates for nuclear hormone receptors?

Back 5

breast, prostate, APL

Front 6

Why are multiple waves of signaling seen in NHRs?

Back 6

NHR's secondary response would be downstream gene activation

Front 7

Do NHRs cause phosphorylation?

Back 7

Not directly… indirectly through other activated gene products

Front 8

What are the 4 classes of stimulating/inhibiting molecule that affect NHR activity?

Back 8

antagonists, agonists, inverse agonists, partial agonists

Hint 8

None

Front 9

Do Antagonists change the ratio (equilibrium)?

Back 9

no

Front 10

What are 3 ways to prevent hormone production?

Back 10

1) remove organ… 2) chemical castration… 3) prevent biosynthesis

Front 11

What is an LHRH agonist? What is its mechanism of action? What cancer is it used to treat?

Back 11

It a method of chemical casatration to prevent the synthesis of hormones… it does it by desensitizing the system and thus shuts the system down… it used in prostate cancer

Hint 11

None

Front 12

What is an aromatase inhibitor? What is its mechanism of action? What type of cancer is it used to treat?

Back 12

It inhibits aromatase, which is an enzyme needed for estrogen and progesterone synthesis (found in fat cells.. Thus obesity is associagted with breast cancer)

Estrogen receptor positive

Hint 12

None

Front 13

which three molecules used in preventing hormone binding to its receptors?

Back 13

Receptor antagonists, partial agonists, anti-androgen,

Hint 13

None

Front 14

What type of hormone interrupting drug is Tamoxifen… and what is it used for?

Back 14

Receptor antagonist/partial
agonist… breast cancer... estrogen receptor positive

Hint 14

None

Front 15

What type of hormone interrupting drug is Flutamide… and what is it used for?

Back 15

pure antiadrogen/receptor antagonist… prostate

Front 16

What is the role of 5-HT3 in cancer and how does it gain its selectivity?

Back 16

5-HT3 is a serotonin ligand gated ion channel, which is related to nausea and vomiting… this receptor is unique when compared to other Serotonin receptors (Na and K)

Front 17

Which receptor is a seven transmembrane protein? What is another name for this type of receptor?

Back 17

G-protein coupled receptor… heptahelical receptor

Front 18

What types of extracellular signals activate G-Protein coupled receptors?

Back 18

Many: Sensory (light, tastes), ions, small peptides, proteins, and enzymes

Hint 18

None

Front 19

Which cell signalling pathway accounts for 70% of all drug sales (including illegal) and 50% of legal drugs

Back 19

GPCR

Hint 19

None

Front 20

Give the pathway for G-proteins.

Back 20

G protein-GDP + GEF + GTP -(loss of GDP)-> G-protein-GTP -> [interaction with effectors -> leads to biological functions] --> G-protein-GTP +GAP -(loss of Pi)-> G-protein-GDP

Hint 20

None

Front 21

What are the components of a GPCR?

Back 21

Receptor, ß, ∂, (ligand that binds the receptor) and GTP or GDP

Front 22

What is the GEF in GPCR?

Back 22

the receptor

Front 23

What binds the GTP in GPCR?

Back 23

the Alpha subunit

Hint 23

None

Front 24

Give the cAMP pathway in a GPCR.

Back 24

G∂ --> Adenylyl cyclase + ATP --> 4-each cAMP + inactive PKA --> active PKA (catalytic subunits) enter nucleus and phosphorylate CREB (transcription factor)

Front 25

What causes Kaposi's sarcoma? ... Which signal transduction pathway (receptor) is implicated in this disease? What is the direct result of this pathway somatick mutation?

Back 25

Human herpesvirus 8 (HHV8), which contains GPCR with constitutive activity --> leads to angiogenosis

Hint 25

None

Front 26

What clinical manifestations would arise from an HHV8 infected AIDS patient?

Back 26

stimulation of angiogenosis --> neoplasms with highly vascular multiple cell types in the skin , lungs and the GI tract (including mouth)

Hint 26

None

Front 27

In Kaposi's sarcoma, what two mechanisms is effected and as a result, what is released from the cells?

Back 27

HHV8 constitutively activates the G-protein coupled receptor signaling pathway --> which leads to secretion of VEGF

Hint 27

None

Front 28

Match the following: APL and CML… fusion of Bcr-to-ABL, PML-to-RAR… which requires a Flt3 mutation.

Back 28

APL: PML-RAR (requires Flt3 mutation)… CML: Bcr-ABL

Hint 28

None

Front 29

Name the receptor type: domains have a specific function

Back 29

NHR

Front 30

Name the receptor type: flt3

Back 30

receptor protein tyrosine kinase

Hint 30

None

Front 31

Name the receptor type: causes APL

Back 31

RAR:nuclear hormone receptor… and Flt3: receptor tyrosine kinase

Front 32

Name the receptor type: implicated in CML

Back 32

non-tyrosine kinase: Bcr-ABL

Hint 32

None

Front 33

Name the receptor type:Rx is retinoic acid

Back 33

PML-RAR: NHR

Front 34

Name the receptor type: Gleevec is used as a Rx

Back 34

ABL- non receptor kinase: Bcr-ABL philidelphia chromosome

Front 35

Name the receptor type: blocked with agonists, antagonists, inverse agonist

Back 35

NHR

Front 36

Name the receptor type:5-HT3

Back 36

ligand gated ion channel: serotonin

Front 37

Name the receptor type: 7 transmembrane receptor

Back 37

G-protein

Front 38

Name the receptor type: associated with scaffolds and signaling complexes

Back 38

receptor protein tyrosine kinase

Front 39

Name the receptor type: wide variety of activating signals

Back 39

g-protein

Front 40

Name the receptor type: activated by dimerization

Back 40

receptor protein tyrosine kinase… cytokine receptors, non-tyrosine kinase (src, Jak-STAT), ErbB2 (RTK example of heterodimers)

Hint 40

None

Front 41

Name the receptor type: receptor acts as GEF

Back 41

g-protein coupled receptor

Front 42

Name the receptor type: associated with ErbB2

Back 42

receptor protein tyrosine kinase

Front 43

How does ErbB2 activate

Back 43

dimerization

Front 44

What is the mechanism of action for Herceptin (ErbB2/Her2/neu?

Back 44

mAb-Her2 (for receptor)... down-regulation or cytoxic mediated

Hint 44

None

Front 45

What is the mechanism for Gleevec?

Back 45

blocks the binding of ATP to Bcr-ABL

Front 46

Name the receptor type: capable of autophosphorylation

Back 46

receptor protein tyrosine kinase

Front 47

Name the receptor type: utilizes the RAS MAP kinase pathway

Back 47

tyrosine and non-tyrosine kinase pathways, including cytokine receptors

Front 48

Name the receptor type: associated with proteolysis

Back 48

Notch signaling

Front 49

Name the receptor type: Jak-STAT and Src Kinase

Back 49

non-tyrosine kinase

Hint 49

None

Front 50

Name the receptor type: implicated in Acute lymphocytic leukemia (ALL)

Back 50

Non-receptor kinase: Bcr-ABL philidelphia chromosome

Hint 50

None

Front 51

What is the role of ABL in CML?

Back 51

influences cell cycle vs. apoptosis

Front 52

Which (ABL or Bcr) expresses src homology, DNA binding, and acting binding domains?

Back 52

ABL

Front 53

Which (ABL or Bcr) expresses kinase and dimerization domains (and GEF/GAP)?

Back 53

Bcr

Front 54

What is Ki-1 lymphoma caused by?

Back 54

fusion of NPM and ALK to produce a constitutively active protein

Front 55

What type of receptor is Ki-1 lymphoma?

Back 55

receptor protein tyrosine kinase

Hint 55

None

Front 56

What is Ki-1 lymphoma (the fusion of proteins NPM and Alk) an example of?

Back 56

bad scaffolding… thus it has abnormal distribution

Hint 56

None

Front 57

Match the functions of NPM and ALK: Oligodimerizes, kinase, found in the nucleus

Back 57

NPM: oligodimerizes + found in the nucleus… ALK: kinase

Front 58

Name the receptor type: associated with erbB2 and Ki-1 lymphoma (NPM-ALK)

Back 58

receptor protein tyrosine kinase

Front 59

Name the receptor type and name: EGFR, heterodimerizing, no known ligand,

Back 59

RTK, erbB2/HER2/neu

Front 60

Who are the candidates for Herceptin? What is the strategy?

Back 60

erbB2/HER2/neu… anti-mAB (which binds the receptor)

Hint 60

None

Front 61

What are the 5 strategies for blocking RTKs?

Back 61

1) bind ligand w/Ab… 2) soluble receptor… 3) block tyrosine kinase itself… 4) stimulate degradation of kinase… 5) block transcription factors

Front 62

what are the 2 proposed mechanisms of Herceptin?

Back 62

1) down regulates Her2/neu... 2) mAB works with cytoxic T-cells...

Hint 62

None

Front 63

What are the side effects of herceptin?

Back 63

cardiotoxicity

Front 64

Which chromosomes are Bcr and ABL found on?

Back 64

bcr=22… abl=9

Front 65

Which disease presents with high WBC, splengomegaly, fatigue and weight loss?

Back 65

CML… bcr-ABL

Front 66

Which translocation mutation leads to adhesion, mitogenesis, inhibition of apoptosis

Back 66

Bcr-ABL: Ph chr...

Hint 66

AIM stripped toothpaste

Front 67

What are possible causes of resistance to STI571? (Gleevec) Which is most likely?

Back 67

increased BCR-ABL, pumpls, point mutations so that it no longer fits in cleft… point mutation in pocket

Front 68

T/F: KSHV GPCR activate more than one signaling pathway

Back 68

True

Front 69

Name the 6 stages of angiogenesis

Back 69

1. Endothelial cell activation
2. Basement membrane degradation
3. Endothelial cell imigration
4. Invasion of the ECM
5. Endothelial cell proliferation
6. New capillary tube formation

Front 70

What 4 things can trigger angiogenesis?

Back 70

1. tumor hypoxia
2. oncogenes
3. cytokines
4. cell growth factors

Front 71

Give 5 reasons why angiogenesis is a good target for chemotherapy.

Back 71

1. Endothelial cells are not malignant
2. Tumors require blood supply
3. Blood vessel density = tumor aggressiveness
4. Angiogenesis inhibition causes tumor regression in mice
5. Many standard chemo-drugs have anti-angiogenic properties

Front 72

What are the two forms of Ab?

Back 72

Cell surface Ab and soluble target Ab

Front 73

Give 3 mechanisms used in antibody-based therapy.

Back 73

1. Ab-Toxin
2. Ab --> activates immune system
3. Alter cell signalling:
- remove growth factor for circulation
- Clearing receptor from the cell

Front 74

What type of toxicity is seen with Avastin? What is the mechanism of action for AV (BV)?

Back 74

1. hypertention (nominal GI perforation)
2. Human mAb directed at VEGF

Front 75

What is Avastin's (BV/AV) mechanism of action?

Back 75

Anti-VEGF mAb

Front 76

Name 4 anti-Angiogenic therapies in clinical trials.

Back 76

1. Endogenously occuring inhibitors: a) Agiostatin... b) Endostatin
2. Inhibition of pro-angiogenic factors: VEGF (Avastin = anti-VEGF mAB)
3. IL-12: upregulates antagonists of KSHV-GPCR.
4. Thalidomide

Front 77

What is the mechanism of pathology behing ErbB2/HER2/neu tumor models?

Back 77

Two hits:
1. Gene amplification --> protein overexpression
2. Transformed cells only occur when overexpression of ErbB2/HER2/neu is accompanied by other EGFR overexpression