Chapter 320 - Molecular targeted therapy

Question 1

What is molecular targeted therapy?

Answer 1

An innovative approach targeting specific molecules to cause functional changes, primarily used in anticancer therapy. It involves two major drug types: small molecules and antibodies.

Question 2

What are the two major types of molecular targeted therapy drugs?

Answer 2

1. Small molecules: Act on cell membrane surface proteins and intracytoplasmic/intranuclear targets
2. Antibodies: Primarily act on cell membrane surface proteins

Question 3

What is Toceranib (TOC) and its primary mechanism of action?

Answer 3

• An orally administered multikinase inhibitor for dogs that acts on multiple receptor tyrosine kinases (RTKs), including KIT, VEGFR2, and PDGFR beta.
• It inhibits cancer signaling and controls angiogenesis.

Question 4

What are the common adverse events associated with Toceranib in dogs?

Answer 4

1. Gastrointestinal toxicosis (anorexia, weight loss, nausea, vomiting, diarrhea)
2. Myelotoxicosis (neutropenia, thrombocytopenia)
3. Musculoskeletal disorders (myalgia, lameness)

Question 5

What types of tumors respond directly to Toceranib in dogs?

Answer 5

1. Mast cell tumors (MCTs)
2. Gastrointestinal stromal tumors (GISTs)
   Particularly effective for MCTs with c-KIT mutations.

Question 6

What is the significance of c-KIT mutations in canine mast cell tumors?

Answer 6

• C-KIT mutations are found in 8-45% of canine MCTs, with higher rates in highly malignant tumors.
• Tumors with these mutations show a better response rate to Toceranib (approximately 69% vs. 37% in mutation-negative tumors).

Question 7

How is Toceranib used in combination with other therapies?

Answer 7

It can be safely combined with:
* Prednisone
* NSAIDs
* Metronomic chemotherapy (including low-dose cyclophosphamide)

Question 8

What is the application of Toceranib in cats?

Answer 8

• Used at similar doses to dogs
• Effective for mast cell tumors, with some potential in oral squamous cell carcinoma.
• Adverse events include GI issues, thrombocytopenia, and hepatotoxicosis.

Question 9

What is Imatinib and its use in veterinary medicine?

Answer 9

An RTK inhibitor originally developed for human chronic myeloid leukemia, used to treat mast cell tumors and gastrointestinal stromal tumors

Question 10

What is Masitinib (MAS)?

Answer 10

An RTK inhibitor marketed in Europe to treat unresectable Patnaik grade 2 or 3 canine mast cell tumors.

Question 11

What is Verdinexor and its primary mechanism?

Answer 11

A selective nuclear export inhibitor that blocks exportin1 (XPO1), preventing the transport of tumor suppressors and growth regulatory proteins from the nucleus.

Question 12

What were the results of Verdinexor in lymphoma treatment of 58 dogs?

Answer 12

Overall response rate: 37%
T-cell lymphoma response rate: 71%

Question 13

What is the significance of c-KIT mutation locations in canine mast cell tumors?

Answer 13

• Mutations are commonly found in exons 11, 8, and 9.
• Internal tandem duplications (ITD) in exon 11 are associated with high recurrence and metastasis,
• ITD mutations in exon 8 may indicate possible long-term survival.

Question 14

What is the mechanism of action for molecular targeted therapy drugs?

Answer 14

• Small molecules act on surface and internal cellular protein targets
• Antibodies primarily target cell membrane surface proteins.
• They aim to disrupt specific molecular pathways involved in cancer progression.

Question 15

What uncommon adverse events are associated with Toceranib?

Answer 15

• Neutropenia
• Lameness (usually acute and reversible)
• Depigmentation
• Hypertension
• Hypothyroidism with prolonged use