Signal Transduction Inhibition Flashcards
(46 cards)
Describe the MAPK pathway.
Serine/threonine kinase
activation –> grab2/SOS –> RAS –> RAF –> phosphorylate MEK, which then phosphorylate ERK
- phosphorylated ERK can go into the nucleus –> promotes transcription
Which canine tumour is known to have a mutation in the MAPK pathway?
iUC: b-raf V595E
oral SCC: H-ras (18%)
pulmonary carcinoma: K-ras or N-ras (17%)
Describe the PI3K pathway.
Starts with ligand + G protien coupled receptor –> PIP2 to PIP3 –> Akt/Pkb –> mTOR –> growth and proliferation
How does RTK-induced signaling effect the cell cycle?
MYC promotes cyclin D/CDK4,6 –> inhibits Rb –> releases E2F –> G1/S (R point) transition
How can RTKs be dysregulated in cancer?
- mutation (activation in the absence of the appropriate ligand): Point mutation (BRAF V600E), deletion, ITD (KIT)
- overexpression (spontaneous dimerization)
- fusion proteins (ex. BCR/ABL)
- autocrine loops (produces both RTK and GF): OSA - MET and HGF; HSA KIT and SCF
What are 3 effects of monoclonal antibodies on signal transduction?
- Prevent GF binding
- Promote internalization of RTK and degradation
- Induce Immune response against cancer cell
What are the 2 types of inhibition by small molecule inhibitors on signal transduction?
- Competitive inhibition – blocking the ATP binding site of the kinases
- Allosteric inhibition – preventing protein-protein interactions
What’s the primary TKI used for CML (BCR/ABL)?
Imatinib
What’s the Raleigh chromosome? Philadelphia chromosome
Raleigh chromosome (in dogs): chromosome 9 and 26
Philadelphia chromosome (in people): chromosome 9 and 22
What’s a specific toxicity of imatinib in dogs?
hepatoxicity
What are some indication of imatinib in dogs?
- MCT 10mg/kg PO daily, 48% RR
also case reports with GIST and meningioma (with hydroxyurea)
What’s the dose of imatinib for cats?
also10mg/kg PO daily
- minimal GI signs
- Systemic mastocytosis with ITD at exon 8 had a favorable response to imatinib within 5 weeks
What are the split kinases targeted by toceranib?
VEGFR, PDGFR, KIT, FLT3
What are some side effects of Pallaida?
- can increase TSH, but none of the dogs were clinically hypothyroid
- hypertension
- proteinuria
What’s the MTD for chemo when combined with Palladia?
Palladia @ 2.75mg/kg PO EOD; all DLT = neutropenia
- CCNU: MTD = 50mg/m2 q3w.
- Carboplatin: MTD = 200mg/m2 q3w.
- Doxorubicin: MTD = 25mg/m2 q3w.
- Vinblastine: 1.6mg/m2 q2w, with 3.25mg/kg Palladia. Though DI for vinblastine is <50%, still have 77% RR
- Piroxicam: safe at standard dose. Dose reduce if there are GI signs
What’s the outcome of Palladia for canine GIST?
- 77% biological response
- Median PFI in dogs with gross disease 110 weeks
- Median PFI in dogs with microscopic disease 67 weeks
- Metastasis at diagnosis and high mitotic index were associated with shorter PFI
What’s the outcome of Palladia with stage 4 AGASACA?
median PFI = 354 days
MST = 532 days
What’s the outcome of Palladia with iUC?
mostly stable disease with TTP of 96 days, MST of 149 days
What’s the outcome of Palladia with chemodectoma?
RR 10% and MST was 823 days
if met present, 28.5% and MST 532 days
What’s the outcome of Palladia with pheochromocytoma?
1 CR, 4 SD.
PFI for PR was 61 weeks, SD no mets 28 and 36 weeks, SD with mets 11 and 18 weeks
What’s the outcome of Palladia with insulinoma?
1 case report surviving 24m
What’s the outcome of Palladia with HCC?
- 6 dogs; PR in 3 dogs, SD in 1 dog
- ALT and ALKP decreased in the cases sensitive to treatment and remained high in resistant cases
What’s the outcome of Palladia with OSA used in a sequential manner after carboplatin?
no improvement noted
Addition of toceranib/piroxicam/cyclophosphamide metronomic therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA
What’s the outcome of Palladia with HSA after doxorubicin?
no improvement in PFI or MST for stag I/II HSA
