Chemo IV: Targeted Therapies

Question 1

What are tyrosine kinases? Where might they be found in the cell? How are they involved in cancer?

Answer 1

They transfer a P from ATP to tyrosine in polypeptides

Found as receptor-type (in the membrane) or non-receptor

Constitutive activation of a TK enzyme can disrupt autoregulation and lead to unchecked cell growth, survival, and drug resistance

Question 2

Imatinib

MOA

Answer 2

Binds and inhibits the BCR-ABL protein product (from a t(9;22))

Inhibits a driver mutation pathway

May also block c-KIT pathway

Question 3

Imatinib

Indications

Answer 3

CML (BCR ABL t(9;22))

Gastrointestinal stromal tumors (c-KIT)

Question 4

Imatinib

Metabolism and its implications

Answer 4

Metabolized in liver by CYP3A4 system

Avoid giving Imatinib with GFJ (inhibitor of CYP) or St John’s wort (inducer of CYP)

Question 5

Imatinib

AEs

Answer 5

Muscle cramps
Superficial edema (periorbital, extremity)

Increased clearance of T4/T3 in patients on thyroid replacement therapy (Monitor TSH levels)

Question 6

Cetuximab

MOA

Answer 6

Monoclonal Ab to EGFR

Question 7

Cetuximab

Indications

Answer 7

Metastatic lung cancer
Colon cancer
Head and neck cancer

Question 8

Cetuximab

AEs

Answer 8

RASH
Diarrhea
Hypomagnesemia
Trichomegaly

Question 9

Cetuximab

Contraindications

Answer 9

If KRAS, NRAS, or both are mutated, the patient will NOT respond to Cetuximab

Question 10

Erlotinib

MOA

Answer 10

Small molecule inhibitor of tyrosine kinase domain assoc with EGFR

Inhibits autophosphorylaion and leads to lower signal transduction downstream

Question 11

Erlotinib

Metabolism

Answer 11

CYP3A4

Question 12

Prototypical patient with EGFR Activating Mutations

Answer 12

Adenocarcinoma, bronchoalveolar carcinoma

Asian woman

Never smoker

Question 13

Bevacizumab

MOA

Answer 13

VEGF inhibitor

Prevents signaling for new blood vessel formation in tumors

Question 14

Bevacizumab

Indications

Answer 14

Prolongs survival in metastatic colorectal cancer and metastatic lung cancer

Question 15

Sorafenin, Pazopanib, Sunitinib

MOA

Answer 15

VEGF receptor TK inhibitors

Question 16

Trastuzumab

MOA

Answer 16

Binds extracellular domain of EGFR receptor Her2/neu

Question 17

Trastuzumab

AEs

Answer 17

Fever, nausea, vomit, diarrhea
Cough, HA, SOB, back pain

Very few get clinical heart failure (risk is highest when receiving concurrent anthracycline)

• Not dose dependent
• Reversible heart failure

Question 18

Vemurafenib

MOA

Answer 18

Inhibits mutated BRAF

Use in melanomas

Question 19

L-asaparaginase

MOA and Indication

Answer 19

Depletes asparagine pools

Since leukemia cells cannot synthesize asparagine, the cells will die

Used in ALL

Question 20

Hydroxyurea

MOA and Indication

Answer 20

Inhibits DNA synthesis by inhibiting ribonucleotide reductase

Used in AML (and used to increase HbF in sickle cell anemia)

Question 21

All-trans retinoic acid

MOA and Indication

Answer 21

Used in APL (t(15;17))

Induces terminal differentiation of leukemic cells in APL

Question 22

Arsenic Trioxide

MOA and Indication

Answer 22

Treatment for relapsed APL, when all-trans retinoic acid didn’t work

Causes QT prolongation