molecular targeted therapy Flashcards
What is the first step in molecular/targeted therapeutics?
Interpret a molecular profile and identify potential targeted therapies.
What are the key components to evaluate for targeted therapies?
Mechanisms of action, target, resistance, and toxicities.
What is the mechanism of action (MOA) of small cell inhibitors?
Block ATP binding site on kinase, leading to reversible or irreversible competitive inhibition.
What happens when ATP is blocked in tumor cells?
No phosphorylation of itself or downstream targets, interrupting a survival/growth signal essential to the tumor cell, resulting in cell death.
What are the types of resistance observed in targeted therapies?
Intrinsic or induced by treatment, involving tumor and host-mediated pathways.
What potential effect can altering the host microenvironment have?
It can lead to metastatic conditioning.
What does Imatinib (Gleevec) target?
Binds the ATP pocket of ABL and the RTKs KIT and PDGFR-α.
What is the target of Vemurafenib (Zelboraf)?
Inhibits B-raf.
What does Rapamycin inhibit?
Inhibits mTOR.
What targets does Sunitinib (Sutent) inhibit?
VEGFR1/2, PDGFR-α/β, KIT, FLT3, CSFR1, and RET.
What are some toxicities associated with Toceranib (Palladia)?
Hypertension, proteinuria, GI upset, bleeding, myelosuppression, azotemia, anemia, lethargy, lameness, disruption of the hypothalamic–pituitary–thyroid axis.
What does Masitinib (MasiVet) inhibit?
Inhibits KIT, PDGFR-α/β, and Lyn.
What is the target of Verdinexor (Laverdia)?
Inhibits XPO-1.
What is Bevacizumab (Avastin)?
Humanized anti-VEGF.
What are some toxicities associated with Bevacizumab (Avastin)?
Hypertension, edema, hemorrhage, thromboembolism, proteinuria, intestinal perforation, impaired wound healing.
What does Trastuzumab target?
Anti-HER2 human Mab.
True or False: The incidence of sterile hemorrhagic cystitis (SHC) in dogs treated with MC cyclophosphamide is up to 34%.
True.
What is a good alternative to chlorambucil without the risk of SHC?
Chlorambucil is a good alternative.
What was the median overall survival with MC cyclophosphamide in an early trial?
178 days.
What was the median overall survival time for dogs receiving metronomic chemotherapy as found in the Wendelburg study?
3.4 months.
In dogs with HSA treated with splenectomy and DOX, did daily cyclophosphamide plus an NSAID improve PFS or OST?
No effect on PFS or OST.
What was the result of the study comparing piroxicam and cyclophosphamide with or without Palladia?
No improvement in median PFS or OST.
What adverse events occurred with the administration of lomustine at a daily oral dose of 2.84 mg/m2?
High incidence of adverse events led to discontinuation in nearly 30% of dogs.
What is the recommended dose of oral chlorambucil in metronomic protocols?
4 mg/m2/day.
What was discovered about chlorambucil when given at higher daily doses?
Increased gastrointestinal and bone marrow toxicities with no improvement in tumor response.
What were the findings regarding the combination of chlorambucil and lomustine?
Well tolerated with minimal adverse effects.
What combination therapy was found to be well tolerated but may not have sufficient duration to detect SHC or cardiotoxicity?
Concurrent MTD doxorubicin with MC cyclophosphamide.
What was the outcome of the study using 5 x 6 Gy for STS followed by metronomic chemotherapy?
Significant increase in OST compared to RT alone.
What did the study on palliative RT plus metronomic CCNU find?
CCNU was well tolerated but did not extend OST compared to palliative RT alone.
What were the immunologic effects of intratumoral electrogene therapy with IL-12 combined with metronomic cyclophosphamide?
Significant decrease in circulating Treg numbers.
What is metronomic chemotherapy dosing?
Chronic administration of chemotherapeutic agents at low doses.
What is the target of metronomic chemotherapy?
More slowly dividing endothelium.
What are the additional actions of metronomic chemotherapy?
Activation of antitumor immunity, induction of tumor dormancy, and inhibition of cancer stem cells.
What is the effect of metronomic therapy on angiogenesis?
Upregulation of thrombospondin-1 and downregulation of pro-angiogenic growth factors.
What happens to circulating endothelial progenitor cells with metronomic therapy?
Decreased with metronomic therapy.
What immunosuppressive cells suppress antitumor immune responses in cancer patients?
Treg and myeloid derived suppressor cells (MDSC).
What are the immunostimulatory effects associated with metronomic delivery of cyclophosphamide?
Decreases in Treg numbers and function, dendritic cell activation, stimulation of tumor-specific cytotoxic T cells.
What cell types are targeted by metronomic chemotherapy?
Cancer stem cells and dormant tumor cells.
