Hem/Onc Exam 2: Lapinsky (mAbs)

____ directly stimulates angiogenesis (new blood vessels form from pre-existing blood vessels) by acting as an agonist at VEGFR2

VEGF

___ and ___ are examples of select biomarkers stimulate cell proliferation and tumor growth

HER2, EGFR

____ tumors break through the basement membrane and can undergo metastasis, enter the lymphatic system or bloodstream, and establish secondary sites of tumor growth

malignant

Note that if mAb name includes "ci," think _____ ____

circulatory system

Bevacizumab (Avastin)

-a recombinant ___ mAb that binds to _____-__ (this is unique because it binds signaling molecule, not receptor)

humanized, VEGF-A

Bevacizumab (Avastin)

-a recombinant humanized mAb that binds to VEGF-A, thus preventing VEGF-A from interacting with the ___-__ _____.

-resulting in inhibition of ____

VEGFR-2, angiogenesis

Bevacizumab (Avastin)

-can be used to treat certain ____ tumors such as colon cancers and non-small cell lung cancer (NSCLC)

solid

Does Bevacizumab (Avastin) attack tumor cell directly?

no

Does Bevacizumab (Avastin) attack tumor blood supply?

yes

Bevacizumab (Avastin) MOA

-inhibits growth of new blood vessels that supply nutrients for continued tumor cell __ and ___

growth, division

Bevacizumab (Avastin) Toxicities

1. inhibition of blood vessel growth can lead to ___ and ___

hypertension, proteinuria

Bevacizumab (Avastin) Toxicities

2. _____/hemorrhage or ___/blood clotting may occur

bleeding, thrombosis

Bevacizumab (Avastin) Toxicities

3. impaired ___ healing

wound

Since Bevacizumab impairs wound healing, it is important to NOT administer for __ days before or after ___

28, surgery

Are there any pharmacogenomic markers for bevacizumab?

-____ (bc VEGF-A is not specific to cancer)

no

Trastuzumab (Herceptin)

-____ mAb of ___

humanized, IgG1

Trastuzumab (Herceptin)

-binds the ___ protein via the Fab region of the monoclonal antibody and blocks its signaling

HER2

HER2 expression is _____ or ____ in cancer cells

overexpressed, amplified

Trastuzumab (Herceptin)

-requires HER2 ____ in cancer cells to use, which can be identified through pharmacogenomic testing.

overexpression

Trastuzumab MOA

1. ____ via the Fc portion of the mAb (ie recruits immune cells to kill cancer cells)

ADCC

Trastuzumab MOA

2. blocks HER2 _____ via the Fab region of the mAb (this inhibits cell proliferation signaling downstream)

dimerization

Trastuzumab Toxicities

-_____ !!

-GI symptoms

-Fever

-Chills

-Headache

cardiotoxicity

Trastuzumab can result in cardiotoxicity by destroying HER2 on ____. Can result in drug-induced ___ ___

cardiomyocytes, heart failure

Trastuzumab Cardiotoxicity Monitoring

-avoid concurrent administration with ____

-at baseline and during treatment, monitor ____!

anthracyclines, LVEF

____ and ___ are proteins that have been linked to cancer

EGFR, KRAS

KRAS

-in its "wild-type," nonmutated form, this protein promotes cell ___, ___, and ___

proliferation, migration, angiogenesis

EGFR Activation Mechanism:

-EGF binds EGFR, causing ___ and ___ ___activation, which triggers signaling pathways that promote cell proliferation and survival

dimerization, tyrosine kinase

EGFR Activation Mechanism:

-EGFR ___ or ___ → uncontrolled tumor growth

overexpression, mutation

If EGFR is mutated, this receptor will still be active even if a mAb is bound (resulting in ___ ____)

drug resistance

If KRAS is mutated, it will always be turned ___, and therefore always be promoting cell proliferation, migration, and angiogenesis. Again, this protein will still be active even if a mAb is bound (resulting in ___ ____)

on, drug resistance

____ (Erbitux), ___ (Vectibix), and _____ (Tarceva) are EGFR inhibitors

cetuximab, panitumumab, erlotinib

EGFR Inhibitors Pharmacogenomics

1. we can test cancer cells for ___ gene expression. If positive, this correlated with better response rates in ___

EGFR, NSCLC

EGFR Inhibitors Pharmacogenomics

2. we can test cancer cells for ___ mutation.

KRAS

We can test cancer cells for KRAS mutation--- To use EGFR inhibitors effectively, the cancer patient must have "__ ___" (normal) KRAS.

wild type

Particularly in ___ cancer, mutated KRAS predicts a poor clinical response

colon

source

Cetuximab: ____

Panitumumab: ___ ___

chimeric, fully human

Hypersensitivity Risk

Cetuximab: ____

Panitumumab: __

higher, lower

Premedicate with steroid or antihistamine?

Cetuximab: ____

Panitumumab: __

yes, possibly

mAb Type

Cetuximab: ____

Panitumumab: __

IgG1, IgG2

ADCC Activity

Cetuximab: ___ :)

Panitumumab: __ :(

strong, minimal

Cetuximab and Panitumumab are "___" EGFR inhibitors that are ___

biologic, injected

Erlotinib is a small molecule, "___" EGFR inhibitor that is given ___

nonbiologic, orally

ANY EGFR inhibitor (cetuximab, panitumumab, erlotinib) can produce a notorious ___ ___ (by decreasing keratinocytes, causing inflammation, causing papules and pustules)

acneiform rash

Acneiform rash from EGFR inhibitor

-usually occurs within first 2 weeks of treatment in 50-100% of patients

-note that if patient has this rash, it indicates the patient will have a ___ clinical response :)

better

Acneiform rash from EGFR inhibitor

-advise patients to avoid ___ and use ___

sunlight, suncreen

Acneiform rash from EGFR inhibitor

-topical emollients, glucocorticoids, antibiotics, etc can be given ____ to reduce skin damage/need for dose reduction OR for treatment of the rash itself

prophylactically

Rituximab (Rituxan)

-___ mAb that works on __ cells

chimeric, B

Rituximab (Rituxan) 3 MOAs

1. activate ___ system (CDC)

2. can trigger natural ___

3. ____ (recruit immune system to help kill cancer cell)

complement, apoptosis, ADCC

Rituximab Pharmacogenomics

-we test cancer cells for B cell antigen ___. MUST be ___ for us to use this mAb

CD20, positive

Rituximab Indications

1. ___-___ B cell lymphoma

2. ___ (chronic lymphocytic leukemia)

3. ___ diseases

non-hodgkin, CLL, autoimmune

Rituximab non-selectively destroys ANY B cell with CD20. Therefore, can result in ___ and increased risk of ___

immunosuppression, infection

Rituximab is used for disease states characterized by B cells that are ____ in number or malignant in ___ (eg non-hodgkin lymphoma or CLL)

excessive, proliferation

Rituximab is used for disease states characterized by B cells that are ____ or ____ (eg automimmune diseases)

overactive, dysfunctional

B-Cell Development

___ ___ cell→ ___-B cell→ ___ B cell → ___ cell→ Antibody secretion

Lymphoid stem, pre, mature, plasma

Which stages of B-cell development are CD20-negative ?

Lymphoid stem cell, Plasma cell

The combined effects of Rituximab results in elimination of B cells expressing CD20, thus allowing a ___ population of healthy B cells to develop from lymphoid stem cells

new

One of the most exciting approaches to cancer immunotherapy involves releasing "the natural breaks" that keep the immune system in check via ___ ___

checkpoint inhibitors

The human immune system already knows how to fight cancer (it just needs a little help). Immune system main cancer fighters = __ cells

T

Immune Checkpoints: T-cell checkpoints (e.g., PD-1) act as brakes on the immune system, turning it ____.

off

Checkpoint Inhibitors like Keytruda or Opdivo take the "brakes" off the immune system, turning it back ___ to fight the cancer cell

on

Protein "Brake" Receptor on the T cell → ___ (programmed cell death-1 receptor protein)

PD1

Protein "Brake" Receptor on the Cancer Cell → ___ (programmed cell death-ligand 1 receptor protein)

PDL-1

When PD1 is bound to PDL-1 → T cell CANNOT ___ the adjacent cancer cell

kill

____ (Keytruda) and ___ (Opdivo) specifically target PD1 on the T cell

pembrolizumab, nivolumab

____ (Bavencio) specifically targets PDL1 on the cancer cell

avelumab

Toxicities of Pembrolizumab (Keytruda) and Nivolumab (Opdivo):

-cause drug-induced ____ ___ (eg colitis, hepatic toxicity, thyroid dysfunction, myocarditis)

automimmune disorders