Antimitotic and Biological response modifiers - Slides 24-43

Question 1

Our genome codes for how many protein kinases and how many protein phosphatases?

Answer 1

550 protein kinases

130 protein phosphatases

Question 2

What are the two types of protein kinases?

Answer 2

Receptor tyrosine kinases (humans - 90)
Insulin receptor
Epidermal growth factor
Platelet derived growth factor
Fibroblast growth factor
Vascular endothelial growth factor

Enzymatic tyrosine kinases (humans - 32)
MAP
RAS
MEEK

Question 3

What are Imatinib, Dasatinib, Nilotinib?

Answer 3

Myeloid tyrosine kinase inhibitors

Question 4

What is Imatinib used for?

Answer 4

CML (BCR-ABL mutation)

CMML (EVT6-PDGFR mutation)

Question 5

How does Imatinib work?

Answer 5

Decreases myeloid TK’s responsible for cell proliferation

Binds closed BCR-ABL kinase

Question 6

How is Imatinib administered?

Answer 6

Oral

Question 7

Toxicities with Imatinib?

Answer 7

Nausea, vomiting, edema

Question 8

How does Dasatinib work?

Answer 8

2nd generation

Binds both open and kinase

Question 9

How does Nilotinib compare to Imatinib?

Answer 9

More potent

Works in Imatinib resistance!

Question 10

What are Gefitinib, Erlotinib?

Answer 10

Epidermal growth factor Tyrosine Kinase inhibitors (ErbB1 or HER1)

Question 11

How is Gefitinib administered?

Answer 11

Oral

Question 12

How does Gefinitib work?

Answer 12

It blocks ATP binding/activation of the TK

Question 13

What is Gefitinib used for?

Answer 13

Non-small cell lung cancer

EGRF mutants

Question 14

Toxicities with Gefitinib?

Answer 14

Diarrhea
Rash (50%)
Nausea
Vomiting
Dry skin

Question 15

What is Erlotinib used for?

Answer 15

2nd line metastatic non-small cell lung cancer

Pancreatic and head and neck cancer

Question 16

Toxicities with Erlotinib?

Answer 16

Diarrhea
Rash
Elevated liver enzymes

Question 17

What is Lapatinib?

Answer 17

ErbB1 (HER1), ErbB2 (HER2) tyrosine kinase inhibitor

Question 18

How does Lapatinib work?

Answer 18

It’s taken orally, has an intracellular site of action

Increases time of tumor growth from 4.4 to 8 months when given with Capecitabine

Enters CNS and is effective in CNS metabolism

Metabolized by CYP3A4

Question 19

Indications for Lapatinib?

Answer 19

CNS metastasis

Metastatic breast cancer no longer sensitive to Trastuzumab

Question 20

Toxicities of Lapatinib?

Answer 20

Rash
Nausea
Fatigue
Anorexia

Question 21

What is Bortezomib?

Answer 21

Proteosome inhibitor

Question 22

MOA of Bortezomib?

Answer 22

Inhibits proteosome breakdown of IKB which stays bound to NF-KB to prevent moving into the nucleus
NF-KB is a potent cell survivor promoter gene

Question 23

Indications for Bortezomib?

Answer 23

Approved for multiple myeloma

In trials for other solid tumors

Question 24

Toxicities of Bortezomib?

Answer 24

Thrombocytopenia (28%)
Fatigue
Neuropathy
Limb pain
Hypotension
CV failure

Question 25

What is Cetuximab?

Answer 25

Antibody to epidermal growth factor receptor (HER1, ErbB1)

Question 26

How is Cetuximab administered?

Answer 26

IV

Question 27

Indications for Cetuximab?

Answer 27

EGRF positive metastatic colorectal cancer (40-50% express the mutant receptor and are resistant) 2nd line in head and neck with cisplatin Being tested in breast, prostate, brain, pancreas, and bladder also expressing HER1

Question 28

Toxicity of Cetuximab?

Answer 28

Infusion reaction Skin rash (75%) Cardiac arrest

Question 29

What is Panitumab?

Answer 29

Recombinant human antibody to extracellular domain of EGRF

Question 30

How is Panitumab administered?

Answer 30

IV

Question 31

Indications for Panitumab?

Answer 31

Metastatic colorectal cancer overexpressing EGRF (after 2 previous therapies!!!) Toxicities: Epidermal toxicity (89%), severe infusion reactions, pulmonary fibrosis, electrolyte abnormalities

Question 32

What is Trastuzumab?

Answer 32

Recombinant human monoclonal antibody to external domain of human epidermal growth factor 2 (HER2/neu, ErbB2)

Question 33

MOA for Trastuzumab?

Answer 33

Antibody prevents the binding of the growth factor, can also down regulate the growth factor receptor

Question 34

Indications for Trastuzumab?

Answer 34

Approved for use in metastatic breast tumors over expressing HER2 (ErbB2) oncogene (30% of breast tumors overexpress)

Question 35

What is BRCA1/BRCA2?

Answer 35

Tumor suppressor genes that activate DNA strand break reair mechanisms BRCA mutations are found in 20-25% of hereditary breast cancer and 10-15% of ovarian cancer

Question 36

How is Trastuzumab administered?

Answer 36

Weekly infusion, given with Doxorubicin and Taxol

Question 37

Toxicities with Trastuzumab?

Answer 37

Fever, chills occur in the first dose in 40% of patients (treat with APAP, diphenhydramine) Nausea, vomiting, headache, dizziness, dyspnea, cough, cardiomyopathy

Question 38

What is Bevacizumab?

Answer 38

Antibody to vascular-endothelial growth factor (VEGF) - prevents angiogenesis

Question 39

How is Bevacizumab administered?

Answer 39

IV infusion or direct injection to the eye (for wet-age related macular degeneration)

Question 40

Indications for Bevacizumab?

Answer 40

In combination for metastatic colorectal, breast***, lung, glioblastoma, renal, pancreatic cancers Macular degeneration too ***FDA removed breast cancer as indication bc there was no survival benefit

Question 41

Toxicities for Bevacizumab?

Answer 41

``` Severe hypertension Proteinuria CHF Perforations of stomach and GI tract Bleeding into lungs Expensive ($8000/month) ```

Question 42

What are Sunitinib, Sorafenib?

Answer 42

Oral VEGF-1,2,3 inhibitors

Question 43

Indications for Sunitinib?

Answer 43

Metastatic renal cell cancer, better response than Bevacizumab

Question 44

Indications for Sorafenib?

Answer 44

Only drug approved for Hepatocellular cancer | Metastatic renal cancer

Question 45

Toxicities for Sunitinib?

Answer 45

Hypothyroidism (40-60%) | Fatigue (50-70%)

Question 46

Toxicities for Sorafenib?

Answer 46

Nausea, vomiting, diarrhea, rash

Question 47

What is Rituximab?

Answer 47

Chimeric human-murine antibody to CD20 antigen on B-lymphocytes

Question 48

What is Rituximab used for?

Answer 48

Non-hodgkin's lymphoma (90% have the CD20 gene) | CLL

Question 49

What is CD20?

Answer 49

It regulates step in cell cycle activation | Blocking CD20 can cause complement mediated lysis, apoptosis, antibody mediated cytotoxicity

Question 50

How is Rituximab administered?

Answer 50

Given as 4 weekly infusions

Question 51

Toxicities of Rituximab?

Answer 51

``` Infusion related flu-like syndrome N/V Urticaria SJS Bronchospasm Mild myelosuppression ```

Question 52

What is Ofatumumab?

Answer 52

CD20 monoclonal antibody

Question 53

Indications for Ofatumumab?

Answer 53

Used for CLL after failure of Alemetuzumab and Fludarabine

Question 54

Toxicities for Ofatumumab?

Answer 54

Immunosuppression Opportunistic infections Hypersensitivity reactions

Question 55

What is Alemtuzumab?

Answer 55

Binds CD52 antigen on T and B lymphomas | Induces cellular cytotoxicity

Question 56

Indications for Alemtuzumab?

Answer 56

B and T cell lymphomas | CLL

Question 57

How is Alemtuzumab administered?

Answer 57

IV

Question 58

Toxicities for Alemtuzumab?

Answer 58

Infusion reaction Decreased T-cells Opportunistic infections

Question 59

What is Gemtuzumab ozogamacin?

Answer 59

Antibody to CD33 antigen linked to Ozagimicin (antitumor antibiotic)

Question 60

Indications for Gemtuzumab ozogamicin?

Answer 60

CD33 positive acute myelogenous leukemia (80%) in first relapse

Question 61

Toxicities for Gemtuzumab ozogamicin?

Answer 61

Infusion reactions | Hepatic and bone marrow suppression