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Sweatman Targeted Anti-Cancer Drugs Flashcards

1
Q

Name the 4 general types of Targeted anti-cancer drugs

A
  1. Mab’s at cell-surface receptors
  2. NIB’s at associated tyrosine kinases
    3 proteosome inhibitors
  3. mTOR inhibitors
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2
Q

Why do off target issues arise with anticancer therapy

A

targets are mammalian and expressed largely throughout the body–> high potential for adverse, off-target effects
*the taregt, while overexpressing in tumor cells, is expressed, and has an essential role, in normal non-tumoral tissues

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3
Q

Major sites of adverse drug effects associated with targeted anti-cancer drugs

A
  1. cardiovascular
  2. endocrine

also, liver, CYP inhibition, fetal caution, some have neurotoxicity

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4
Q

target and indication for bevacizumab

A

VEGF

colorectal, non-small cell lung carcinoma

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5
Q

target and indication for cetuximab

A

EGFR

colorectal, head & neck

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6
Q

target and indication for panitimumab

A

EGFR

colorectal

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7
Q

rituximab: target and indication

A

CD20 (expressed on mature B cells)

chronic lymphocytic leukemia, non-hodgkin’s lymphoma

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8
Q

target and indication for trastuzumab

A

HER-2

breast cancer

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9
Q

target and indication for ipilimumab

A

CTLA-4 (positively regulates T cell immune activation and proliferation)
*all that remains is the B7-cd28 proliferative response

melanoma

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10
Q

ofatumumab target and indication

A

CD20

chornic lymphocytic leukemia

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11
Q

Other non Mab drugs ending in -mib indicates what?

A

small molecule that is an inhibitor agent

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12
Q

bortezomib target and indication

A

26-s proteosome

multiple myeloma ( a b cell tumor that causes amyloidosis)

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13
Q

cancer: an uncontrolled state o proliferation brought on by (2)

A
  1. loss of function for tumor suppression genes

2. over-amplification of oncogenes

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14
Q

targets of anticancer therapy are an attempt to

A
  1. down regulate oncogene products

2. upregulate tumor suressor gene products such as p53

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15
Q

name the TSG’s that are methylated or d

A

p53, Rb, PTEN, hMSH2, hMLH1, BRCA1/2, VHL, p16/CDKN2

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16
Q

Trastuzumab MOA

A

Mab that binds to HER-2–> imediate inhibition of stim. signal

HER2 is then downregulated, CDKI (p27 accumulates and CELL CYCLE ARREST OCCURS

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17
Q

HER2 is associated with another cell-surface receptor

A

HER-2 phosporylates the cytoplasmic domain of HER-3–> which promotes PI3Kinase cascade

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18
Q

Mab that blocks HER2 heterodimerization of HER3

A

pertuzumab–> prevents PI3K cascade (decrease in cell signalling leading to cell cycle arrest)

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19
Q

Cetuximab and Panitumumab bind to/inhibit?

A

EGRF

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20
Q

Ipilimumab MOA

A

binds to CTLA4 on t cells–> prevents CLTA4 and B7 binding which removes the “off” signal and only leaves the CD28 and B7 interaction which activates T cells

*result is POSITIVE REGULATION OF T CELLS AND T CELL PROLIFERATION

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21
Q

ANTI-CANCER effects of ipilimumab are direct/indirect

A

indirect

–> fight cancer by upregulating T cells anti-tumor immune responses–> do not act on the cancer cell directly

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22
Q

Rituximab binds to?

A

CD20 on mature B cells

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23
Q

what does CD20 do?

A

important in ACTIVATION/INITIATION SIGNAL FOR B cell development into plasma cells and regulates T independent B cell immune response

  • ->controls B CELL CYCLING
  • RESULT IS DEPLETION OF B CELLS WHICH IS DESIRED FOR B CELL CANCERS
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24
Q

rituximab is useful in which cancers

A

leukemias, lymphomas, transplant rejection, autoimmune disorders
* causes immune suppression and depletion of b cell (humeral response)

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25
WEGF pathway is especially important for which tumor type
large solid tumors that are outgrowing their vascular supply
26
How is VEGF upregulated
in low O2 (hypoxic state) tumor expresses Hypoxia induced factor HIF1--> continued growth only worsens this low O2 problem and HIF1 is degraded by proteosome--> degradative products go to nucelus and upregulate VEGF production-->
27
VEGF IS RESPONSIBLE FOR
ANGIOGENESIS promoting metastasis proliferation survivial
28
mAb penetration of solid tumors
poor | --> IgG based, high MW, IV admin
29
novel drug that promotes active immunotherapy and increases efficiency of immune surveillance
ipilimumab
30
mAb's can cause infusion related reactions (anaphylaxis, angioedmea and pulmonary toxicity)--> what do you give to counteract this
antihistimines and/or corticosteroids
31
other key adverse effects of mAb's
cardiovascular problems leading to CHF (left ventricular failur, HTN) *TKI's also cause this
32
Different outcomes of MAB-epitope binding
CDCC ADCC DIRECT PROMOTION OF APOPTOSIS DELIVERY OF CYTOTOXIC DRUGS (easliy cleaved hydrolysable region frees up the drug and MAB locally cytotoxic drugs)
33
Mab causing cardiomyopathy, and infusion reaction
trastuzumab (herceptin)
34
mechanism of trastuzumab (herceptin)
apoptosis, ADCC, | targets: EGFR-2 and Her2/neu
35
Mab which causes HTN, CHF, pulmonary hemorrhage and GI perforation
Panitimumab
36
mechanism of Panitimumab
apoptosis and ADCC Target: EGFR1, HER1
37
All currently available tyrosine kinases work via:
a highly conserved ATP binding site within which the TKI must enter into and inhibit to maintain activity staurosporine has the widest array of activity
38
Most common ATP BS mutation in RTK's
t3151 (BCR-ABL) mutation (inhibits appropriate binding of first gen. drugs *other mutations include KIT (T6701) AND EGFR (T790M)
39
mechanisms of resistance to TKI's (3)
1. binding site mutations (T3151) etc. 2. kinase OVERESPRESSION 3. OTHER MECHANISMS?
40
what is unique to RTK muatations
they contain a homologous mutation of conserved "gatekeeper" threonine residue
41
Does an ATP binding mutation totally inactivate RTK activity
NO, do not competely prevent from binding, but alter the POTENCY OF EFFECT OF A GIVEN DOSAGE
42
what would you expect to see in a dose/concetration curve regarding a RTK mutation
shift to the RIGHT - -> displays LOWER postency and a higher Km--> this now makes it trickier to stay within the therapeutic window while remaining below the Mean Toxic Dose * dose required to kill cancer cell will now not be potent enough to cause toxicity in the tumor cell * having to increase concentration to reach a certain potency greatly increases the "off-target" effects of the drug
43
TKI administration
Small molecules--> administered orally
44
Are TKI's susceptible to first-pass metabolism
yes--> reduced bioavailability and important CYP interations
45
most TKI's are substrates for
CYP3A4 | *and are inhibitors or other important CYPs
46
Are MAB's suspect to 1st pass metabolism
NO--> HMW administed parenterally only | *i dont think there are drug-drug interactions? but not sure
47
will you see drug-drug interactions with TKI's
YES!
48
Suboptimal plasma concentrations of TKI's means--->
tx failure and likely resistance
49
cytotoxic drugs cause myelosuppression--> indicates the drugs is working and properly dosed
lack of Adverse effects with cytotoxic drugs tells the Dr. that it is underdosed
50
Lack of AE's with TKI's does not help determine
underdosage
51
what do you monitor with TKI's
ENDOCRINE DYSFUNCTION!!!! thyroid fnxn, bone density, PTH, 25-OH Vit D children--> growth and pubertal development diabetics--> glucose levels
52
are NKI's safe for pregnancy
NO
53
Do NKI's have CV adverse effects?
yes
54
Which TKI's cause cardiovascular effects
Lapatinib--> reduction in LVEF, QT prolong, hepatotoxicity, (LFT's needed) Nilotinib-->QT prolong, pancytopenia, hyperbilirubinemia, serum lipase increased
55
Some EGFR MAB's required testing for mutations in which protein markers
KRAS AND BREF
56
ORDER OF SIGNALING INSIDE THE CELL
KRAS> BREF>MEK>ERK/MAPK
57
WILL PT.'S WITH MUTATIONS IN KRAS/BREF RESPONDE TO EGRF MAB THERAPY
NO--> PATHWAY WILL BE CONSTITUTIVELY ON REGARDLESS OF WHETHER YOU BLOCK THE EGFR FROM RECEIVING SIGNAL OR NOT
58
MOR TO TKI'S
>INCREASED EFFLUX/DECREASED ACCUMULATION VIA P-GP >INCREASED PLASMA PROTEIN BINDING (DECREASED AVAILABILITY) >AMPLIFICATION OF KINASE RECEPTOR >CLONAL EVOLUTION OF KINASE-INDEPENDENT MECHANISMS (CELL SIMPLY WORKS AROUND THE NEED FOR TYROSINE KINASE ACTIVATION) >MUTATIONS IN ATP-BS (ALTERED TARGET)
59
DOMINANT RTK'S
EGFR | ErbB2
60
secondary TK's
c-Met PDGFR IGF-1R *can be recruited if dominant ones are blocked
61
dominant and secondary TK's converge on fragile pt's in the network such as
ATK
62
appropriate medical management should include (regarding Tk's)
target multiple TK's or fragile points in the network
63
central regulator of cell proliferation, angiogenesis, and cell metabolism
mTOR | *by activation or inhibiting protein synthesis upon receipt of appropriate biochemical signals
64
How is mTOR inhibited by SMW drugs
SMWdrugs form a 3 way complex with mTOR and FK-BP12--> thus inhibitoing mTOR FK BP12-SMWdrug inhibits mTOR directly
65
mTOR inhibitors for anti-cancer therapy
everolimus temsirolimus sirolimus--rapamune (an immunosupressant)
66
inhibitor of NFKB
IKB-alpha--> under normal circumstances is broken down by 26s proteosome--> leaving NFkB free to do its proliferative thang in the nucleus
67
Bortezomib MOA
inhibits proteosome from cleaving Ikb-alpha--> prevents NFkB from getting to the nucleus to increase prolifersative signals
68
Consequences of proteosome inhibition
increase pro-apoptotic and decrease anti-apoptotic forces within the tumor cell
69
examples of proteins affected by Ub-Proteasome pathway--> when its action is inhibited
IkB (NfkB is inhibited), CDK's (leads to G1-S cell-cycle arrest and apoptosis), P53 (apoptosis via p21 pathway and bax overexpression), BAX (bax elevation due to non-degredation leads to overcoming of BCL-2 overexpression ad apoptosis), Cyclins (disordered signal leads to apoptosis), Damaged proteins (accumulation leads to apoptosis)
70
side effects of bortezomib
SEVERE SENSORY AND MOTOR PERIPHERAL NEUROPATHY - ->hypotension (postural and orthostatic - ->cardiotoxicity (CHF, decreased LVEF and QT prolong) - ->hepato-toxicity - ->pregnancy risk
71
Biggest problem in efficacy of effective drug therapy-->
absence of prolonges clinical response because of the emergence of resistant sub-clones
72
future tx of tumors will involve
1. multiple drugs target treatments 2. tx of inflammatory microenvironment (NSAIDS) 3. tx of surrounding cells

CMOD (19 decks)

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