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11 Apr 2012

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1. Wnt/B-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of
the mutant kinas BRAFv600E in human melanoma
Wnt/B-catenin signaling pathway linked to melanoma pathogenesis and patient
BRAF signaling constitutively activated by BRAFv600E mutation, inhibits Wnt/B-
catenin signaling in human melanoma cells
B-catenin required for PLX4720-induced apoptosis of melanoma
Activation of Wnt-B-catenin signaling synergyzed with PLX4720 decreased tumor
growth, increased apoptosis
Apoptosis: decresed B-catenin, AXIN1
AXIN1 mediator, not marker of apoptosis
Wnt/B-catenin signaling, AXIN1 regulate efficacy of inhibitors of BRAFv600E
Manipulation of Wnt/B-catenin pathway can be combined with BRAF inhibitors to
treat melanoma
2. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF mutant
Tumors dependent on RAF/MEK/ERK pathway. Inhibiting BRAF kinase to benefit
melanoma patients.
PLX4032 inhibitor of BRAF kinase activity
a. Selectively inhibits RAF/MEK/ERK pathway
b. Inhibits ERK phosphorylation, but no tumor regression
c. Increased drug inhibited ERK phosphorylation, but also a positive clinical
response (tumor regression)
BRAF mutated melamonas depend on BRAF kinase activity
PLX4032 demonstrated dose-dependent inhibition of tumor growth with higher
exposure tumor regression
3. Synthetic lethal screen of an EGFR-centered network to improve targeted therapies
Cellular resistanece factors limit efficacy of targeted cancer therapy.
Synthetic lethal screen genes linked to their targets enriched for drug resistance
Develop protein network no EGFR, use siRNA screening to prove for proteins that
regulate effectiveness of EGFR targeted agents and nonspecific cytotoxic agents
Drug targeting proteins in EGFR network synergies with EGFR antagonists reduce
cell viability and tumor size
4. FZD7 has a critical role in cell proliferation in triple negative breast cancer
Breast cancer is heterogeneous
TNBC acks benefit from targeted therapy
Overexpression of Wnt pathway genes in TNBC (e.g. FZD7)
Use of FZD7 shRNA knock down FZD7 expression, decreases proliferation,
invasiveness, colony formation
Silencing of canonical Wnt signaling pathways, loss of accumulated B-catenin,
decreased transcription of TCF7
FZDshRNA inhibited tumor formation through decreased proliferation
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