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CMOD > Sweatman Targeted Anti-Cancer Drugs > Flashcards

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
Q

WEGF pathway is especially important for which tumor type

A

large solid tumors that are outgrowing their vascular supply

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26
Q

How is VEGF upregulated

A

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–>

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27
Q

VEGF IS RESPONSIBLE FOR

A

ANGIOGENESIS
promoting metastasis
proliferation
survivial

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28
Q

mAb penetration of solid tumors

A

poor

–> IgG based, high MW, IV admin

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29
Q

novel drug that promotes active immunotherapy and increases efficiency of immune surveillance

A

ipilimumab

30
Q

mAb’s can cause infusion related reactions (anaphylaxis, angioedmea and pulmonary toxicity)–> what do you give to counteract this

A

antihistimines and/or corticosteroids

31
Q

other key adverse effects of mAb’s

A

cardiovascular problems leading to CHF
(left ventricular failur, HTN)

*TKI’s also cause this

32
Q

Different outcomes of MAB-epitope binding

A

CDCC
ADCC
DIRECT PROMOTION OF APOPTOSIS

DELIVERY OF CYTOTOXIC DRUGS (easliy cleaved hydrolysable region frees up the drug and MAB locally cytotoxic drugs)

33
Q

Mab causing cardiomyopathy, and infusion reaction

A

trastuzumab (herceptin)

34
Q

mechanism of trastuzumab (herceptin)

A

apoptosis, ADCC,

targets: EGFR-2 and Her2/neu

35
Q

Mab which causes HTN, CHF, pulmonary hemorrhage and GI perforation

A

Panitimumab

36
Q

mechanism of Panitimumab

A

apoptosis and ADCC

Target: EGFR1, HER1

37
Q

All currently available tyrosine kinases work via:

A

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
Q

Most common ATP BS mutation in RTK’s

A

t3151 (BCR-ABL) mutation (inhibits appropriate binding of first gen. drugs

*other mutations include KIT (T6701) AND EGFR (T790M)

39
Q

mechanisms of resistance to TKI’s (3)

A
  1. binding site mutations (T3151) etc.
  2. kinase OVERESPRESSION
  3. OTHER MECHANISMS?
40
Q

what is unique to RTK muatations

A

they contain a homologous mutation of conserved “gatekeeper” threonine residue

41
Q

Does an ATP binding mutation totally inactivate RTK activity

A

NO, do not competely prevent from binding, but alter the POTENCY OF EFFECT OF A GIVEN DOSAGE

42
Q

what would you expect to see in a dose/concetration curve regarding a RTK mutation

A

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
Q

TKI administration

A

Small molecules–> administered orally

44
Q

Are TKI’s susceptible to first-pass metabolism

A

yes–> reduced bioavailability and important CYP interations

45
Q

most TKI’s are substrates for

A

CYP3A4

*and are inhibitors or other important CYPs

46
Q

Are MAB’s suspect to 1st pass metabolism

A

NO–> HMW administed parenterally only

*i dont think there are drug-drug interactions? but not sure

47
Q

will you see drug-drug interactions with TKI’s

A

YES!

48
Q

Suboptimal plasma concentrations of TKI’s means—>

A

tx failure and likely resistance

49
Q

cytotoxic drugs cause myelosuppression–> indicates the drugs is working and properly dosed

A

lack of Adverse effects with cytotoxic drugs tells the Dr. that it is underdosed

50
Q

Lack of AE’s with TKI’s does not help determine

A

underdosage

51
Q

what do you monitor with TKI’s

A

ENDOCRINE DYSFUNCTION!!!!

thyroid fnxn, bone density, PTH, 25-OH Vit D

children–> growth and pubertal development
diabetics–> glucose levels

52
Q

are NKI’s safe for pregnancy

A

NO

53
Q

Do NKI’s have CV adverse effects?

A

yes

54
Q

Which TKI’s cause cardiovascular effects

A

Lapatinib–> reduction in LVEF, QT prolong, hepatotoxicity, (LFT’s needed)

Nilotinib–>QT prolong, pancytopenia, hyperbilirubinemia, serum lipase increased

55
Q

Some EGFR MAB’s required testing for mutations in which protein markers

A

KRAS AND BREF

56
Q

ORDER OF SIGNALING INSIDE THE CELL

A

KRAS> BREF>MEK>ERK/MAPK

57
Q

WILL PT.’S WITH MUTATIONS IN KRAS/BREF RESPONDE TO EGRF MAB THERAPY

A

NO–> PATHWAY WILL BE CONSTITUTIVELY ON REGARDLESS OF WHETHER YOU BLOCK THE EGFR FROM RECEIVING SIGNAL OR NOT

58
Q

MOR TO TKI’S

A

> 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
Q

DOMINANT RTK’S

A

EGFR

ErbB2

60
Q

secondary TK’s

A

c-Met
PDGFR
IGF-1R
*can be recruited if dominant ones are blocked

61
Q

dominant and secondary TK’s converge on fragile pt’s in the network such as

A

ATK

62
Q

appropriate medical management should include (regarding Tk’s)

A

target multiple TK’s or fragile points in the network

63
Q

central regulator of cell proliferation, angiogenesis, and cell metabolism

A

mTOR

*by activation or inhibiting protein synthesis upon receipt of appropriate biochemical signals

64
Q

How is mTOR inhibited by SMW drugs

A

SMWdrugs form a 3 way complex with mTOR and FK-BP12–> thus inhibitoing mTOR

FK BP12-SMWdrug inhibits mTOR directly

65
Q

mTOR inhibitors for anti-cancer therapy

A

everolimus
temsirolimus
sirolimus–rapamune (an immunosupressant)

66
Q

inhibitor of NFKB

A

IKB-alpha–> under normal circumstances is broken down by 26s proteosome–> leaving NFkB free to do its proliferative thang in the nucleus

67
Q

Bortezomib MOA

A

inhibits proteosome from cleaving Ikb-alpha–> prevents NFkB from getting to the nucleus to increase prolifersative signals

68
Q

Consequences of proteosome inhibition

A

increase pro-apoptotic and decrease anti-apoptotic forces within the tumor cell

69
Q

examples of proteins affected by Ub-Proteasome pathway–> when its action is inhibited

A

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
Q

side effects of bortezomib

A

SEVERE SENSORY AND MOTOR PERIPHERAL NEUROPATHY

  • ->hypotension (postural and orthostatic
  • ->cardiotoxicity (CHF, decreased LVEF and QT prolong)
  • ->hepato-toxicity
  • ->pregnancy risk
71
Q

Biggest problem in efficacy of effective drug therapy–>

A

absence of prolonges clinical response because of the emergence of resistant sub-clones

72
Q

future tx of tumors will involve

A
  1. multiple drugs target treatments
  2. tx of inflammatory microenvironment (NSAIDS)
  3. tx of surrounding cells

CMOD (19 decks)

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