Targeted Cancer Therapy

Question 1

What are the three definitions of targeted cancer therapy

Answer 1

1) Act on specific molecular targets associated with cancer
2) Targeted therapies are deliberately chosen or designed to interact with their target
3) Targeted therapies are often cytostatic, blocking tumor cell proliferation

Question 2

What are key differences between targeted therapies and chemotherapy

Answer 2

Chemotherapies act on ALL rapidly dividing normal AND cancerous cells, standart chemotherapies were identified because they kill cells, chemotherapy agents are most often cytotoxic

Question 3

How does tamoxifen work against breast cancer

Answer 3

Works as antangonist when bound to the estrogen receptor causing different gene products to be synthesized when acting as a transcription factor

Question 4

T/F: Targeted therapies do not necessarily target cancer cells but target a specific biomolecule driving growth, survival, or spreading of cancer cells

Answer 4

True

Question 5

What are consequences of targeted therapies being cytostatic instead of cytotoxic

Answer 5

Adeverse events are linked to on-target effects of the target biomolecule in normal cells, resistance occurs through a mutated target or upregulated pathways circumventing the target

Question 6

Which cancer therapies are most known to have resistance

Answer 6

Tyrosine kinase inhibitors, Receptor and RTK antagonists, antimetabolites, and DNA targeting agents

Question 7

What are three ways receptor tyrosine kinases are targeted extracellularly

Answer 7

Antibodies bind the receptor, antibodies binding the ligand of the receptors, antibodies inhibit dimerization

Question 8

What are the ways receptor tyrosine kinases are targeted intracellularly

Answer 8

Small molecules inhibit the receptor, small molecules inhibit downstream signaling

Question 9

What is the receptor tyrosine kinase antibody that is a humanized mouse monoclonal antibody, what does it bind

Answer 9

Bevascizumab (Avastin), binds VEGF-A blocking activation of VEGFR-A preventing blood supply to tumors (anti-angiogenic)

Question 10

What is the receptor tyrosine kinase antibody that is chimeric antiobdy, what is a caveat of it working properly

Answer 10

Cetuximab (Erbitux), blocks gowth factor binding/ no effect in mutant kRAS

Question 11

What is the key characteristic that is found in chronic myeloid leukemia (CML)

Answer 11

Translocation from chromosome 9 to chromosome 22 creating the protien BCR/ABL leading to uncontrolled cell growth and proliferation in white blood cells

Question 12

In patients with CML what is the previous domain that negatively regulates the activity of ABL, what is the target for patients with CML

Answer 12

SH3 domain (BCR/ABL fusion produces an abnormally active tyrosine kinase),

Question 13

What is the first generation tyrosine kinase inhibitor, MOA

Answer 13

Imatinib: competitively binds to the active site where ATP would bind allowing for no phosphorylation

Question 14

What is the biggest resistance to Imatinib

Answer 14

Point mutations in the BCR-ABL kinase domain that affect imatinib binding

Question 15

What second generation TKI was approved for patients with resistance or tolerance to imatinib in chronic, accelerated or blast phase in CML, what makes it different

Answer 15

Dasatinib: inhibits multiple oncogenic tyrosine kinases including BCR/ABL and SRC family kinases while being more potent imatinib and having activity against nost common resistant mutations

Question 16

T/F: Second generation TKIs do not develop resistance

Answer 16

False: Dasatinib can develop secondary resistance in 3 to 12 months

Question 17

Which EGFR inhibitor (TKI) is used in advanced metastastatic Non-small cell lung cancer (NSCLC), what other is used but known for having a specific mutation, what other inhibits EGFR and HER2 but also has a downside, which is effect against a specific mutation

Answer 17

Gefitinib: binds to the ATP binding site of the enzyme (only works in mutant and overexpressed EGFR), Erlotinib: T790M mutation in within 12 months, Afatinib: inhibits EGFR and Her2 BUT NOT EFFECTIVE in T790 mutant, Osimertinib: T790M mutant EGFR

Question 18

What is the most common adverse effect of EGFR inhibitors, what does it signify

Answer 18

Papulopustular rash that spreads across the face and torso (90%), the rash indicates the drug’s antitumor effect is working

Question 19

What are RTK inhibitors that have broad kinase inhibition (VEGFR, PDGFR, FLT3), which has more

Answer 19

Sorafenib and Sunitinib, Sunitinib ( RET, cKIT, and CD135)