Targeted Therapy Flashcards Preview

Block 2 Pharmacology > Targeted Therapy > Flashcards

Flashcards in Targeted Therapy Deck (51):
1

What does "MAB" mean in the spelling of a medication?

Monoclonal antibody; target will be a cell surface receptor that activates a signaling cascade leading to proliferation

2

Drug names that end in "ib" indicate what?

The drug is an inhibitor agent of tyrosine kinase receptors

3

Trastuzumab

A monoclonal antibody drug

Target: Binds to and down-regulates HER-2 receptor

Effect: Cell cycle arrest

Cancer: Breast cancer

4

Which drug binds to and down-regulates the HER-2 receptor?

Trastuzumab

5

Which drug prevents dimerization of the HER-2 and HER-3 receptors, thereby preventing HER-2 from phosphorylation HER-3? What cascade does it prevent?

Pertuzumab

PI3K

6

Pertuzumab

Monoclonal antibody drug

Target: HER-2 and HER-3

Effect: Recall that HER-2 dimerizes with and phosphorylates HER-3, and they then promote the PI3K cascade. Pertuzumab prevents formation of the heterodimer.

Cancer: Breast cancer

7

T-DM1

These drug types contain in their structure both an antibody and a cytotoxic agent. In Sweatman's example, they are binding the EGFR.

1) Antibody action finds the receptor
2) Delivery of a cytotoxic agent to the tumor target, thus minimizing distribution of the native drug throughout the body.

8

Ipilimumab

A monoclonal antibody drug

Target: Binds CTLA-4 so that the tumor cell cannot send its B7 to bind. Normally, if B7 binds CTLA-4, the T-cell gets the message that it need to activate and proliferate. Because this antibody drug takes up the CTLA-4 binding site, the only other one open for B7 is CD28, which activates the T-cell, perhaps giving it a chance to attack tumor cells.

Cancer: Melanoma

Interesting note: This drug was the first to utilize active immunotherapy, as opposed to the suppression tactic.

9

Which drug binds the CTLA-4 receptor on T-cells to prevent B7 (CD80/86) from binding?

Ipilimumab

10

Rituximab

A monoclonal antibody drug

Target: Binds to the surface of the transmembrane protein CD20, which is found on precursor and mature B-cells. Recall that CD20 regulates early steps in the activation process for cell cycle initiation and differentiation.

Effect: Binding of the antibody drug produces rapid and sustained depletion of B-cells, lasting for several months. ADCC, apoptosis, and CDC

Cancer: Chronic lymphocytic leukemia and non-Hodgkin's lymphoma

11

VEGFR pathway normally activated with whom and when?

This pathway is activated in large, solid tumors that are beginning to outgrow their vascular supply. Because the cancer needs increased blood supply to spread, the VEGFR is a great target for monoclonal antibody drugs.

12

Hypoxia inducible factor-1 (HIF-1) in times of oxygen deprivation

In times of oxygen deprivation, VHL (Von Hippel Lindau) allows this molecule to translocate to the nucleus to promote up-regulation and expression of VEGF and PDGF, which then promotes angiogenesis.

The ultimate result is metastatic tumor spread, proliferation, and survival.

13

HIF-1 in times of plentiful oxygen

When oxygen levels are sufficient, any HIF-1 produced is sent by VHL (Von Hippel Lindau) to the 26s proteasome complex for degradation.

14

General Characteristics of MABs

(Route of admin, immunoglobulin on which they're based, general target)

Administered by injection

Large protein structures

Based on IgG

Traditionally target classical proliferative cell surface targets

Ipilimumab, which you'll recall targets CTLA-4, is the first drug to take the approach of immune system activation.

15

Adverse effects of monoclonal antibodies

Recall that we're targeting mammalian targets, and that these targets, while OVERexpressed in tumor cells, are regularly expressed in non-tumor cells; thus, we see things like:

1) Cardiovascular problems, including CHF and HTN

2) Depletion of cell populations in blood where target is expressed in component of this tissue

3) Infusion related reactions, like anaphylaxis, angioedema, and pulmonary toxicity. To mitigate this issue, give antihistamines and/or corticosteroids.

16

Cetuximab

A monoclonal antibody drug

Target: EGFR-1, HER-1

Effect: Apoptosis, ADCC of cell

17

Panitumumab

A monoclonal antibody drug

Target: EGFR-1, HER-1

Effect: Apoptosis, ADCC

18

Which two drugs target EGFR-1 , HER-1? Their killing mechanisms?

Cetuximab and Panitumumab

ADCC and apoptosis

19

Bevacizumab

Target: VEGF

Effect: Prevents angiogenesis and neovascularization

20

Which drug targets VEGF to prevent angiogenesis by tumor cells?

Bevacizumab

21

Ofatumumab

Target: CD20

Effect: Apoptosis, ADCC, CDC

Cancer: chronic lymphocytic leukemia

22

Which drugs target CD20?

Rituximab and Ofatumumab

23

The ATP-binding site of tyrosine kinases is highly ___________.

Conserved

24

T3151 of the ATP binding site

When a tyrosine kinase inhibitor drug is given to a patient, response is initially great…but then we see resistant clones emerge. This is largely due to a mutation in T3151, which prevents binding of first-generation drugs.

25

Solution drug for the problems that a mutation in T3151 causes?

Ponatinib, a later generation of tyrosine kinase inhibitor.

26

Whisper in my ear the sweet nothings about tyrosine kinase inhibitors. The good, the bad, the ugly. I want to know it all.

Target binding site?

Resistance?

What do they look like?

How are they taken and metabolized?

They bind in the ol' highly conserved ATP binding domain of the tyrosine kinase receptor

Resistance follows an initial successful response to the drugs; accomplished by kinase over-expression and binding site mutations.

Mutations impact drug binding but do not inactivate kinase function

Small, orally active drugs

Bioavailability can vary depending on food and CYP3A4

The potential for drug-drug interaction is very real.

27

What do mutations in the ATP binding site of the tyrosine kinase receptor do to the therapeutic window and the dose-response curve?

They change or diminish the therapeutic window, possibly making it impossible to achieve adequate clinical effect without initiating significant adverse effects caused by "off target" actions.

They shift the dose response curve to the right

28

Are there certain body parts that are especially affected by TKR inhibitors?

Yeah. Make sure to check your patient's thyroid function, bone density, PTH, and vitamin D

If he's a diabetic, monitor blood glucose

If it's a she, warn her about fetal development

If it's a kid, make sure it's growing right, complete with puberty

29

List some adverse effects of tyrosine kinase inhibitors

Usual uncomfortable effects like N/V, fatigue, and rash

QT prolongation

Blood dyscrasia (this means dat blood fucked)

hand-foot syndrome

Basically anybody who takes these meds is going to look super hawt.

30

Crizotinib

ALK, HGFR

non-small-cell lung carcinoma

31

Erlotinib

EGFR

pancreatic cancer

32

Imatinib

BCR-ABL, c-KIT, and PDGFR

CML

33

Sunitinib

VEGFR, PDGFR, c-KIT

pancreatic tumor, GIST

34

Vemurafenib

BRAF

metastatic melanoma

35

Are down-stream mutations important to consider when preparing to administer a TKR inhibitor?

If so, provide an example

Bet your sweet bippy!

If a patient is to receive an EGFR monoclonal antibody, you must check for KRAS and BRAF first, as these are downstream of EGFR. A patient with KRAS and/or BRAF mutations are less likely to respond to anti-EGFR therapies because those mutations keep KRAS and BRAF constitutively active, regardless of what's happening at the receptor.

36

Mechanisms of resistance to oral TKR inhibitors

Amplification of kinase

Mutating the ATP binding site

Evolution of kinase-independent mechanism

Decreased intracellular drug levels

P-gp mediated efflux

37

Explain the redundant nature of TKRs

There are dominant receptors, as well as secondary receptors that can kick in if the dominant goes out. These all converge on a "fragile point" in the pathway, such as AKT. Medical management should include inhibition of dominant and back-up receptors, as well as fragile points. Regardless, the TKs can still manage to find third, or even fourth string TKs to get shit done.

38

Is mTOR important in cancer? If so, why?

Yes. De-regulation of mTOR is associated with many types of human cancer.

39

Are there drugs that target mTOR?

Yes. Temsirolimus, sirolimus, and everolimus

In addition, small molecular weight drugs can form a three-way complex involving the inhibiting drug, FKBP-12, and mTOR, leading to mTOR's inhibition.

40

The relationship among NfKB, IkB-alpha, and bortezomib

Nf-kB is a transcription factor that is inhibited by IkB-alpha. Inhibition is ended when Ikb-alpha is broken down by the 26S proteasome, allowing Nf-kB to get to the nucleus and instigate proliferative signaling. Bortezomib inhibits 26S so that IkB-alpha stays bound to Nf-kB, inhibiting it from causing proliferation.

41

So we have this drug called bortezomib that can inhibit the 26S proteasome. What are some of the other molecules affected by this inhibition?

P53 (leads to BAX over-expression)

BAX (overcomes Bcl-2 over-expression)

IkB-alpha of course (growth inhibition and reduced angiogenesis)

42

Who bortezomib?

Why an inhibitor of IkB-alpha of course!

Administered by INJECTION

Cardiotoxicity with our old friend prolonged QT.

Severe sensory and motor peripheral neuropathy (most unusual)

Put on your chastity belt! Or your accidental baby is gunna have a bumpy ride. (Teratogen)

43

Dag yo. It's like…every time I think we're getting somewhere, I end up nowhere! I guess that magic bullet just doesn't exist…or does it?

NO.

44

For monoclonal antibodies: after these guys bind a target, what is the means of death for the cell?

For most of the drugs, it is apoptosis and ADCC. For drugs that target CD20 on B-cells (rituximab and ofatumumab), add CDC.

Finally, VGFR is the exception - only anti-angiogenesis occurs with this kid.

45

Dasatinib

Targets BCR-ABL

Cancer: CML, ALL

46

Gefitinib

Targets EGFR-1/HER-1

Cancer: non-small cell lung carcinoma and pancreatic cancer

47

Lapatinib

Targets EGFR and HER-2

Cancer: Breast cancer

48

Nilotinib

Targets BCR-ABL

Cancer: CML

49

Pazopanib

Targets: VEGF

Cancer: soft tissue carcinoma and RCC

50

Sorafenib

Target: VEGF and BRAF

Cancer: RCC and hepatocellular carcinoma

51

Which tyrosine kinase receptor inhibitors cause thyroid dysfunction?

In simple terms: the VEGF inhibitors, the BCR-ABL inhibitors, and erlotinib of EGFR

List:
sorafenib
sunitinib
pazopanib
imatinib
dasatinib
nilotinib