Novel Targets in Cancer Therapy and Cancer Therapy Resistance

Question 1

What are the major side effects of cancer therapies that target rapidly growing cells?

Answer 1

1) Gut lining-mucositis
2) Bone marrow-myelosuppression
3) Hair follicles-alopecia

Question 2

Define oncogene.

Answer 2

A gene that normally directs cell growth.

- If altered, an oncogene can promote or allow the uncontrolled growth of cancer

Question 3

What is a tumor suppressor gene?

Answer 3

Tumor suppressor genes are normal genes which are lost or altered and cause malignancy (recessive mutations)
- Tumor suppressor genes cooperate with oncogenes in carcinogenesis.

Question 4

What is imatinib mesylate (Gleevec)?

[2nd generation drugs nilotinib and dasatinib]

Answer 4

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).

Question 5

Describe the kinetics of Gleevec/ imatinib mesylate.

Answer 5

Orally well absorbed with hepatic (CYP3A4) metabolism.

Question 6

What is the major adverse drug reaction of imatinib mesylate?

Answer 6

Cardiac toxicity.

Question 7

What interactions should be considered in patients taking imatinib mesylate?

Answer 7

Cyp inhibitors CYP3A4

Question 8

What is Trastuzumab (Herceptin)?

Answer 8

Trastuzumab is an antibody that has single agent activity in advanced estrogen resistant breast cancers
- when combined with chemotherapy enhanced clinical responses are observed.

Question 9

What is the mechanism of action of trastuzumab?

Answer 9

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.

Question 10

Describe the kinetics of trastuzumab.

Answer 10

Median half-life of 5.8 days after a 4mg/kg of body weight loading dosage. (given IV)

Question 11

What major adverse drug reactions is associated with trastuzumab?

Answer 11

Cardiac toxicity and dyspnea.

Question 12

What major interaction should be considered in patients on trastuzumab?

Answer 12

Possible allergic reaction

Question 13

What is the importance of the EGFR pathway in lung cancer?

Answer 13

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)

Question 14

To what drug class does Erlotinib belong?

Answer 14

Small molecule epidermal growth factor receptor (EGFR) inhibitor.
- Active against lung and pancreatic cancers.

Question 15

What is the mechanism of action of Eroltinib?

Answer 15

Inhibits kinase activity of this receptor and is active against lung cancers having kinase domain activating mutations.

Question 16

Describe the kinetics of Eroltinib.

Answer 16

• Well absorbed orally and half-life is about 36 hours.

- Hepatic (Cyp3A4) and biliary metabolism.

Question 17

What major adverse drug reactions are associated with Eroltinib?

Answer 17

Rash, diarrhea, and dyspnea.

Question 18

What interactions should be considered in patients on Erlotinib?

Answer 18

Smoking and Cyp3A4 inhibitors

Question 19

What are the advantages of anti-angiogenic factors?

Answer 19

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

Question 20

What is Bevacizumab (Avastin) and what is it used for?

Answer 20

• 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

Question 21

To what class does Bevacizumab (Avastin) belong?

Answer 21

Anti-vascular endothelial growth factor antibody (VEGF, humanized monoclonal).

Question 22

What is the action of bevacizumab?

Answer 22

Blocks the angiogenic actions of VEGF in colon and lung cancers.

Question 23

What are the adverse side effects of bevacizumab?

Answer 23

Bleeding, allergic reactions, wound healing, and GI perforation.

Question 24

What are the major drug interactions with bevacizumab?

Answer 24

Possible allergic reactions

Question 25

What is vemurafenib?

Answer 25

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

Question 26

To what drug class does vemurafenib belong?

Answer 26

Protein kinase inhibitor

Question 27

What is the mechanism of action for vemurafenib?

Answer 27

Specifically targets metastatic melanoma with the V600E B-Raf mutation

Question 28

Describe the kinetics of vemurafenib.

Answer 28

hour half-life, majority liver excreted

Question 29

What are the major adverse drug reactions of vemurafenib?

Answer 29

arthralgia, skin rash, photosensitivity

Question 30

What are the major drug interactions to be considered with patients on vemurafenib?

Answer 30

CYP3A4 substrate

Question 31

What are the mechanisms of pharmacokinetic cancer therapy resistance?

Answer 31

Pharmacokinetic (extracellular)= systemic or tumor mass level

• Poor absorption
• Increased systemic catabolism
• Rapid drug clearance
• Poor tumor vascularity
• Anatomic sanctuaries = testes, brain

Question 32

What are the mechanisms of cytokinetic cancer therapy resistance?

Answer 32

Cytokinetic = growth rate based

• Tumor is in inappropriate phase of cell cycle for specific drug
• Low growth fraction

Question 33

What are the mechanisms of cellular resistance to cancer therapy?

Answer 33

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

Question 34

What occurs with the over expression of p-glycoprotein?

Answer 34

Overexpression of P-glycoprotein causes enhanced efflux of many drugs including:
- Vinca alkaloids, antracyclines, taxanes, etoposide, teniposide, camptothecins, imatinib mesylate, and mitoxantrone

Question 35

How does decreased topoisomerase II lead to cancer therapy resistance?

Answer 35

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.

Question 36

How does increased DNA repair lead to cancer therapy resistance?

Answer 36

Increased repair of DNA: responsible for resistance to several cancer drugs, most alkylating agents and cisplatin.

Question 37

How does glutathione-S-transferase induction lead to cancer therapy resistance?

Answer 37

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.

Question 38

What are strategies to circumvent cancer drug resistance (6)?

Answer 38

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