Lecture 5 Flashcards
examples of “macro” differences in cancer cells vs normal cells
– Proliferative rates
– DNA synthesis rates
– Ineffecient repair of damage
Possible novel targets of chemotherapeutics
– Signal transduction – Angiogenesis – Evasion of apoptosis – Immune tolerance – Cell Cycle dysregulation – Tissue invasion and metastasis
Abberant expression of growth receptors and /or mutated signal transduction elements related to:
– potential for proliferation, invasion, metastasis – angiogenesis –Shortened survival of patients –Poor response to standard chemotherapy –Poor prognosis
Main mediator of cell signaling (what surface protein?)
receptor tyrosine kinase
Changes in receptor kinase proteins causes what 3 consequences?
–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
Primary targeted RTKs
–EGFR-HER-2 family (epidermal growth factor receptor)
–C-Kit (proto-oncogene coding for an RTK)
–VEGFR‘s (vascular endothelial growth factor receptor)
Higher tumour grades associated with what mutation?
C-kit (esp MCTs)
RTK treatments
–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
Side effect of RTK treatments
–Significant GI and potential bone marrow suppression from both.
Uses for RTKs
thyroid carcinoma, anal gland adenocarcinoma, maybe metastatic OSA
importance of tumor blood vessels
–Delivery of nutrients, growth factors, hormones, oxygen
–Removal of wastes and toxins
–Immune surveliance
Vascular disrupting
agents (VDAs) function how?
Preferentially destroy established tumor
blood vasculature
Two methods of targeting tumor blood flow?
Vascular disrupting
agents (VDAs) and Supression of endothelial cell growth and
recruitment from bone marrow
How to use agents that suppress endothelial growth?
– given continously
– Most useful when tumor burden is low
two categories of drugs that target tumor vasculature
biologics and small molecules
biologics as a drug that targets tumor vasculature
antibodies or peptides that deliver toxins and
procoagulant and pro-apoptotic effectors to tumor
endothelium
• VEGF often antigenic target (lots of others too)
small molecules as a drug that targets tumor vasculature
agents that exploit known differences
between tumor and normal endothelium to induce severe
vascular dysfunction- often blocking receptors
• Thalidomide
• Toceranib
strategies used in vetmed to block tumor angiogensis
– 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
drugs used it meteronomic chemotherapy
Chlorambucil, cyclophosphamide, lomustine, satraplatin
two pathways of apoptosis
• Intrinsic (mitochondrial) – Affected by conventional therapies – Mutations commonly occur rendering tumors resistant to conventional therapies • Extrinsic (receptors) – Novel therapies targeting here may circumvent resistance
Mechanism of immune tolerance by tumors
they are recognized as “self”
3 mechanisms of mitigating immune tolerance by tumors
- Active Nonspecific immune stimulation
- Active Specific- Tumor vaccines
- Passive- Antibody administration
goals of tumor vaccines
- Activate T-cells (↑ MHC on cell surface)
* Activate antigen presenting cellsvgfb0gtfr
Why can targeting T cells be helpful in immune therapy
– Destroy immunosuppressive environment around the tumor – May use conventional drugs • Metronomic chemo • Cimetidine
Why is gene therapy promising in treating cancer
– Correct the genetics of the tumor- e.g.inhibit
oncogenes, stimulate/replace tumor suppressor
genes
– Stimulate cytokine production
– Limitations- transduction efficiency
how does PGE play a role in cancer development?
– Conversion of pro-carcinogens to carcinogens – Stimulation of tumor cell growth – Prevention of apoptotic cell death – Promotion of angiogenesis – Immune suppression
