Elsaid Targeted Therapies

What are human epidermal receptors

growth factor receptors that can cause cancer due to overexpression

Explain the difference between the different monomers of HER

ErbB2 has no ligand binding region only a dimerization binding domain, ErbB3 has no tyrosine kinase domain

Describe the general structure of a HER receptor

extracellular: ligand binding domain, dimerization domain intracellular: tyrosine kinase domain

HER1 dimer components

ErbB1 + other

HER2 dimer component

ErbB2 + other

ErbB3 receptor is a homo or heterodimer

heterodimer, since it needs another receptor with functional tyrosine kinase intracellular domain

HER activation results in

• activation of PI3K/AKT pathway that increases cell survival and decreases apoptosis - MEK/ERK pathway to promote cell proliferation - PLC gamma that promotes cell proliferation

What are some methods to prevent over expression of HER in cancer

• mAB that bind to ligand binding domain or dimerization domain - Tyrosine kinase inhibitors to prevent signal transduction and blocks transphosphroylation

Eroltiniib is selective for

TKI for EGFR

Gefitinib is selective for

TKI for EGFR

Afatinib MOA

second gen irreversible TKI

Cetuximab MOA

mAB against EGFR

Panitumumab MOA

mAB against EGFR

Trastuzumab (Herceptin) MOA

mAB against ErbB2 in HER2 that blocks dimerization, activates ADCC, and influences HER2 internalization

How does resistance to trastuzumab occur

heterodimerization with HER1, 3 or 4, increase alternate tyrosine kinase receptors (IGF-1R or C-MET), loss of function in PTEN (inhibitor of PI3K/AKT pathway)

Describe why drugs may be conjugated to trastuzumab

target the mechanism of HER2 internalization as a result of trastuzumab activating ErbB2 to deliver cytotoxic drugs (emtansine)

Emtansine MOA

targets microtubules

Lapatinib MOA

small molecule inhibitor of HER1/HER2 receptor equally selective for ErbB1 and ErbB2

What is philadelphia chromosome

Chromosomal translocation of 9 to 22

What effect does expression of BCR-ABL have

ABL normally is a regulated kinase, but becomes unregulated with the fusion BCR-ABL therefore has activated PI3K-AKT and MAPK pathways that can lead to CML, AML, and ALL

Imatinib MOA

binds to ATP pocket of inactive BCR-ABL conformation to lock it

Why does imatinib resistance occur

1. Mutated binding site (T315I) Threonine → Isoleucine at 315 prevents formation of hydrogen bond between TKI and imatinib

2. Mutation at other site that prevent enzyme’s ability to assume inactive conformation (imatinib only binds to inactive form)

List 2nd gen BCR-ABL inhibitors and their binding affinity

nilotinib dasatinib: stronger binding affinity than imatinib and can overcome some mutations (not T315I)

List 3rd gen BCR-ABL inhibitor and their binding affinity

ponatinib, can inhibit T315I BCR-ABL

Why is angiogenesis relevant to cancer

rapid growth of cancer relies on angiogenesis to supply nutrients, inhibiting the switch to turn on angiogenesis can inhibit proliferation

List proangiogenic signals

VEGF, FGF, PDGFB, EGF

Activation of which VEGFR result in angiogenesis

VEGFR2 > VEGFR1

What ligand activates both VEGFR involved in angiogenesis and what drugs target this

VEGF-A, bevacizumab, aflibercept

Bevacizumab MOA

mAB that neutralizes VEGF-A

Aflibercept MOA

fusion protein that binds to VEGF-A

What drugs inactivate the TK involved in angiogenesis

sorafenib, sunitinib, axitinib, pazopanib

Sorafenib MOA

(sunitinib and pazopanib as well) inhibit TK on the intracellular portion of VEGF but can also reduce tumor growth

Axitinib MOA

ONLY inhibits TK on the intracellular component of VEGF