Signal Transduction Inhibition Flashcards
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
What’s the most common hematologic and serum biochemistry changes for cats on Palladia?
- anemia (14.5%) and thrombocytopenia (7.2%)
- ALT (7.2%) and azotemia (14.5%)
What’s the outcome of Palladia for feline MCT?
- Clinical benefit 80% (40/50); 86% (19/22) with cutaneous, 80% (8/10) with visceral and 76% (13/17) with GI involvement
- Median duration of treatment in cats experiencing clinical benefit was 36 weeks, 48 weeks and 23 weeks for cutaneous, visceral and GI cases.
- 60% (30/50) of cats experienced adverse events. Majority low-grade (grade 1 or 2) GI or hematologic events that resolved with treatment break and/or dose adjustment
What’s the response of Palladia for feline oral SCC?
BOR: 56.5%
MST = 123 days
What’s the response of Palladia for FISS?
no measurable response
What are the targets of masitinib?
PDGFR, kit, Lyn
What’s the response of masitinib for canine MCT?
- 12.5mg/kg PO daily
- kit mutation was not prognostic
- increased TTP from 75 days (placebo) to 118 days
What’s the response of masitinib for non-resectable canine MCT?
RR: 50-82%
MST: 617-630 days for responders
M TTP: 79 days, MST 159 days (2016 study)
What’s the response of masitinib for canine epitheliotropic LSA?
CR 2/10 dogs for median 85 days
PR 5/10 dogs for median 60.5 days
KIT receptor was negative
What’s the outcome for masitinib for canine stage III/IV malignant melnoma?
Only mild effectiveness in end-stage disease; not an appropriate single agent option for treatment of advanced malignant melanoma in dogs
What’s the target for vemurafenib?
V600E MUtated bRAF INhIBition
Amino acid position number 600 on the B-Raf protein, the normalvaline is replaced byglutamic acid
How does vemurafenib promote tumour growth?
paradoxical stimulation of normal BRAF in tumours without mutations
Which canine cancer could be a good candidate for vemurafenib?
iUC
Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer–Evidence for a Relevant Model System and Urine-Based Diagnostic Test
How common is the BRAF mutation in canine iUC?
87%
What’s the % of BRAF mutation detection in canine urine with CADET BRAF test?
83% in iUC and prostatic carcinoma patients
What can CADET BRAF PLUS detect?
copy number imbalance in canine iUC (copy number aberrations, CNAs)
CNAs were detected in 67% (12 of 18) of urine DNA specimens derived from UC patients
CADETBRAFmust be run first to determinethe suitability of the specimen for CADETBRAF-PLUS, since not all samples submitted are suitable for CADETBRAF-PLUS. Suitability of aspecimen for CADETBRAF-PLUSis indicated in all CADETBRAFreports
What are the targets of imatinib?
kit, Abl, PDGFR
How is Palladia metabolized?
by the liver,
it’s also highly protein bound
How is Palladia elimnated?
90% of metabolites are excreted in feces, 10% in the urine
What are the most common side effects of Palladia and MasiVet?
diarrhea, vomiting, hyporexia
GI bleeding = less common
What’s the labelled dose for Palladia in dogs and cats?
dogs = 3.25mg/kg EOD
cats: 2.7mg/kg MWF
What’s the recommended dose of masitinib for dogs?
12.5mg;kg PO q24h, reduce to 9mg/kg if there are unacceptable toxicities
