Lecture 5

Question 1

examples of “macro” differences in cancer cells vs normal cells

Answer 1

– Proliferative rates
– DNA synthesis rates
– Ineffecient repair of damage

Question 2

Possible novel targets of chemotherapeutics

Answer 2

– Signal transduction
– Angiogenesis
– Evasion of apoptosis
– Immune tolerance
– Cell Cycle dysregulation
– Tissue invasion and
metastasis

Question 3

Abberant expression of growth receptors and /or mutated signal transduction elements related to:

Answer 3

– potential for proliferation, invasion, metastasis
– angiogenesis
–Shortened survival of patients
–Poor response to standard chemotherapy
–Poor prognosis

Question 4

Main mediator of cell signaling (what surface protein?)

Answer 4

receptor tyrosine kinase

Question 5

Changes in receptor kinase proteins causes what 3 consequences?

Answer 5

–Overexpression of RTK protiens
–Functional alterations caused by mutations in the corresponding genes. Gain of function
–Abnormal stimulation by autocrine growth factor loops. Increased stimulation

Question 6

Primary targeted RTKs

Answer 6

–EGFR-HER-2 family (epidermal growth factor receptor)
–C-Kit (proto-oncogene coding for an RTK)
–VEGFR‘s (vascular endothelial growth factor receptor)

Question 7

Higher tumour grades associated with what mutation?

Answer 7

C-kit (esp MCTs)

Question 8

RTK treatments

Answer 8

–Toceranib phosphate (Palladia -Pfizer)
•Overall response in grade II tumors 42.8%
•Duration of response 12 weeks
–Masitinib (AB Science- Masivet or Kinavet)
•Better time to progression than placebo
•Not available in U.S. anymore

Question 9

Side effect of RTK treatments

Answer 9

–Significant GI and potential bone marrow suppression from both.

Question 10

Uses for RTKs

Answer 10

thyroid carcinoma, anal gland adenocarcinoma, maybe metastatic OSA

Question 11

importance of tumor blood vessels

Answer 11

–Delivery of nutrients, growth factors, hormones, oxygen
–Removal of wastes and toxins
–Immune surveliance

Question 12

Vascular disrupting

agents (VDAs) function how?

Answer 12

Preferentially destroy established tumor

blood vasculature

Question 13

Two methods of targeting tumor blood flow?

Answer 13

Vascular disrupting
agents (VDAs) and Supression of endothelial cell growth and
recruitment from bone marrow

Question 14

How to use agents that suppress endothelial growth?

Answer 14

– given continously

– Most useful when tumor burden is low

Question 15

two categories of drugs that target tumor vasculature

Answer 15

biologics and small molecules

Question 16

biologics as a drug that targets tumor vasculature

Answer 16

antibodies or peptides that deliver toxins and
procoagulant and pro-apoptotic effectors to tumor
endothelium
• VEGF often antigenic target (lots of others too)

Question 17

small molecules as a drug that targets tumor vasculature

Answer 17

agents that exploit known differences
between tumor and normal endothelium to induce severe
vascular dysfunction- often blocking receptors
• Thalidomide
• Toceranib

Question 18

strategies used in vetmed to block tumor angiogensis

Answer 18

– Toceranib
• Direct inhibitor of VEGF signaling
– Metronomic chemotherapy
• Low dose daily dosing of traditional drugs
• Theory- stop endothelial cells from multiplying in, and homing to
neoplastic tissues

Question 19

drugs used it meteronomic chemotherapy

Answer 19

Chlorambucil, cyclophosphamide, lomustine, satraplatin

Question 20

two pathways of apoptosis

Answer 20

• Intrinsic (mitochondrial)
– Affected by conventional therapies
– Mutations commonly occur rendering
tumors resistant to conventional
therapies
• Extrinsic (receptors)
– Novel therapies targeting here may
circumvent resistance

Question 21

Mechanism of immune tolerance by tumors

Answer 21

they are recognized as “self”

Question 22

3 mechanisms of mitigating immune tolerance by tumors

Answer 22

• Active Nonspecific immune stimulation
• Active Specific- Tumor vaccines
• Passive- Antibody administration

Question 23

goals of tumor vaccines

Answer 23

• Activate T-cells (↑ MHC on cell surface)

* Activate antigen presenting cellsvgfb0gtfr

Question 24

Why can targeting T cells be helpful in immune therapy

Answer 24

– Destroy immunosuppressive
environment around the tumor
– May use conventional drugs
• Metronomic chemo
• Cimetidine

Question 25

Why is gene therapy promising in treating cancer

Answer 25

– Correct the genetics of the tumor- e.g.inhibit
oncogenes, stimulate/replace tumor suppressor
genes
– Stimulate cytokine production
– Limitations- transduction efficiency

Question 26

how does PGE play a role in cancer development?

Answer 26

– Conversion of pro-carcinogens to
carcinogens
– Stimulation of tumor cell growth
– Prevention of apoptotic cell
death
– Promotion of angiogenesis
– Immune suppression