Novel Targets in Cancer Therapy and Cancer Therapy Resistance Flashcards
What are the major side effects of cancer therapies that target rapidly growing cells?
1) Gut lining-mucositis
2) Bone marrow-myelosuppression
3) Hair follicles-alopecia
Define oncogene.
A gene that normally directs cell growth.
- If altered, an oncogene can promote or allow the uncontrolled growth of cancer
What is a tumor suppressor gene?
Tumor suppressor genes are normal genes which are lost or altered and cause malignancy (recessive mutations)
- Tumor suppressor genes cooperate with oncogenes in carcinogenesis.
What is imatinib mesylate (Gleevec)?
[2nd generation drugs nilotinib and dasatinib]
Gleevec is a tyrosine kinase inhibitor of Bcr-Abl fusion protein in CML (chronic myelogenous leukemia)
- Blocks phosphorylation of downstream protein targets.
- Also inhibits platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit (in gastrointestinal stromal tumors).
Describe the kinetics of Gleevec/ imatinib mesylate.
Orally well absorbed with hepatic (CYP3A4) metabolism.
What is the major adverse drug reaction of imatinib mesylate?
Cardiac toxicity.
What interactions should be considered in patients taking imatinib mesylate?
Cyp inhibitors CYP3A4
What is Trastuzumab (Herceptin)?
Trastuzumab is an antibody that has single agent activity in advanced estrogen resistant breast cancers
- when combined with chemotherapy enhanced clinical responses are observed.
What is the mechanism of action of trastuzumab?
Trastuzumab recognizes the Her2/neu receptor and blocks it so growth factor cannot bind.
- Her-2/neu receptor is over-expressed in a subset of poor prognosis breast cancers.
Describe the kinetics of trastuzumab.
Median half-life of 5.8 days after a 4mg/kg of body weight loading dosage. (given IV)
What major adverse drug reactions is associated with trastuzumab?
Cardiac toxicity and dyspnea.
What major interaction should be considered in patients on trastuzumab?
Possible allergic reaction
What is the importance of the EGFR pathway in lung cancer?
In lung cancers a subset of patients have an activating mutation of the EGFR which sensitizes them to EGFR inhibitors
- EGFR pathway can be blocked by receptor specific antibodies (e.g. Cetuximab and Panitumumab) or by small molecule tyrosine kinase inhibitors (Erlotinib and Gefitinib)
To what drug class does Erlotinib belong?
Small molecule epidermal growth factor receptor (EGFR) inhibitor.
- Active against lung and pancreatic cancers.
What is the mechanism of action of Eroltinib?
Inhibits kinase activity of this receptor and is active against lung cancers having kinase domain activating mutations.
Describe the kinetics of Eroltinib.
- Well absorbed orally and half-life is about 36 hours.
- Hepatic (Cyp3A4) and biliary metabolism.
What major adverse drug reactions are associated with Eroltinib?
Rash, diarrhea, and dyspnea.
What interactions should be considered in patients on Erlotinib?
Smoking and Cyp3A4 inhibitors
What are the advantages of anti-angiogenic factors?
1) Resistance is infrequent (normal vascular cells are targeted)
2) Activity does not depend on tumor cell targeting
3) Chronic therapy could prevent vascularization of tumors
What is Bevacizumab (Avastin) and what is it used for?
- Bevacizumab recognizes vascular endothelial growth factor (VEGF) and blocks its angiogenic activity.
- Used to treat colon and lung cancers and has shown some use for macular degeneration and retinal diseases
To what class does Bevacizumab (Avastin) belong?
Anti-vascular endothelial growth factor antibody (VEGF, humanized monoclonal).
What is the action of bevacizumab?
Blocks the angiogenic actions of VEGF in colon and lung cancers.
What are the adverse side effects of bevacizumab?
Bleeding, allergic reactions, wound healing, and GI perforation.
What are the major drug interactions with bevacizumab?
Possible allergic reactions
What is vemurafenib?
Vemurafenib is a first-in-class selective inhibitor of the BRAF serine-threonine kinase, used for the treatment of metastatic melanoma harboring activating BRAF mutations
To what drug class does vemurafenib belong?
Protein kinase inhibitor
What is the mechanism of action for vemurafenib?
Specifically targets metastatic melanoma with the V600E B-Raf mutation
Describe the kinetics of vemurafenib.
hour half-life, majority liver excreted
What are the major adverse drug reactions of vemurafenib?
arthralgia, skin rash, photosensitivity
What are the major drug interactions to be considered with patients on vemurafenib?
CYP3A4 substrate
What are the mechanisms of pharmacokinetic cancer therapy resistance?
Pharmacokinetic (extracellular)= systemic or tumor mass level
- Poor absorption
- Increased systemic catabolism
- Rapid drug clearance
- Poor tumor vascularity
- Anatomic sanctuaries = testes, brain
What are the mechanisms of cytokinetic cancer therapy resistance?
Cytokinetic = growth rate based
- Tumor is in inappropriate phase of cell cycle for specific drug
- Low growth fraction
What are the mechanisms of cellular resistance to cancer therapy?
Cellular Resistance (cellular) = changes to tumor cells
- E.g. gene amplification or overexpression, chromosome rearrangements, point mutations, epigenetic changes in chromatin.
- Hallmark = Increased Genomic Instability
What occurs with the over expression of p-glycoprotein?
Overexpression of P-glycoprotein causes enhanced efflux of many drugs including:
- Vinca alkaloids, antracyclines, taxanes, etoposide, teniposide, camptothecins, imatinib mesylate, and mitoxantrone
How does decreased topoisomerase II lead to cancer therapy resistance?
Decreased expression of topoisomerase II (Topo II):
- DNA intercalating agents like doxorubicin and etoposide, exert their cyctocidal activity by interacting with Topo II leading to DNA breaks.
How does increased DNA repair lead to cancer therapy resistance?
Increased repair of DNA: responsible for resistance to several cancer drugs, most alkylating agents and cisplatin.
How does glutathione-S-transferase induction lead to cancer therapy resistance?
Glutathione-S-transferase induction (GST) catalyzes conjugation of electrophilic compounds to glutathione (GSH).
- Enhances conjugate detoxification and elimination.
- GST substrates include cisplatin, the anthracyclines and alkylating agents.
What are strategies to circumvent cancer drug resistance (6)?
1) Collateral sensitivity is when resistance to one drug results in biochemical changes that make the cell more sensitive to a second drug.
2) Combination therapy with non-cross-resistant drugs
3) Dose escalation with or without bone marrow transplant
4) Constant infusion
5) Adjuvant therapy
6) Early detection and treatment of malignancy before resistance develops
