Anti-Cancer Drugs: Signal Transduction Inhibitors

Question 1

Signal Transduction Inhibitors includes?

Answer 1

1. Inhibitors of EGFR (ErbB1) and HER2/neu (ErbB2)
2. Inhibitors of BCR-ABL and C-KIT
3. Inhibitors of RAS/MAP kinase pathways
4. Proteasome Inhibitors
5. Angiogenesis Inhibitors

Question 2

What is signal transduction?

Answer 2

Transmission of molecular signals from a cell’s exterior to its interior
–signals received by cells must be transmitted effectively into the cell to ensure an appropriate response

Question 3

Protein kinases are critical components of signal transduction pathways that regulate cell growth and adaptation to the extracellular environment. Protein Kinases can be classified into what?

Answer 3

1. Tyrosine Kinases: Phosphorylate Tyrosine Residues
2. Serine and Threonine Kinases: Phosphorylate Serine and Threonine Residues
3. Kinases with activity toward all three residues

Question 4

What are the drugs for Inhibitors of EGFR (ErbB1) and HER2/neu (ErbB2)?

Answer 4

1. Gefitinib: Inhibitor of the EGFR tyrosine kinase (non small cell lung cancer)
2. Erlotinib: inhibitor of the EGFR tyrosine kinase (non small cell lung cancer and carcinoma of the pancreas)
3. Lapatinib: Inhibitor of EGFR and ErbB2 (non small cell lung cancer and carcinoma of the pancreas)
4. Cetuximab: Monoclonal Antibody Against EGFR. (Colorectal cancer – restricted to patients with tumors expressing wild type KRAS)
5. Trastuzumab: Monoclonal Antibody Against ErB (HER2)(cardiotoxic)(breast cancer with HER2 overexpression)

Question 5

What are the drugs for Inhibitors of BCR-ABL and c-KIT?

Answer 5

Imatinib: Inhibits the Bcr-Abl tyrosine kinase and Inhibits c-kit (receptor for tyrosine kinase)
CML, Kit positive GI stromal tumor and Idiopathic hypereosinophilic syndrome

Question 6

What are the drugs for Inhibitors of RAS/MAP kinase pathways?

Answer 6

Sorafenib: inhibits the RAF serine/threonine kinase and Inhibits VEGF-R2 and VEGF-R3 and PDGFR-B
Renal Cell Carcinoma

Question 7

What are the proteasome Inhibitors?

Answer 7

Bortezomib: Induces growth inhibition and apoptosis of tumor cells
Multiple Myeloma and Mantle Cell Lymphoma

Question 8

What are the Angiogenesis Inhibitors?

Answer 8

Sunitinib: Inhibits VEGFR-1, VEGFR-2 and PDGFR
Renal Cell Carcinoma
GI stromal tumor

Question 9

The last drugs are the Miscellaneous Agents: Asparaginase, Hydroxyurea, Interferon alpha. First lets start with Asparaginase, what is the MOA?

Answer 9

Hydrolyzes circulating L-asparagine to aspartic acid and ammonia
Tumor cells in ALL lack asparagine synthase, so they require an exogenous source of L-asparagine. Thus depletion of L-asparagine results in effective inhibition of protein synthesis.

Question 10

What are the clinical application and AE of Asparaginase?

Answer 10

Clinical:
–Childhood Acute Lymphobalstic Leukemia (ALL)
AE:
–Hypersensitivity, decrease in clotting factors, liver abnormalities, pancreatitis and seizures

Question 11

The second miscellaneous agent is Hydroxyurea, what is the MOA?

Answer 11

Inhibits ribonucleotide reductase which converts ribonucleoside diphosphate to deoxyribonucleoside diphosphate

• –depletion of deoxyribonucleosides trisphosphate pool thereby inhibiting DNA synthesis
• -kills cells in S phase

Question 12

What are the clinical applications and Adverse effects of Hydroxyurea?

Answer 12

Clinical:
Malignant melanoma, chronic myelocytic leukemia, ovarian cancer, primary squamous cell carcinoma of the head and neck, excluding the lip
Used to tx adult sickle cell disease 
AE:
--Myelosuppression

Question 13

Last Miscellaneous drug is Interferon Alpha. What is the MOA?

Answer 13

MOA:

• –stimulates natural killer cells to kill the transformed cells
• -increases the expression of HLA molecules on tumor cells

Question 14

What are the clinical applications and AE for Interferon Alpha?

Answer 14

Clinical:
--Kaposi Sarcoma 
--Hairy Cell Leukemia
---Renal Cell Carcinoma
--Antiviral Activity Against HPV, HBV and HCV
AE:
--Flu like symptoms