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Fall 2018/P3 Year' > Therapeutics Exam 1 (Wendt and Dykhous) > Flashcards

Therapeutics Exam 1 (Wendt and Dykhous) Flashcards

1
Q 
6 essential characteristics of cancer?
sustaining \_\_\_\_\_\_\_\_
evading \_\_\_\_\_\_\_
activating \_\_\_\_\_\_
enabling \_\_\_\_\_\_\_
inducing \_\_\_\_\_\_
resisting \_\_\_\_\_\_
A

sustain: proliferative signaling
evade: growth suppressors
activate: invasion and metastasis
enable: replicative immortality
induce: angiogenesis
resist: cell death

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2
Q

2 newer/emerging hallmarks of cancer
deregulating _______
avoiding ______

A

deregulate: cellulare energetics
avoid: immune destruction

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3
Q

Terminology:

Cancer?

A

any malignant neoplasm

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4
Q

Terminology:

Tumor

A

nonspecific term meaning lump or swelling

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5
Q

Terminology:

Neoplasm

A

any new growth - benign or malignant

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6
Q

Terminology:

Neoplasia

A

process of expansion due to defects in the molecular controls that regulate cellular proliferation/cell death

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7
Q

Terminology - the “plasias”:

Hyperplasia

A

increase in NUMBER of cells

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8
Q

Terminology - the “plasias”:

Metaplasia

A

SUBSTITUTION of one type of adult tissue to another adult tissue

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9
Q

Terminology - the “plasias”:

Dysplasia

A

LOSS OF NORMAL architecture/ abnormal cellular proliferation

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10
Q

Terminology - the “plasias”:

Anaplasia

A

loss of STRUCTURAL DIFFERENTIATION

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11
Q

Terminology - the “plasias”:

Desmoplasia

A

formation and proliferation of CONNECTIVE TISSUES and cells

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12
Q

Terminology - the “omas”:

Carcinoma

A

malignant neoplasm of EPITHELIAL cell origin

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13
Q

Terminology - the “omas”:

Adenoma

A

epithelial neoplasm derived from glandular tissue

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14
Q

Terminology - the “omas”:

Papilloma

A

surface epithelium in which neoplastic cells grow outward in finger like fibrovascular stalks

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15
Q

Terminology - the “omas”:

Teratoma

A

germ cell neoplasm –> several different differentiated cell and tissue types

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16
Q

Terminology - the “omas”:

Sarcoma

A

malignant neoplasm from mesenchymal tissues (aka soft tissues Ex: muscle)

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17
Q

Terminology - the “omas”:

Lymphoma or Leukemia

A

malignant neoplasms of hematopoietic tissues

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18
Q

Terminology - the “omas”:

Blastoma

A

more common in children —

caused by malignancies in precursor cells

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19
Q

Terminology - the “omas”:

Melanoma

A

cancer of pigment producing cells

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20
Q

_____ is the most lethal aspect of cancer

A

Metastasis

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21
Q

Metastatis is a multi step process:

Normal epithelium –> _____ –> _________ –> ______ –> intravasation/extravasation –> metastatis

A

dysplasia; carcinoma in situ; invasive carcinoma

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22
Q

Metastatis is highly _____ process

A

inefficient

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23
Q

unlike carcinomas, sarcomas arise from ______

A

soft tissues

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24
Q

leukemia is the cancer of _____ cells

A

white blood

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25
Q

lymphomas arise from cells that populate from _____

A

lymph nodes

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26
Q

what is a reed-sternberg cell?

A

a binucleated cell - a part of Hodgkin’s Lymphoma

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27
Q

Staging of Carcinomas

stage 0

A

in situ carcinoma; no sign of local invasion

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28
Q

Staging of Carcinomas

stage I

A

microscopic invasion of surrounding tissue

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29
Q

Staging of Carcinomas

stage II

A

4 - 9 surrounding lymph nodes are involved

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30
Q

Staging of Carcinomas

stage III

A

10 + surround lymph nodes are involved

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31
Q

Staging of Carcinomas

stage IV

A

distant metastases are detected

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32
Q

what stage # for carcinoma?

in situ carcinoma - no sign of local invasion

A

0

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33
Q

what stage # for carcinoma?

microscopic invasion of surrounding tissue

A

1

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34
Q

what stage # for carcinoma?

4 - 9 surrounding lymph nodes are involved

A

2

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35
Q

what stage # for carcinoma?

10+ lymph nodes are involved

A

3

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36
Q

what stage # for carcinoma?

distant metastases are detected

A

4

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37
Q

what is another specific staging system for tumors?

A 
TNM staging 
(primary tumor (T); regional lymph nodes (N), distant Metastasis (M)
X: cant be evaluated
0: no evidence
1+: present
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38
Q

summary staging for cancer:

in situ?

A

abnormal cells are present only in the layer of cells in which they develop

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39
Q

summary staging for cancer:

localized?

A

cancer is ONLY in the organ where it BEGAN

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40
Q

summary staging for cancer:

regional?

A

spread beyond primary site to NEARBY lymph nodes or tissues and organs

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41
Q

summary staging for cancer:

distant?

A

aka has metastasized - gone to distant tissues or organs…..

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42
Q

what is tumor grading?

A

way to grade the tumor based on how abnormal the tumor cells and tissues look under a microscope

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43
Q

is G1 or G4 more concerning for a tumor?

A

G4 is more concerning

G4 is undifferentiated = high grade

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44
Q

well differentiated or undifferentiated tumor is worse?

A

undifferentiated

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45
Q

___ differentiated cells in tumors will look like normal cells and tissues

A

well - differentiated

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46
Q

_________ receptors can dimerize to each other and drive cell growth

A

EGF receptor family (HER 2,3,4)

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47
Q

what does RSV stand for?

A

rous sarcoma virus

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48
Q

why is RSV relevant to tumors?

A

RSV is a retrovirus and encodes a protein (v-SRC) that is capable of driving proliferation and tumor progression

aka it is like an oncogene

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49
Q

At least 6 viruses are thought to contribute to cancer —-

_____ and _____ viruses

A

DNA and RNA

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50
Q

proto-oncogenes act as ______ alleles

A

dominant

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51
Q

____ of function mutations in tumor suppressor genes can lead to cancer

A

loss

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52
Q

tumor suppressor genes are ______ alleles

A

recessive

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53
Q

_____ mutations in tumor suppressor genes are more often transmitted as ______ mutations and therefore assoc. w/ heritable forms of cancer

A

heterozygous;

germ line

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54
Q

HER2 - is an proto oncogene or tumor suppressor?

A

oncogene —
slide also shows that test a cell with dysplasia with Antibodies - lots of dark spots because antibody binds to lots of HER2 receptors

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55
Q

slide in ppt about DIAGNOSTIC molec. pathology: lung biospies can be tested via PCR for a particular mutation in _____ - if so pts can go on specific anti____ therapies

A

EGFR; EGFR

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56
Q

PROGNOSTIC Molec pathology example?

A

oncotypeDX
like 21 genes that will show if a patient is at high or low risk for metastasis in the next five years — if high chance will probably do chemo

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57
Q

OncotypeDx and Mammaprint:

can prevent ______ because predict recurrence

A

overtreatment

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58
Q

OncotypeDx and Mammaprint:
T or F:
Drive indications for specific therapies

A

falseeeee

just predicting recurrence

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59
Q

Main cancers that hormones regulate proliferation of

A

Breast
Endometrial
Prostate

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60
Q

Hormonal Therapies for Cancer:

primarily _____ and ______ is targeted (for breast/endometrial and prostate cancer, respectively)

A

estradiol

dihydrotestosterone

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61
Q

Androgens and estrogens have ____ effects

A

opposing

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62
Q

Steroid receptors:

they are ______ hormone dependent ______ factors

A

cytosolic; transcription

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63
Q

what is the base material for making estradiol and testosterone?

A

cholesterol

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64
Q

Steroid receptors barely bind to the _____

A

surface

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65
Q

Steroids diffuse easily or poorly

A

easily

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66
Q

what are the 2 main classes of anti estrogen therapy

A

aromatase inhibitors

SERMs (selective estrogen receptor modulators)

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67
Q

aromatase inhibitors will stop estrogen ______
and
SERMs stop estrogen ______

A

production

function

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68
Q

Steroid Feedback Loop:

Hypothalamus release ____ to work on _____

A

GnRH

work on pituitary

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69
Q

Steroid Feedback Loop:

Pituitary makes _____ and _____ to work on the _____

A

FSH and LH;

works on ovaries and testis.

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70
Q

Steroid Feedback Loop:

Estrogen and Progesterone act as a ______ feedback loop on the _____

A

negative; pituitary

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71
Q

when LH (decrease or increases) estrogen will decrease

A

increase

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72
Q

_____ is a potent stimulant of breast cancer cell proliferation

A

estradiol

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73
Q

what are some protective factors against breast cancner

A

early age of 1st full term pregnancy
lactation
physical activity during reproductive years

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74
Q

Breast Cancer:
Well differentiated tumors - more likely to be ER___
and poorly differentiated tumors are likely to be ER___

A

+

-

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75
Q

Poorly differentiated tumors - have ____ growth fractions and are generally more _____ to cytotoxic agents

A

higher growth

more sensitive

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76
Q

_____ correlation b/w presence of estrogen receptor and the likelihood of response to hormone therapy

A

highly significant

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77
Q

____ in breast cancer risk 5 years after lactation

A

increased risk

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78
Q

the risk for breast cancer _____ with increasing age

A

increases

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79
Q

ER+ tumors should be treated with ____ therapy and why

A

hella estrogen receptors (aka ER+) tumors should get ENDOCRINE therapy - because there is actually receptors are endocrine stuff to affect….

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80
Q

what are the 4 different types of breast cancer

A

ductal carcinoma in situ (preinvasive)
invasive ductal carcinoma (invasive)
lobular carcinoma in situ (preinvasive)
invasive lobular carcinoma (invasive)

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81
Q

what drugs are SERMs

A

Tamoxifen
Raloxifene

Toremifene
clomiphene
fulvestrant (SERD)

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82
Q

which SERM is also used for osteoporosis

A

raloxifene

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83
Q

how can a SERM be helpful for osteoporosis

A

it is an ER AGONIST in the bone — estrogen agonist will promote bone growth

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84
Q

tamoxifen wasnt used for awhile because what else was needed?

A

needed to know if someone is ER+ or ER-

if ER+ – tamoxifen would be effective

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85
Q

Tamoxifen is a _______ that that is metabolized by _____

A

prodrug; CYP2D6

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86
Q

what is the active form of tamoxifen?

A

4-OH-Tam

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87
Q

T or F: Tamoxifen has antagonist activity only

A

False;

agonist and antagonist – it is a SERM (they do both…selective….)

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88
Q

tamoxifen:

binds to ____ receptor and inhibits both _____ and _______

A

estrogen receptor;

translocation; DNA binding

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89
Q

Tamoxifen:

blocks _______ dependent breast cancer ________

A

estrogen ; proliferation

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90
Q

Tamoxifen: Estrogen AGONIST effects
increase incidence of _______ cancer
will preserve _________ in postmenopausal women
can cause ________

A

incidence of endometrial
preserve bone density
blood cots

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91
Q

Tamoxifen: Side effect of hot flashes happens because of..?

A

estrogen ANTAGonist activity

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92
Q

Tamoxifen:

used in pre or post menopausal women?

A

both!!!

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93
Q

______ was the first drug approved for breast cancer prevention

A

tamoxifen

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94
Q

tamoxifen: dosage route?

A

oral

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95
Q

tamoxifen:

primary use is treatment of ________?

A

resected ER+/PR+ breast cancer

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96
Q

take tamoxifen for about ______ when treating resected ER+/PR+ breast cancer

A

3 -5 years

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97
Q

Tamoxifen: antagonist or agonist at these specific parts and its impact?

Brain

A

antagonist –> hot flashes and thermoregulation

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98
Q

Tamoxifen: antagonist or agonist at these specific parts and its impact?

breast

A

antagonist — why we use it for ER+ breast cancer

antiproliferative

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99
Q

Tamoxifen: antagonist or agonist at these specific parts and its impact?

blood

A

agonist – leads to increased coagulability and clots VTE risk

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100
Q

Tamoxifen: antagonist or agonist at these specific parts and its impact?

Uterus

A

agonist —- endometrial hyperplasia — endometrial cancer increased risk

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101
Q

Tamoxifen: antagonist or agonist at these specific parts and its impact?

bone

A

partial agonist — blocks bone resorption — yay healthy bones

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102
Q

Raloxifene: antagonist or agonist at these specific parts and its impact?

brain

A

antagonist —> hot flashes and thermoregulation

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103
Q

Raloxifene: antagonist or agonist at these specific parts and its impact?

breast

A

antagonist – duh bc treating breast cancer

*not as strong of an antagonist to as tamoxifen in the breast though

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104
Q

Raloxifene: antagonist or agonist at these specific parts and its impact?
blood

A

agonist —

increased coag/VTE risk

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105
Q

Raloxifene: antagonist or agonist at these specific parts and its impact?
uterus

A

antagonist !!! aka NO endometrial hyperplasia risk!

difference from tamoxifen

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106
Q

4 strong 2D6 inhibitors? (aka drugs to avoid with contaminant tamoxifen because they will make tamoxifen less effective/not to its active metab…)

A

fluoxetine
paroxetine
quinidine
bupropion

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107
Q

what drug is a SERD?

A

fulvestrant

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108
Q

why is a SERD different than a SERM? (structure and MOA)

A

structure: similar to estradiol but has a long carbon chain: this will lead to a proteosome to break down the estrogen receptor

it is a PURE estrogen antagonist

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109
Q

Fulvetrant: T or F: has agonist and antagonist effects

A

falseeee

only an antagonist —

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110
Q

Fulvestrant:

binds to ER and inhibits ______ binding — which leads to rapid _____

A

DNA binding;

receptor degradation

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111
Q

fulvestrant will cause a dramatic loss of cellular ____ levels and reduce ____ expression

A

cellular ER levels

reduce PR expression

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112
Q

fulvestrant: dosage form route?

A

IM injection once per month

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113
Q

fulvestrant is approved for who and what condition?

A

ER+ metastatic breast cancer in POSTMENOPAUSAL women who have progressed on other antiestrogen therpay

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114
Q

aromatase enzyme is important in steroid generation why?

A

aromatase makes enone A ring of androgen into a aromatic a ring in estrogens

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115
Q

Aromatase inhibitors block synthesis of _______ but not ______ and ______

A

block: estrogens
not: androgens and progesterone

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116
Q

________ (type of cell) is the principal source of estrogen in postmenopausal women

A

adipocytes

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117
Q

primary target of aromatase inhibitors is ______ tissue not the ______

A

peripheral/adipose

not ovary

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118
Q

primary application is estradiol suppression in what group of patients?

A

POSTmenopausaul women

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119
Q

Aromatase Slide:
Androstenedione is made in the _____ gland and released to circulation:
aromatase takes andorostenedione to _____

A

adrenal gland

estrone

(estrone will then go to estradiol)

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120
Q

2 main subclasses of aromatase inhibitors?

A

steroidal and on-steroidal

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121
Q

what drugs are NON-steroidal aromatase inhibitors

A

anastrozole

letrozole

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122
Q

Anastrozole and letrozole are potent and selective ______ inhibitors for _____ activity

A

competitive;

aromatase

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123
Q

primary indication for Anastrozole and letrozole ?

A

tx of breast cancer in POSTmenopausal women

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124
Q

dosage route of anastrozole and letrozole?

A

orally - everyday

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125
Q

ADEs of letrozole and anastrozole?

A

hot flashes
bone/join/muscle pain
asthenia (weakness)
increased fracture risk (will increase the extent of bone density loss – because decreasing estrogen…)

Potential fetal damage - avoid in pregnant women!!

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126
Q

what drug is a steroidal aromatase inhbitiors?

A

exemestane

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127
Q

exemestane has similar structure to _________

A

androstenedione

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128
Q

Exemestane MOA: is a fake substrate to ______ and gets converted to a reactive intermediate: then this intermediate binds _____ at the ____ site which inactivates the enzyme

A

aromatase; irreversibly; active

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129
Q

exemestane: dosage route?

A

orally - daily

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130
Q

primary indication for exemestane?

A

tx of estrogen responsive breast cancer in POSTmenopausal women – who have progressed on antiestrogen therapy

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131
Q

ADEs of exemestane?

A

hot flashes
occasional peripheral edema and weight gain
increased cholesterol levels (remember estrogen can help keep ladies’ cholesterol in check

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132
Q

brand of exemestane?

A

aromasin

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133
Q

Treating with progesterone will inhibit ____ and ____

A

LH; FSH

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134
Q

Decreased FSH leads to _____ aromatase and _____ estrogen

A

decreased; decreased

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135
Q

A progesterone _____ will suppress estrogen receptor expression

A

agonist

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136
Q

progesterone derivs (like medrooxyprogesterone) primary indication?

A

prevention of endometrial cancer in postmenopausaul women

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137
Q

other effects/uses for medrooxyprogesterone

A

appetite stimulation/wt gain – good for anorexia/cachexia in cancer/AIDS

antiemetic properties: reduced N/V in cancer patietns

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138
Q

Chronic administration of LHRH analogues will downregulate ______ LHRH receptors and lead to _________

A

pituitary; pituitary desensititzation

139
Q

what are examples of LHRH analogs?

A

GnRH
Leuprolide
Goselerin

140
Q

Acute admin vs Chronic admin of LHRH agonists

A

acute: will increase levels of all steroid hormones
chronic: downregulates pituitary LHRH receptors–> pituitary desensititzation

141
Q

Chronic admin of LHRH agonists will cause a severe _____ of _____ in 3- 4 weeks

A

estrogen

142
Q

long term ADEs of LHRH analogs?

A

since decreased estrogen — hot flashes and sexual dysfunction

143
Q

what drug class related to steroid hormones will have transient worsening of symptoms

A

LHRH analogs (because acutely increase all steroid levels)

144
Q

what hormonal therapy options are for premenopausal women

A

LHRH agonists (goserelin and luporlide)
Surgical oophorectomy
tamoxifen

145
Q

what drug can be used as a hormonal therapy option for both pre and post menopausal women

A

Tamoxifen

146
Q

what hormonal therapy options are for postmenopausal women

A 
tamoxifen
Nonsteroidal aromatase inhibitors
steroidal aromatase inhibitors
pure anti-estrogens
progestin
147
Q

testosterone is rapidly and irreversibly converted to DHT (dihydrotestosterone) in ____ cells by _______

A

prostate cells; type 2 5 alpha reductase

148
Q

DHT binds to what receptor in prostate cells?

A

androgen receptor (AR)

149
Q

what are GnRH analogs used in men for prostate cancer?

A

Leuprolide and goselerin

150
Q

what are some long term side effects of men being on GnRH agonists

A

(low testosterone…)
gynecomastia
sexual dysfunction

151
Q

what is the pro of LHRH receptor antagonists or GnRH agonists for men?

A

the ANTAGNOISTS will not have the tumor flare

152
Q

what drugs are GnRH receptor antagonists

A

abarelix

degarelix

153
Q

abarelix and degarelix are used for what?

A

prostate cancer (they are GnRH receptor antagonists)

154
Q

what drugs are androgen antagonists

A

enzalutamidide and apalutamide

155
Q

enzalutamidide and apalutamide are what kind of drugs

A

androgen receptor antagonists

156
Q

MOA of androgen receptor antagonists?

A

prevent AR translocation to the nucleus and inhibits AR from binding to DNA

157
Q

what are androgen receptor antagonists used for?

A

prostate cancer (dur - anti testosterone)

158
Q

what drug inhibits the function of 17-a hydroxylase and C17,20 lyase

A

Abiraterone

159
Q

what is the benefit or Abiraterone

A

it inhibits the enzymes further up in the hormone synthesis process

160
Q

what is an ADE of Abirtaerone

A

since it inhibits further up in the hormone synthesis process – it will increase cholesterol

161
Q

what drugs are 5 alpha reductase inhibitors

A

finasteride

dutasteride

162
Q

finasteride or dutasteride?

_____ inhibits only type 2

______ inhibits both type 1 and 2

A

finasteride

dutasteride

163
Q

5 alpha reductase inhibitors may delay the growth of ______

A

benign prostate tumors

164
Q

what drug was the first kinase inhibitor?

A

Imatinib

165
Q

what are the 3 main parts of ATP

A

triphosphate
ribose
adenine base

166
Q

________ balance the activity of kinases by removing phosphates

A

phosphotases

167
Q

Type 1, 2, 3/4 or Covalent kinase Inhibitors?

bind to the active conformation of the kinase

A

type 1

168
Q

Type 1, 2, 3/4 or Covalent kinase Inhibitors?

bind to inactive conformation

A

type 2

169
Q

Type 1, 2, 3/4 or Covalent kinase Inhibitors?

bind to allosteric pocket

A

3/4

170
Q

Type 1, 2, 3/4 or Covalent kinase Inhibitors?

has irreversible inhibition - binds with cysteine residues

A

covalent!

171
Q

what drugs are only EGFR kinase inhibitors

A 
Gefitinib
Erlotinib
Afatinib
Neratinib
osimertinib
172
Q

EGFR functions through ______ activity and EGFR signaling induces cell _______

A

tyrosine kinase; proliferation

173
Q

Erlotinib and Gefitinib: approved for tx of ______ cancer for tumors that have EGFR _____ and _____ mutations

A

tx of NSCLC (non small cell lung cancer);

exon 19 and exon 21 mutations

174
Q

a rash with the drug _____ can be a good thing —- skin rash on chest and back may mean longer survival

A

Erlotinib

175
Q

what mutation can cause resistance to Erlotinib and Gefitinib

A

T790M

176
Q

what drug is a second gen EGFr inhibitor

A

Afatinib

177
Q

what drug was the first approved covalent EGFR inhibitor

A

afatinib

178
Q

Afatinib was made to overcome the T790M resistance in EGFR inhibitors — did it work?

A

Nooooo it didnt - but was a covalent inhibitor

179
Q

Afatinib - currently approved for?

A

metastatic NSCLC - where tumors have EGFR exon 19 deletions or exon 21 mutations as detected by an FDA approved test

180
Q

what drug was made/successfully overcomes the resistance from T790M mutation in the EGFR inhibitor

A

osimertinib

181
Q

what EGFR inhibitors are are selective for ErbB/Her2

A

Lapatinib

Nerabtinib

182
Q

HER2 inhibitors - all have risk of _____

A

CHF: it is reversible tho

183
Q

the HER2 inhibitors: Lapatinib or Nerabtinib

which one is reversible and which one is covalent

A

lapatinib: reversible

Nerabtinib: covalent

184
Q

VEGFR is critical for tumor ______

A

angiogenesis

185
Q

why are VEGFR inhibitors efficacy limited?

A

they are not paired with a molecular dianostic

186
Q

cMET is a the receptor for ______

A

HGF (hepatocyte growth factor)

187
Q

what drugs are inhibitors of cMET

A

Crizotinib and Cabozantinib

188
Q

out of the cMET inhibitors:

______ can overcome ______ resistance that results to mutations in another receptor ROS1

A

cabazanitib; crizotinib

189
Q

explain BCR-ABL gene

A

BCR normally on chromosome 22; ABL on 9

sometimes they translocate and get near each other and this leads to constitutive growth etc

190
Q

what drug was the first type 2 inhibitor (kinase inhibitor)

A

Imatinib

191
Q

BCR-ABL pathway:

BCR or ABL is a tyrosine kinase?

A

ABl

192
Q

Imatibnib will inhibit the _____ kinase, and ______ receptor and the stem cell factor known as _____

A

ABL tyrosine; PDGFR (platelet derived growth factor receptor); c-Kit

193
Q

primary indication for imatinib?

and what is the other thing it is effective for?

A

CML - chronic myelocytic leukemia

GIST - GI stromal tumor

194
Q

Toxicities of Imatinib

A

N/V
Fluid retention/edema
Neutropenia/thrombocytopenia

195
Q

resistance to imatinib results from mutations from kinase domain — can use _____ instead because it can still inhibit BCR-ABL even if there are some mutations

A

use Nilotinib

196
Q

what drugs are BCR-Abl inhibitors

A 
imatinib
nilotinib
ponatinib
dasatinib
bosutinib
197
Q

which BCR-Abl inhibitor is the one that is notably able to inhibit all major mutant forms of BCR-Abl even the “gatekeeper mutation” of T3151

A

Ponatinib

198
Q

All compounds that bind BCR-Abl (as kinase inhibitors) bind it in the _____ confirmation

A

“DFG out”

199
Q

what drugs can be used for the ELM4-ALK translocation?

A

Crizotinib and Alectinib

200
Q

EML4 or ALK is the tyrosine kinase?

A

ALK…

201
Q

melanoma tends to have ____ mutations

A

BRAF

202
Q

Sorafenib can inhibit RAF – but the drug is not effective because it is blocked by the ____ mutation that is very common in melanoma

A

V600

203
Q

what drugs are for BRAF and can inhibit when the V600 mutation is present - and which one is the drug of choice

A

Vemurafenib;

Dabrafenib (this one is DOC)

204
Q

BRAF inhibitors and wild type enzyme – what is the result

A

a bad result of where they can actually activate normal B-raf and promote tumor growth

205
Q

what drugs are RAF inhibitores

A

Sorafenib
Vemurafenib;
Dabrafenib

206
Q

what drugs are MEK inhibitors (kinase inhibitors)

A

trametinib

Cobimetinib

207
Q

which MEK inhibitor was the 1st approved type 3 (allosteric) inhibitor

A

trametinib

208
Q

limitation of Trametinib

A

not indicated for the tx of pts who have already received BRAF inhibitor therapy

209
Q

Limitation of Cobimetinib?

A

not indicated for pts with the wild type BRAF melanoma

210
Q

PI3K is a ___kinase that leads to the downstream activation of _________ — this pathway is critical for cancer cell survival

A

lipid; activation of PKB (protein kinase B)

211
Q

what drug was the first lipid kianse inhibitor

A

Idelalisib

212
Q

idelalisib is approved for treating?

A

CLL (chronic lumphocytic leukemia)

213
Q

Ibrutinib:
is a _____ kinase inhibitor
inhibits ____ which is the downstream of the _____ receptor

indicated for ______

A

is a BTK

downstream of BCR (b-cell receptor)

b-cell leukemia

214
Q

what drugs are BTK inhibitors

A

Ibrutinib

Acalabrutinib

215
Q

which BTK inhibitor is more selective and potent

A

Acalabrutinib

216
Q

Ibrutinib and Acalabrutinib are what type of kinase inhibitor (type 1,2,3,covalent?)

A

covalent

the BTK inhibitors are covalent

217
Q

the rapalogs are also known as ______ and inhibit ______

A

Rapamyacins and inhibit M-TOR

218
Q

what drugs are Rapalogs

A

sirolimus
everolimus
Temsirolimus
Deforolimus

219
Q

m-TOR is a ______ kinase

A

serine-threonine

220
Q

PI3K will lead to the stimulation of _____

A

AKT

221
Q

what drugs are CDK4/6 inhibitors

A

palbociclib
ribociclib
abemaciclib

222
Q

con of CDK inhibitors?

CDK = cyclin dependent kinase

A

they work down stream of so many of the receptors that it really isnt specific/not really targeted therapy

also the ADEs are neutropenia/N/V/D/fatigue - v similar to chemo

223
Q

T Cells:

arise in ______ but migrate to the _____ to mature

A

bone marrow

thymus gland

224
Q

T Cells:

T or F: T Cells cannot recognize an antigen alone

A

true

T cell receptors can only recognize an antigen if bound to cell membrane proteins (aka MHC molecule)

225
Q

2 main kinds ot t Cells?

A

CD4-TH (helper)
CD8-TC (cytotoxic)

there is also suppressor T cells

226
Q

Positive vs Negative selection of T Cells?

A

+: allows T cells to survive if they are capable of recognizing SELF MHC molecules

-: gets rid of T cells that react to strongly to self MHC molecules

Overall goal is Central Tolerance

227
Q

Antibody production: the _____ arm of the immune system

A

humoral

228
Q

B Cell matures to a _____ cell

A

plasma

229
Q

idea behind HUMANIZED anitbodies?

A

can construct a cell line secretes antibodies that are mostly human except for the CDR (complementary determining region)

230
Q

idea behind fully human antibodies?

A

transgenic mice have been constructed to express the human VDJ regions of the genome so they make fully human antiboides

231
Q

Monoclonal antibodies end with _____

A

-mab

232
Q 
Monoclonal antibodies: substems
if its a mouse: \_\_\_\_
chimeric: \_\_\_\_\_
humanized: \_\_\_\_
fully human: \_\_\_\_\_\_
A

mouse: -o
chimeric: -xi
humanized: -zu
fully human: -u

233
Q

Antibody production:

from mice — take a antibody forming cells — fuse it with a _____ and this makes a _____

A

fuse with a tumor cell

makes a hybridoma (hybirdoma will make hella cells that make the same antibody)

234
Q

why can an antibody binding can lead to several anticancer events?

A

the antibody binding can lead to CDC (complement dependent cytoxicity) and ADCC (antibody dependent cellular cytotoxicity) and selective elimination of the tumor cell

235
Q

what 2 antibody drugs are specific for the HER2 receptor

A

Trastuzumab

Pertuzumab

236
Q

Trastuzumab and pertuzumab both inhibit HER2 — but why are they be used together at the same time

A

Tras: blocks internalization/causes ADCC

Pertuz: blocks oligermization/dimerization

237
Q

what antibody drugs are for EGF receptors

A

Cetuximab

Panitumumab

238
Q

why is there a high chance of an infusion reaction with cetuximab?

A

it is a chimeric antibody!! (aka hella mouse proteins)

239
Q

what cancers is cetuximab used for?

A

colorectal, head and neck

NOT LUNG - the drug is for EGFR and the lung cancers will have kinase mutations and the receptor blockage wont do much…

240
Q

Cetuximab and panitumumab are used for colorectal after _____ status is checked

A

KRAS mutation

if KRAS mutation is present — antibody won’t be effective —- KRAS is downstream from EGFR

241
Q

Panitumumab is a ______ type of antibody that binds specifically to ______

A

fully human antibody

binds to EGF receptor

242
Q

why do we want to target CD20 for cancer?

A

CD20 - plays role in B Cell proliferation — important in lymphophomas

243
Q

what drugs are antibodies for CD20? (which are second gen)

A

Rituximab

2nd gen:
Ofatumumab
Obinutuzumab

244
Q

Bevacizumab: binds to _______ not ______

A

VEGF not VEGFR!!!

245
Q

Bevacizumab:

toxicities?

A

related to bleeding — since it is block ing VEGF we are blocking vascularization

Minor or Major hemorrhage (nosebleed common)
GI perforations and wound healing complications
Deep vein thrombosis

246
Q

Ramucirumab: binds to _____ not _____

A

VEGFR not VEGF

247
Q

what is an ADC?

A

antibody drug conjugates

248
Q

explain the components of the current approved ADC? that wendt mentioned..there might be more of course..)

A

TDM1 aka Ad-Trastuzumab Emtansine

a cytotoxic agent (mertansine) linked to the antibody trastuzumab

249
Q

TDM1: the ADC
trastuzumab binds to ________
then
mertansine ______ and inhibits ________

A

binds to HER2/Neu receptor

enters cell and inhibits microtubule assembly

250
Q

why do we care to target CD30 in cancer cells?

A

CD30 is expressed on reed sternberg cells – these are in hodgkins lymphoma

251
Q

what drug is an anti-CD30 antibody conjugated with MMAE

A

brentuximab vedotin

252
Q

what is MMAE

A

monomethyl auristatin E —is conjugated with teh CD30 antibody to make brentuximab vedotin for hodgkins lymphoma

it is a microtubule destabilizing agent

so toxic — cannot be used by itself

253
Q

major goal of cancer immunotherapy is getting the immune system recognize and destroy cancer —- this can be done by altering ____ cells

A

T

254
Q

Cancer Immunotherapy:
_____ and _____ act as brakes or checkpoints in the immune system — blocking these interactions with antibodies can lead to keep T Cells activated!!

A

CTLA-4

PD1

255
Q

what drug can bind to CTlA-4 and reverse the CTL (cytotoxic T lymphocyte) inhibition

(this inhibition is done by dendritic cells via the CTLA-4 receptor)

A

Ipilimumab

256
Q

ADE’s of Ipilimumab

A

MOA: the drug reverses CTL (cytotoxic T lymphocyte) inhibition and thus more T cells are active and doing their thing ==== INFLAMMATION!!

ADE’s Sseen
Enterocolitis/Hepatits (Gi tract inflammation)
Dermatitis, neuropathy, endocrinopathy

257
Q

How to overcome/help with the inflammation ADE’s seen with Ipilimumab?

A

high dose corticosteroids

258
Q

Cancer Immunotherapy: T Cells

PD-1 and PD-L1

one is expressed on macrophages/tumor cells the other on T cells - which is which?

A

PD-1 = T cells

PD-L1 = macropaghages; tumor cells

259
Q

Cancer Immunotherapy: T Cells

PD-1 and PD-L1

what does PD stand for

A

program death!

thus inhibit death of T -cells they can attack the tumor!

260
Q

what drugs are PD1 antibodies

A

Pembrolizumab and Nivolumab

will bind to the receptor on T cells

261
Q

what drugs are PD-L1 antibodies

A

Atezolizumab; Avelumab

will bind to receptor on macrophages and tumor cells

262
Q

Cancers with (more or less) mutations will respond better to T cell therapy?

A

more mutations!

more mutations = less like self = T cells will attack more easily

263
Q

what types of cancer responds (possibly) best to T cell therapy?

A

melanoma – because it will have helllla mutations

264
Q

Colorectal cancer can be very responsive to T cell therapy if the cells are _____ deficient

A

mismatch repair – if they cant fix their mutations then they will be very unlike self cells –> t cells will wreck them

265
Q

Cancer immunotherapy /Antitumor immunity is worse or better if it preceded with radiation?

A

better!
the remaining cells after radiation will be the ones with hella mutations – thus T cell therapy will recognize them easily a

266
Q

The idea behind bispecific antibodies?

A

to physically bring an activated T cell into proximity with a tumor cell

267
Q

what drug is a bispecific antibody (aka BiTE = bi-specific T cell engager)

A

Blinatumomab

268
Q

Blinatumomab binds to ____ and _____

A

CD19 AND CD3

CD3 ON T CELLS
AND CD19 ON B CELLS

269
Q

Alkylating Agents:

they are electrophilic or nucleophilic?

A

electrophilic

270
Q

Alkylating agents tend to react with _____ groups that are found on _____ and _____

A

nucleophilic; DNA and Proteins

271
Q

Alkylating agents

major mechanism of action involves alkylation of ______ bases in DNA

A

purine

272
Q

Alkylating agents

the most common site of alkylation is?

A

Guanine N7

273
Q

Alkylating agents

crosslinking will inhibit DNA ______ and ______

A

replication; transcription

274
Q

the cross linking of DNA, done by alkylating agents, is repaired ______

A

not efficiently!!!

DNA doesn’t encounter this much and thus cant fix it super well

275
Q

what DNA bases are purines?

A

Adenine and Guanine

Ag – “pur”e as gold

276
Q

What other nucloephiles can Alkylating agents react with?

A

thiols, Cysteine/lysine, and GLUTATHIONE

277
Q

Alkylating agents:

cells are more susceptible in which phase?

A

late G1 - S (aka replication prep time) - is most effective

buuut alkylating agents are effective all the time - non cell cycle specific

278
Q

Alkylating agents
normal cell populations rapidly proliferate and therefore are more sensitive to DNA alkylation/cross linking: those areas are _______ and _____

A

bone marrow; gut mucosa

279
Q

especially with very strong Alkylating agents — there is a measurable incidence of second ______

A

malignancies

280
Q

what are some other names for mustard gas

A

Mechlorethamine!!
mustargen
mustine

281
Q

what are some mechloethamine derivs

A

Bendamustine
Chlorambucil
Melphalan

282
Q

Mustard gas (mechloethamine) facts:
EXTREMELY reactive compound
half life in plasma is about ____

A

1 minute

283
Q

what are side effects of all Alkylating agents

A

myleosuppression
N/V
carcinogenic/teratogenic

284
Q

since mechloethamine is reactive and wild — what are the strategies to make them less wild

A
  1. decrease the nucleophilicity by ADDING ARYL GROUPS

2. prodrug strategy

285
Q

the mechloethamine deriv drugs are made by doing what

A

adding an aryl group to decrease the nucleophilicity of nitrogen

this lets the have a long half life!!!

286
Q

for akylating agents it is best for the conjugate acid pKa to be basic or acidic?

A

acidic!!

stronger acid = weaker conjugate base = resonance stabilzed (done with aromatic ring)

287
Q

what is an example of a prodrug Alkylating agents of the mustard family

A

Cyclophosphamide

288
Q

Cyclophosphamide:
is a PRODRUG needs hydroxylation from _____
its metabolite is ______ and it will cross link DNA

A

hepatic P450

metabolite: phosphoramide mustard (PMM)

289
Q

Cyclophosphamide:
the metabolite, PM, will be made in _____ cells
PM is highly (polar or non polar)
PM has a (short or long) half life

A

made in tumor cells
highly polar — does NOT readily dissuse into cells
short half life! (why good thing it is a prodrug)

290
Q

Cyclophosphamide:

its PM metabolite is inactivated by ?

A

aldehydrogenase dehydrogenase

291
Q

what is the by product made when Cyclophosamide is made into PM

A

acrolein

292
Q

what are the two most current/useful alkylating agents

A

cyclophosphamide and ifosfamide

293
Q

cyclophosphamide and ifosfamide are the preferred alkylating agents why?

A

side effects are most mild compared to other alkylating agents
MILD bone marrow toxicity !

294
Q

cyclophosphamide and ifosfamide will lead to ______ cystitis and why?

A

hemorrhagic cystitis;

acrolein is toxic to bladder mucosa

295
Q

acrolein is toxic to ________

A

bladder mucosa

296
Q

what drug is used in combo with cyclophosphamide to prevent hemorrhagic cystitis

A

mesna

297
Q

how does mesna help prevent hemorrhagic cystitis

A

this drug accumulates in the urine because it is a charged molecule and does not penetrate cells

it is a reactive thiol with a charged sulfonate group — will react with/inactivate cyclophosphamide metabolites in the urine

298
Q

alkylating agents are strongeraliphatic or aromatic

A

aliphatic

(remember use aromatic ones to to “calm” them down”

299
Q

what drugs are nitrosoureas

A

carmustine

lomustine

300
Q

Nitrosoureas:

chemically stable or unstable?

A

unstable

301
Q

Nitrosoureas are converted to _____ by a non enzymatic reaction (just chemically unstable)

A

diazonium ion

302
Q

the diazonium ion comes from ______

A

carmustine or

lomustine

303
Q

diazonium ion is highly (nucleo or electro - phillic) and has a _____ half life

A

electrophilic! (duh diazonium ions are from alkylating agents and those are electrophillic)

extremely short half life

304
Q

Nitrosoureas:

are hydro or lipo phillic?

A

lipo!!!

they will cross blood brain barrier!!!

305
Q

what alkylating agents are used for glioblastoma

A

nitrosoureas (they are lipophillic)

306
Q

what is different about the dosing of nitrosoureas?

A

since myleosuppression is DELAYED and prolonged — longer interval b/w doses is needed compared to other agents

307
Q

what drug is an alkyl sulfonate

A

busulfan

308
Q

busulfan has what notable toxicity

A

pulmonary fibrosis “ busulfan drug”

309
Q

when is busulfan used? (per dykhousen notes)

A

given with cyclophosphanide before bone marrow transplant to eradicate all hematopoetic cells —
this drug is v toxic

310
Q

Mitomycin C:

can form _________ adducts

A

bifunctional (aka crosslinks…)

311
Q

Mitomycin C:
similarities to _______ compounds
______ containing natural product
_______ is dose limiting

A

nitrogen mustard;
aziridine
myleosuppression

312
Q

what drugs are monoalkylating agents

A

DTIC and TMZ

313
Q

DTIC: is a monoalkylating agent that needs to be activated by ________

A

N demethylation by P450 enzyme

314
Q

both DTIC and TMZ get converted to _______

A

MTIC

but DTIC - is done by P450 enzyme

TMZ is chemically converted

315
Q

DTIC or TMZ:

cross blood brain barrier?

A

TMZ

316
Q

DTIC or TMZ:

has 100% bioavailabilty

A

TMZ

317
Q

DTIC or TMZ:

is poorly absorbed

A

DTIC

318
Q

what is the other name for DTIC

A

Dacarbazine

319
Q

T or F:

Platinum drugs are monoalkyating drugs`

A

false as hell

they do cross linking (covalently!)
but they are not alkylating groups because they do not have alkyl groups…

320
Q

Cisplatin:

has a planar complex with leaving groups of _____ and has ___ geometry

A

Chloride groups

cis geometry

321
Q

Cisplatin:

undergoes _______ in aqueous solution

A

reversible hydrolysis

322
Q

Cisplatin:
Equilibrium favors _____ in plasma (because of _____)

Equilibrium favors _____ inside the cell (because of _____)

which one rapidly reacts with other nucleophiles (especially thiols)

A

plasma: Cisplatin because high Cl- concentration

inside cell: aquo form: b/c low Cl- concentration

aquo form reacts fast

323
Q

Platinum crosslink geometry:

aquo form reacts primarily with _______ and ____ in DNA

A

guanine N-7

Adenine N-7

324
Q

Platinum crosslink geometry:
cross links are mainly _____strand
this leads to severe geometrical constraints on DNA and makes a _____ int he cross link strand

A

intrA

sharp bend

325
Q

what are the platinum drugs

A

cisplatin
Carboplatin
oxaliplatin

326
Q

Cisplatin has dose limiting _____

but minimal ______

A

nephrotoxicity

bone marrow toxicity

327
Q

can cisplatin used be at any time in the cell cycle?

A

yes!!

best in G1 phase over S phase though

328
Q

Pro of Carboplatin and Oxaliplatin compared to cisplatin

A

minimal nephrotxicity

329
Q

Carboplatin and Oxaliplatin

are they converted to aquo form slower or faster than cisplatin

A

slower

330
Q

Carboplatin or Oxaliplatin

has dose limiting toxicity of acute sensory nephropathy

A

oxaliplatin

331
Q

Carboplatin or Oxaliplatin

has significant bone marrow toxicity

A

carboplatin

332
Q

Drug resistance to alkylating agents can happen via what 3 main events

A

increased expression of DNA repair enzymes

increased intracellular concentration of non protein thiols (like glutathione)

increased expression of GST (glutahtione s transferase)

333
Q

Drug resistance to alkylating agents:increase expression of DNA repair enzymes:
2 main options of repiar?

A

excision repair (cut out the alkylated bases and replae)

or alkyl group is removed by guanine o-alkyl transferase

334
Q

Other DNA damaging agents from alkylating lecture:

Radium 223 dichloride
gets absorbed selectively into \_\_\_\_\_ and is used to treat \_\_\_\_\_\_ metastases
and
Procarbazine
biggest pro is that \_\_\_\_\_\_
A

radium: bone; bone
pro: it is not cross resistant w/ other alkylating agents

335
Q

Difference b.w nucleobase, nucleoside, and nucleotide

A

base: just the base
side: has the sugar
tide: sugar and phosphate

336
Q

Most antimetabolites are enzyme inhibitors and work as
_______ mimics
_______ mimics

A

substrate

cofactor

337
Q

which nucleobases are the double ringed ones?

A

A & G (purines)

338
Q

Uridine analogs

primarily inhibit ______ synthesis

A

thymidine

339
Q

Antimetabolite Lecture:

Folate typically acts a _____ donor

A

methyl

340
Q

Antimetabolite Lecture:

what drugs are uridine analogs?

A

5-FU (5-fluorouracil)
FUdR (fluorodeoxyuridine)
Capecitabine

341
Q

Antimetabolite Lecture:

5-FU gets translated to _____ by a 2 step transformation

A

FdUMP

342
Q

Antimetabolite Lecture:

what enzymes and steps are used in the 5-FU transformation

A

1st step: thymidine phosphorylase (adding a sugar)

2nd step: thymidine kinase (adding a phosphate)

343
Q

Antimetabolite Lecture:

Uracil or thymidine has a methyl group?

A

thymidine!!

folate is needed to make thymidine — folate will donate the methyl group

344
Q

for uridine analogs:

______ replacement can be given to treat toxicities

A

thymidine

Fall 2018/P3 Year' (16 decks)

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