Small Molecule Inhibitors Flashcards
What is a proposed mechanism of the GI upset seen with palladia?
inhibition of the kit protein on the interstitial cells of cajal, causing intestinal hypomotility
Masitinib blocks the following receptor(s):
i. VEGFR ii. FLT-3 iii. KIT iv. PDGFR v. RET
a. i, ii, iii
b. iii, iv
c. ii, iv, v
d. i, iv, v
e. iii, iv, v
B (Kit, PDGFR)
Based on a clinical trial, what is the overall biological response to Palladia for dogs with non-resectable grade 2 and 3 mast cell tumors?
a. 45%
b. 50%
c. 55%
d. 60%
e. 65%
D (60%)
London, Cheryl A., et al. “Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision.” Clinical Cancer Research 15.11 (2009): 3856-3865.
Which of the following is TRUE regarding toceranib phosphate (Palladia)?
a. Palladia is an irreversible competitive inhibitor of stem cell factor binding
b. Palladia blocks VEGFR2, PDGFR, and KIT only
c. Palladia is most closely associated with bevacuzimab
d. Palladia binds to a intracellular binding site
e. Palladia is a prodrug
D (binds to intracellular site)
a) Palladia is a reversible competitive inhibitor of ATP binding; b) Palladia has a broad spectrum of activity to approx. 500 human tyrosine kinases; c) most closely associated with sunitinib; e) not a prodrug.
What is the reported response rate to Palladia for canine mast cell tumors with KIT mutations?
a. 37%
b. 55%
c. 61%
d. 69%
e. 74%
D (69%)
According to London et al, the reported response rate for MCT with KIT mutations was 69%, compared to 37% for MCT without KIT mutations.
Which of the following is TRUE regarding the combination of Palladia and radiation therapy for canine non-resectable mast cell tumors?
a. Palladia was administered at 3.25mg/kg EOD during radiation therapy.
b. Radiation-induced toxicities were more commonly seen in Palladia-treated dogs than patients receiving radiation alone.
c. The median survival time was 2.6 years.
d. Patients received a treatment regimen of 8 Gy once weekly for 4 weeks.
e. An objective response was noted in approximately three-quarters of dogs.
E (response in about 75%)
Carlsten KS, London CA, Haney S, et al. Multicenter prospective trial of hypo- fractionated radiation treatment, toceranib, and prednisone for measurable canine mast cell tumors. J Vet Intern Med 2012;26:135–41.
Explanation: a) Palladia was administered at 2.75mg/kg MWF, starting 1 week prior to therapy. b) This was not a controlled trial, however radiation-induced toxicity did not appear heightened with Palladia administration. c) The MST was not reached; the median follow-up time was 374 days. The median PFI was 316 days. d) Patients received 6 Gy once weekly for 4 weeks.
Which small molecule inhibitor was shown to enhance doxorubicin sensitivity in canine and human OSA cell in vitro and in vivo?
a. Bortezomib
b. Valproic acid
c. KPT-335
d. Crizotinib
e. Vemurafenib
B (valproic acid)
Wittenburg LA, Gustafson DL, Thamm DH. Phase I pharmacokinetic and phar- macodynamic evaluation of combined valproic acid/doxorubicin treatment in dogs with spontaneous cancer. Clin Cancer Res 2010;16:4832–42.
Explanation: Valproic acid is an AED that is also a HDAC inhibitor. A phase I clinical trial showed it was well-tolerated when administered prior to doxorubicin chemotherapy and did not potentiate doxorubicin-induced myelosuppression. Histone hyperacetylation was noted in tumor and peripheral blood mononuclear cells. The objective response rate was 23.8% with an additional equal amount achieving SD.
Of the examples listed below, identify the most correct answer for the tumor type and the protein mutation that has been identified to occur in canine caners.
a. Gastrointestinal stromal tumor and EGFR point mutations
b. Canine osteosarcoma and MET and HGF
c. Canine hemangiosarcoma and BCR-ABL fusion protein
d. Canine mast cell tumor and point mutation BRAF
B (OSA, MET, HGF)
Based on a case study in which 1 dog underwent almost complete disease regression, a case study in which one dog had a partial response, as well as a phase I clinical trial in 57 dogs, which tumor types has Palladia been reported to have biological activity (off label) against?
i. Hemangiosarcoma
ii. Lymphangiosarcoma
iii. Monocytic Leukemia
iv. Metastatic osteosarcoma
v. Multiple myeloma
a. i, iii, v
b. ii, iii, v
c. i, v
d. i, ii, iii, iv, v
D (all of them)
- London C, Mathie T, Stingle N, et al. Preliminary evidence for biological activity of toceranib phosphate (Palladia) in solid tumors. Vet Comp Oncol 2012; 10:194-205
- Marcinowska A, Warland J, Brearley M, et al. A novel approach to treatment of lymphangiosarcoma in a boxer dog. J Small Animal Pract 2013:54:334-7
- Perez ML, Culver S, Owen JL, et al. Partial cytogenetic response with toceranib and prenisone treatment in a yound dog with chronic monocytic leukemia. Anticancer drugs 2013; 24: 1098-103
Identify the most correct answer in regards to the mechanisms of drug resistance associated with imatinib treatment in humans.
a. The primary cause for relapse is the development of point mutations in the protein that often prevents imatinib binding
b. Down-regulation of BCR-ABL mRNA, resulting in protein under expression
c. Decreased p-glycoprotein expression and with decreased multidrug efflux
d. Amplification of the gene encoding MET, which upregulates MET protein expression
A (point mutations that alter binding)
a. Explanation: upregulation of BCR-ABL mRNA, resulting in protein over expression that overwhelms the ability of imatinib to block function actually occurs; elevated
p-glycoprotein expression and with enhanced multidrug efflux actually occurs; Amplification of the gene encoding MET, which upregulates MET protein expression actually occurs with the drug erlotinib as it is and EGFR inhibitor
Which of the following targets are shared by toceranib and masitinib?
i. VEGFR
ii. PDGFR
iii. KIT
iv. Lyn
v. Flt3
A. i, ii, iii
B. ii, iii
C. i, iii, iv
D. ii, iii, v
B (KIT, PDGFR)
KIT and PDGFR are the two shared targets by toceranib and masitinib
Toceranib targets and blocks VEGFR, PDGFRβ, KIT, and FLT3.
Masitinib targets and blocks PDGFR, KIT, and Lyn (cytoplasmic).
What is the approximate response rate observed with masitinib for canine mast cell tumors in the face of gross disease?
A. 25%
B. 40%
C. 50%
D. 75%
C (50%)
Smrkovski et al. Masitinib mesylate for metastatic and non-resectable K9 MCTs. VCO (2013)
26 dogs were included in the study and some of them failed previous therapies. The median survival time for responders was 630 days (vs 137d for no responders).
What is the approximate objective response rate of canine mast cell tumors treated with toceranib and vinblastine in combination?
A. 50%
B. 60%
C. 70%
D. 80%
C (70%)
Robat et al. Safety evaluation of VBL combined with Palladia: A phase 1 dose-finding study. VCO (2012). Palladia was given at a dose of 3.25mg/kg EOD and the MDT of VLB was determined to be 1.6mg/m2.
In a phase I clinical trial, 57 dogs with a variety of tumor types received Palladia. What was the overall biological response rate?
A. 9%
B. 22%
C. 31%
D. 54%
D (54%)
London CA, Hannah AL, Zadovoskaya R, et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res 2003;9:2755–68.
Although Palladia is labeled for treatment of mast cell tumors in dogs, later studies have shown effectiveness against a variety of other canine tumors. This includes which of the following?
i. nasal adenocarcinomas
ii. high grade soft tissue sarcomas
iii. thyroid carcinomas
iv. cutaneous lymphoma
v. anal gland adenocarcinoma
A. i, ii, v
B. i, iii, v
C. ii, iii, iv
D. iii, iv, v
B. (nasal adeno, thyroid, anal gland)
London C, Mathie T, Stingle N, et al. Preliminary evidence for biologic activity of toceranib phosphate (Palladia) in solid tumours. Vet Comp Oncol 2012;10:194–205.
