New Cancer Therapies Flashcards
For lectures 1-4 make sure you go over the paper notecards
- JUST DO IT
When can surgery, chemotherapy, and radiation not be enough?
- For particularly aggressive, metastatic diseases
What types of differences do cancer therapies tend to exploit?
- MACRO differences
- E.g. proliferative rates, DNA synthesis rates, inefficient repair of damage
When do cancer treatments that exploit macro differences have a high therapeutic index?
- Genomic stability
- Rapid cell turnover (e.g. liquid tumors)
What are novel targets for cancer therapies?
- Signal transduction**
- Angiogenesis
- Evasion of apoptosis
- Immune tolerance
- Cell cycle dysregulatio n(harder)
- Tissue invasion and metastasis (harder)
Which are the best possible novel targets?
- Signal transduction
- Evasion of apoptosis
- Angiogenesis
- Immune tolerance
Signal transduction in tumors
- Aberrant signal transduction elements are present in most tumors
- Mutated signal proteins are often oncogenic
- Constitutive activation of signaling elements canc onfer autonomy
- Cell is getting turned on inappropriately
Aberrant expression of growth receptors in tumors relates to these two areas
- Increased potential for proliferation, invasion, and metastasis
- Increased angiogenesis
What are three outcomes changed by aberrant expression of growth receptors related to potential for proliferation/invasion/metastasis and angiogenesis?
- Shortened survival of patients
- Poor response to standard chemotherapy
- Poor prognosis
What are receptor tyrosine kinases?
- Main mediators of the signaling network that transmits extracellular signals into the cell
What do receptor tyrosine kinases control?
- Cellular differentiation and proliferation
How do RTKs relate to cancer?
- Constitutive RTK signaling –> dysregulated cell growth –> cancer
Three ways that RTKs can be altered to dysregulate cell growth?
- Overexpression
- Functional alterations caused by mutations in the corresponding genes (gain of function)
- Abnormal stimulation by autocrine growth factor loops and increased stimulation.
RTK homology
- Homology in the protein tyrosine kinase domain (intracytoplasmic)
- The outsides are quite different, but they often do very similar things inside of the cell
What are the three families targeted by tyrosine kinase inhibitors?
- EGFR-HER-2
- C-kit
- VEGFR
EGFR-HER-2 family
- Epidermal growth factor receptor
- TKR
C-kit family
- Proto-oncogene coding for an RTK
VEGFR family
- Vascular endothelial growth factor receptor
Which tumors contain C-kit mutations?
9-33% of MCTs
- Higher tumor grades associated with more frequent C-KIT mutations (30-50% of grade II/III MCTs contain mutations
What are the two primary RTK inhibitors?
- Toceranib
- Masitinib
Which RTK inhibitor is licensed in the US?
- Toceranib
Toceranib response and duration of response?
- Overall response in grade II tumors was 40%
- Duration was ~12 weeks
Side effects of toceranib and masitinib?
- GI and potential bone marrow suppression from both
How long are animals on toceranib and masitinib?
- Once started continue for life or until lack of effect
Other drugs that might respond to tyrosine kinase inhibitors?
- Thyroid carcinoma
- Anal gland adenocarcinoma
- With piroxicam
- Head and neck carcinomas
- Metastatic osteosarcoma
- OSA - post amputation, no help over traditional therapy
- HSA, soft tissue sarcoma
- Lymphoma, histiocytic SA
TKI and cats with vaccine associated fibrosarcoma?
- VAS cell line
- Inhibits PDGF-induced phosphorylation receptor
- Decreased cell proliferation and apoptosis
TKI and cats with squamous cell carcinoma
- Modest activity
What aspect of the metastasis cascade do anti-angiogenic agents impact?
- Establishment of new growth
Reminder: what are the five aspects of the metastasis cascade?
- Cell detachment and vascular invasion
- Transport and survival in circulation (evasion of host defense)
- Aggregation with platelets and fibrin and arrest in new location
- Extravasation into surrounding parenchyma
- Establishment of a new growth
At what point is tumor growth dependent on vascular growth and neovascularization?
- > 1 mm cubed
- Delivery of nutrients, growth factors, hormones, oxygen
- Removal of wastes and toxins
- Immune surveillance
Is tumor vasculature similar to normal vasculature?
What is the significance of this?
- No, they are quite different
- This is why tumor endothelium represents a valuable target for cancer therapy
VDAs - what are they and what do they do?
- Preferentially destroy ESTABLISHED tumor blood vasculature
- Vascular disrupting agents