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Therapeutics Fall 2016 > Module 3 - Oncology > Flashcards

Module 3 - Oncology Flashcards

1
Q

6 essential characteristics of cancer

A
  1. enabling replicative immortality
  2. inducing angiogenesis
  3. resisting cell death
  4. sustaining proliferative signaling
  5. evading growth suppressors
  6. activating invasion and metastasis
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2
Q

neoplasm definition

A

a new growth, may be benign or malignant

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3
Q

neoplasia definition

A

a process of expansion d/t defects in the molecular controls that regulate cellular proliferation and/or death

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4
Q

cancer terminology definition

A

any malignant neoplasm

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5
Q

tumor definition

A

nonspecific term meaning lump or swelling

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6
Q

hyperplasia definition

A

increase in organ/tissue size d/t an increase in the NUMBER of cells

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7
Q

metaplasia definition

A

an adaptive substitution of one type of tissue to another type of tissue

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8
Q

dysplasia definition

A

an abnormal cellular proliferation in which there is loss of normal architecture

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9
Q

anaplasia definition

A

a loss of structural differentiation

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10
Q

desmoplasia definition

A

the formation and proliferation of connective tissues and cells

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11
Q

carcinoma definition

A

malignant neoplasm of epithelial cell origin

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12
Q

adenoma definition

A

epithelial neoplasm which produces or is derived from GLANDULAR tissue

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13
Q

papilloma definition

A

benign tumor of surface epithelium in which neoplastic cells grow outward in finger-like fibrovascular stalks

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14
Q

teratoma definition

A

a germ cell neoplasm made of several differentiated cell/tissue types (that are not normally present at the site)

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15
Q

sarcoma definition

A

malignant neoplasm with origin in mesenchymal tissues or its derivatives (connective tissues- muscles, nerves, bones, etc)

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16
Q

lymphoma and leukemia definition

A

malignant neoplasms of hematopoietic tissues; leukemia: bone marrow
lymphoma: lymphatic system

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17
Q

blastoma definition

A

cancer caused by malignancies in precursor cells (blasts)

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18
Q

melanoma definition

A

cancer of pigment (melanin) producing cells, melanocytes

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19
Q

Which type of cell diagnoses Hodgkin’s Lymphoma?

A

Reed-Sternberg cells

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20
Q

Staging vs Grading of carcinomas

A

Staging (TNM, 0-IV): based on tumor size, location, and number.
Grading (0-4): based on differentiation of tumor cells and tissue.

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21
Q

What does HER2 stand for?

A

Human Epidermal Receptor-2

proto-oncogene

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22
Q

What is the purpose of Oncotype Dx and Mammaprint?

A

Gene signatures that measures the expression of specific genes to:
1. predict recurrence of breast cancer
2. prevent overtreatment
do NOT drive indications for specific therapies

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23
Q

Steps of metastasis

A

(primary neoplasm) progressive growth, vascularization, invasion, detachment, embolization, survival in circulation, arrest, extravasation, evasion of host defense, progressive growth (metastasis)

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24
Q

Summary Staging

A
  • In situ: only in layer of cells where developed.
  • Localized: limited to organ where began.
  • Regional: spread to nearby lymph nodes or tissues/organs.
  • Distant: spread to distant lymph nodes or tissues/organs.
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25
Q

TNM Staging System (abbreviation meaning)

A

T: primary tumor
N: regional lymph nodes
M: distant metastasis
(0-4 each based on extent)

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26
Q

How does Rous Sarcoma Virus (RSV) lead to tumor formation?

A

RSV is a retrovirus that encodes a protein (v-Src) that mimics the eukaryotic protein Src. These proteins drive proliferation and tumor progression (oncogenes).

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27
Q

Which type of cancer is not a hormone-responsive disease?

A 
Ovarian cancer
(although ovaries are hormone-producing organs)
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28
Q

What hormones are primarily targeted in the treatment of hormone-dependent cancers?

A

estradiol (breast, endometrial)

dihydrotestosterone (prostate)

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29
Q

What is the starting point for steroid hormone biosynthesis?

A

Cholesterol

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30
Q

What are the two major classes of anti-estrogen therapy?

A
  1. Aromatase inhibitors (stop estrogen production)

2. SERMs (stop estrogen function)

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31
Q

Tamoxifen MOA

A

SERM (prodrug activated by CYP2D6)

  • in mammary gland: binds ER and blocks estrogen-dependent cell proliferation
  • in bone: activates ER to treat osteoporosis
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32
Q

Tamoxifen indication

A

prevention/treatment for ER+/PR+ breast cancer

  • *effective in BOTH pre- and post-menopausal women
  • *less effective with CYP2D6 variant
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33
Q

Estrogen agonist/antagonist effects

A 
Agonist effects:
-increases incidence of endometrial cancer
-preservation of bone density
-blood clots
Antagonist effects:
-hot flashes
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34
Q

Where are Tamoxifen and Raloxifene estrogen receptor (ER) agonists vs antagonists?

A

Antagonist: breast, brain, uterus (raloxifene)
Agonist: blood, bone, uterus (tamoxifen)

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35
Q

What do SERM and SERD stand for?

A

SERM: Selective Estrogen Receptor Modulator
SERD: Selective Estrogen Receptor DownModulator

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36
Q

Where is the principle source of estrogen in postmenopausal women?

A

Adipocytes

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37
Q

Aromatase inhibitor MOA

A

MOA: inhibit enzyme that produces estrogen
(androgens and progesterone not affected)
Use: estradiol suppression in POSTMENOPAUSAL women

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38
Q

Non-steroidal Aromatase Inhibitors (list, MOA, indication)

A

Letrozole and Anastrozole

  • competitive inhibitors of aromatase
  • treatment of ER+ breast cancer in postmenopausal women
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39
Q

Steroidal Aromatase Inhibitors (list, MOA, indication)

A

Exemestane

  • suicide inhibitor of aromatase (mimics androstenedione)
  • treatment of ER+ breast cancer in postmenopausal women
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40
Q

medrooxyprogesterone acetate (Provera) MOA and indication

A

MOA: progesterone agonist that suppresses estrogen production and induces differentiation of endometrium

Indication: prevention of endometrial cancer in postmenopausal women

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41
Q

LHRH analogs in women (list, MOA, indication)

A

Leuprolide acetate and Goselerin
MOA: GnRH mimics that downregulate pituitary LHRH receptors (severe loss of estrogen w/in 3-4 weeks)
Indication: PREmenopausal breast cancer

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42
Q

LHRH analogs SE in women

A

Acute administration: surge of LH/FSH (agonist/flare effect); transient worsening of sx

Chronic administration: loss of estrogen w/in 3-4 weeks (hot flashes, sexual dysfunction)

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43
Q

Fulvestrant MOA and indication

A

SERD; pure ER antagonist

MOA: binds to ER and degrades receptor
Indication: ER+ metastatic breast cancer in post-menopausal women

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44
Q

Difference between SERM and SERD

A

SERMs and SERDs bind and modulate estrogen receptors

SERDs also degrade estrogen receptors

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45
Q

List SERM and SERD drugs

A

SERM: tamoxifen, raloxifene
SERD: fulvestrant

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46
Q

Which hormonal therapies can be used to treat breast cancer in premenopausal women?

A
  1. LHRH agonists (goserelin, luprolide)

2. Tamoxifen (SERM)

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47
Q

Which hormonal therapies can be used to treat breast cancer in postmenopausal women?

A
  1. tamoxifen (SERM)
  2. nonsteroidal aromatase inhibitors (anastrozole, letrozole)
  3. steroidal aromatase inhibitor (exemestane)
  4. pure anti-estrogen; SERD (fulvestrant)
  5. progestin (megestrol acetate)
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48
Q

LHRH analogs in men (list, MOA, indication)

A

Leuprolide acetate, Goselerin
MOA: prolonged treatment decreases LH receptors and leads to potent loss of T. production within 3-4 weeks (“chemical castration”)
Indication: palliative treatment of advanced prostate cancer

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49
Q

LHRH analogs in men SE

A

Acute administration: surge of LH/FSH (agonist/flare effect); transient worsening of sx

Chronic administration: potent loss of testosterone; gynecomastia, sexual dysfunction (“feminization”)

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50
Q

LHRH antagonists (list, MOA, indication)

A

Abarelix, Degarelix
MOA: blockade of GnRH receptors decreases testosterone production; immediate effects vs LHRH agonists (avoids tumor flare)
Indication: treatment of prostate cancer

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51
Q

Androgen Antagonists (list, MOA, indication)

A

Flutamide, Nilutamide, Bicalutamide, Enzalutamide
MOA: pure AR antagonist- blocks DHT binding (prevents nuclear translation of DHT-AR and binding to DNA)
Indication: treatment of metastatic prostate cancer

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52
Q

Androgen Antagonists SE

A
  • Gynecomastia, hot flashes, impotence (reversible upon d/c)
  • Acute hepatotoxicity (flutamide; rare, fatal)
  • Diarrhea (flutamide)
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53
Q

Abiraterone (indication, MOA, SE)

A

Indication: treatment of prostate cancer
MOA: steroid analogue that inhibits 17 a-hydroxylase and 17,20 lyase
-prevents hormone synthesis from much higher step
SE: increased cholesterol

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54
Q

5-alpha-reductase inhibitors

A

finasteride, dutasteride

  • may delay growth of benign prostate tumors
  • prolonged use may select for more aggressive AR-independent tumors
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55
Q

What is the goal of endocrine (hormonal) therapies?

A

To prolong progression (not curative)

-all patients that initially respond will develop resistance

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56
Q

Which breast cancer treatment is administered as an IM injection once per month?

A

Fulvestrant (SERD)

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57
Q

Types of kinase inhibitors

A

Type I: bind active conformation of kinase
Type II: bind inactive conformation of kinase
Type III and IV: bind allosteric pocket
Covalent: irreversibly bind cysteine residue (blocks ATP binding site)

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58
Q

List the first generation EGFR inhibitors and their MOA

A

Erlotinib and Gefitinib

MOA: small molecule TYPE 1 competitive inhibitors of EGFR tyrosine kinase (turn off proliferative signal)

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59
Q

Indication of Erlotinib and Gefitinib?

A

Treatment of EGFR-mutant metastatic NSCLC

require positive Cobas EGFR Mutation Test

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60
Q

What does EGFR stand for?

A

Epidermal Growth Factor Receptor

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61
Q

What does NSCLC stand for?

A

Non-Small Cell Lung Cancer

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62
Q

Where do tyrosine kinase inhibitors bind?

A

diffuse through membrane and bind intracellularly on the tyrosine kinase domain

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63
Q

What mutation causes resistance to Erlotinib and Gefitinib?

A

T790M mutation

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64
Q

What is the second generation EGFR inhibitor and its MOA/indication?

A

Afatinib
MOA: forms covalent bond with Cys797 on EGFR
Indication: EGFR-mutant NSCLC
(does not benefit patients with T790M mutation)

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65
Q

What is the third generation EGFR inhibitor and its MOA/indication?

A

Osimertinib
MOA: covalent kinase inhibitor specific for T790M mutant EFGR
Indication: metastatic NSCLC that has progressed on other EGFR inhibitor therapy and tests + for the T790M mutation

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66
Q

What does HER2 stand for?

A

Human EGF Receptor 2 (ErbB2)

proto-oncogene genomically amplified in breast and gastric cancers

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67
Q

Lapatinib MOA/indication

A

MOA: small molecule type 1 TKI that inhibits both EGFR and HER2 signaling
Indication: treatment of HER2+ breast cancer and gastric cancer that have failed other therapies (such as trastuzumab)

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68
Q

Herceptin (brand)

A

trastuzumab (generic)

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69
Q

What is a side effect of blocking HER2?

A

Decrease in cardiac function (reversible)

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70
Q

What does VEGFR stand for?

A

Vascular Endothelial Growth Factor Receptor

critical to tumor angiogenesis

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71
Q

Which drugs target cMET and what are their indication?

A

Crizotinib and Cabozantinib
MOA: Type II kinase inhibitors of cMET
Indication: treatment of lung cancers in which cMET is amplified

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72
Q

What does HGF stand for?

A

hepatocyte growth factor

-ligand of cMET (amplified in some lung cancers)

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73
Q

What cancer is associated with the BCR-Abl fusion protein?

A

chronic myelocytic leukemia (CML)

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74
Q

How does the BCR-Abl protein result in malignancy?

A

*Abl protein is a tyrosine kinase

BCR-Abl protein’s kinase activity is constitutively active (very common in CML)

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75
Q

What stem cell factor is associated with GIST and what does GIST stand for?

A

c-Kit
(tyrosine kinase)
Gastrointestinal Stromal Tumor

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76
Q

Gleevec (brand)

A

imatinib (generic)

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77
Q

What does CML stand for?

A

chronic myelocytic leukemia

associated with BCR-Abl fusion protein

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78
Q

What is the MOA and indication of Imatinib?

A

(Gleevec)
MOA: type II small molecule inhibitor of Abl tyrosine kinase (also inhibits c-Kit)
Indication: treatment of CML and GIST

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79
Q

What is the MOA and indication of Ponatinib?

A

MOA: type II tyrosine kinase inhibitor effective against all major mutant forms of BCR-Abl, including T315 gatekeeper mutation
Indication: treatment of CML

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80
Q

What are the BCR-Abl inhibitors that are indicated in the treatment of CML?

A
  1. Imatinib
  2. Nilotinib
  3. Ponatinib
  4. Dasatinib
  5. Bosutinib
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81
Q

What cancer is associated with the ELM4-ALK fusion protein?

A

Occurs in 6% of non-small cell lung cancers (NSCLC)

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82
Q

How does the ELM4-ALK protein result in malignancy?

A

ALK is a tyrosine kinase that becomes constitutively active when fused to ELM4
(results in NSCLC)

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83
Q

What does ALK stand for?

A

Anaplastic Lymphoma Kinase

tyrosine kinase similar to EGFR that may inappropriately fuse to ELM4 gene and cause NSCLC

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84
Q

Crizotinib MOA and indication

A

targets non-specific kinase domain:

  1. inhibits ALK and treats NSCLC caused by EML4-ALK fusion gene
  2. inhibits cMET (HGF receptor) and treats lung cancer
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85
Q

Sorafenib MOA and indication

A

general kinase inhibitor
MOA: inhibits RAF, VEGFR, and p38 MAPK
Indication: advanced renal cell carcinoma, or hepatocellular carcinoma

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86
Q

Vemurafenib (indication, MOA, SE)

A

Indication: metastatic melanoma (requires B-Raf mutation diagnostic test)
MOA: selective inhibitor for B-Raf with V600E mutation, but also activates normal B-Raf and could promote tumor growth if wild-type enzyme
SE: skin legions and arthralgias

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87
Q

Dabrafenib (indication, MOA)

A

Indication: Braf V600E/K mutant metastatic melanoma (in combo with Trametinib)
MOA: second generation Braf-V600 inhibitor

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88
Q

Trametinib (indication, MOA, SE)

A

Indication: Braf V600E/K mutant metastatic melanoma (in combo with Dabrafenib to prevent toxicities with wild-type Braf)
MOA: inhibits kinase activity of MEK1 and MEK2; only approved Type III allosteric inhibitor**
SE: rash

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89
Q

PI3K

A

Phosphoinositide 3-Kinase

lipid kinase that leads to downstream activation of PKB (needed for cancer cell survival)

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90
Q

Idelalisib (indication, MOA)

A

Indication: relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma
MOA: PI3K inhibitor (first approved lipid kinase inhibitor)

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91
Q

Braf inhibitors (indication, list)

A

Indication: Braf-mutant melanoma

  1. Sorafenib
  2. Vemurafenib
  3. Dabrafenib (in combo with Trametinib)
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92
Q

What is the only approved Type III allosteric inhibitor and what is its indication?

A

Trametinib

Indication: Braf V600 mutant melanoma in combination with Dabrafenib (if no prior Braf inhibitor therapy)

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93
Q

Ibrutinib (indication, MOA)

A

Indication: B-cell leukemia
MOA: covalent kinase inhibitor of BTK (downstream from BCR)

94
Q

List two general tyrosine kinase inhibitors that are indicated for renal cell carcinoma

A

Sunitinib

Pazopanib

95
Q

What two kinase inhibitors are indicated for the treatment of metastatic thyroid cancer and what do they inhibit?

A

Cabozantinib: RET (also c-MET and VEGFR)
Vandetanib: RET (also EGFR and VEGFR)

96
Q

What is the order of the proteins in the RAS pathway?

A

RAS -> RAF -> MEK -> MAPK

97
Q

Which drugs are Rapalogs (Rapamycin Analogs) and what do they target?

A
  1. Sirolimus
  2. Temsirolimus
  3. Everolimus
  4. Deforolimus
    Inhibit mTOR (mammalian target of rapamycin)
98
Q

What is mTOR?

A

mammalian target of Rapamycin

serine-threonine kinase

99
Q

What is the MOA of Sirolimus?

A

mTOR inhibitor

MOA: inhibits immune response by blocking IL-2 signaling transduction

100
Q

Temsirolimus (indication, MOA)

A

Indication: treatment of renal cell carcinoma
MOA: mTOR inhibitor

101
Q

Everolimus (indication, MOA)

A

Indication: treatment of renal cell carcinoma and prevention of organ transplant rejection
MOA: mTORC1 inhibitor

102
Q

What are the covalent kinase inhibitors?

A
  1. Afatinib (EGFR, NSCLC)
  2. Osimertinib (EGFR, NSCLC)
  3. Ibrutinib (BTK, B-cell leukemia)
103
Q

What are the driver mutations in lung cancer?

A

EGFR, KRAS, EML4-ALK, cMET

104
Q

What is the substem nomenclature associated with the humanization of monoclonal antibodies?

A 
(all monoclonal antibodies, stem is -mab)
mouse = -o
chimeric = -xi
humanized = -zu
fully human = -u
105
Q

Trastuzumab (indication, MOA)

A

Brand: Herceptin
Indication: treatment of HER2+ breast cancer
MOA: humanized mAb that binds to HER2 and activates the immune system (induces ADCC)

106
Q

Pertuzumab (indication, MOA)

A

Indication: treatment of HER2+ breast cancer in combination with trastuzumab (Herceptin)
MOA: humanized mAb that binds to HER2 and inhibits dimerization*

107
Q

Cetuximab (indication, MOA, SE)

A

Indication: treatment of colorectal and head and neck cancers
MOA: chimeric mAb that competitively inhibits EGF and TNFa binding to EGFR (blocks activation of EGFR-associated kinases and leads to apoptosis)
SE: severe infusion reaction warning, acneiform rash

108
Q

An acneiform rash is a side effect associated with which class of drugs

A

EGFR inhibitors: cetuximab, panitumumab

predictive of better clinical outcome

109
Q

Panitumumab (indication, MOA, SE)

A

Indication: treatment of colorectal and head and neck cancers
MOA: fully human mAb that competitively inhibits EGF and TNFa binding to EGFR (blocks activation of EGFR-associated kinases and leads to apoptosis)
SE: no infusion related toxicities (advantage over cetuximab), acneiform rash

110
Q

Rituximab (indication, MOA)

A

Indication: treatment of B-cell non-Hodgkin’s lymphoma
MOA: chimeric mAb that binds to CD20 and recruits immune effectors to lyse cells (CDC, ADCC)

111
Q

Where is the CD20 protein expressed?

A
  • normal B lymphocytes

- immature pre-B cells

112
Q

What are the second generation anti-CD20 antibodies and what are they used to treat?

A

Ofatumumab and Obinutuzumab

-treat chronic lymphocytic leukemia (CLL)

113
Q

Bevacizumab (indication, MOA)

A

Brand: Avastin
Indication: metastatic colorectal cancer in combination with 5-FU chemotherapy
MOA: humanized mAb that binds VEGF (ligand) and blocks its interaction with epithelial receptors

114
Q

Ramucirumab (indication, MOA)

A

Indication: metastatic colorectal cancer in combination with 5-FU chemotherapy
MOA: human mAb that binds VEGFR2 (receptor) and prevents it from binding to its ligands

115
Q

TDM1 (MOA, indication)

A

Ado-Trastuzumab Emtansine: trastuzumab linked to mertansine (ADC)
MOA: Trastuzumab binds HER2, Mertansine inhibits microtubule activity (cytotoxic)
Indication: HER2+ metastatic breast cancer

116
Q

Brentuximab vedotin (MOA, indication)

A

ADC: anti-CD30 Ab linked to MMAE
MOA: Ab binds CD30 on Reed-Sternberg cells, MMAE inhibits microtubules (cytotoxic)
Indication: Hodgkin’s Lymphoma

117
Q

What cell surface receptors act as brakes or checkpoints on the immune system to prevent T-cell attack?

A

CTLA-4 and PD-1

use Ab binding to prevent inhibitory signaling interaction with T-cells and thereby allow activation of T-cells

118
Q

Ipilimumab (MOA, indication)

A

MOA: human mAb that binds to CTLA-4 receptor on T cells to reverse T cell inhibition
Indication: treatment of advanced metastatic melanoma
SE: severe immune mediated adverse reactions (over-activated immune system; may need high dose CS)

119
Q

What antibodies were designed to bind to inhibitory brake receptors that prevent T-cell activation?

A

CTLA-4: Ipilimumab
PD-1: Pembrolizumab, Nivolumab
PD-L1: Atezolizumab

120
Q

Which type of cells is PD-1 vs PD-L1 expressed on?

A

PD-1: on T-cells
PD-L1: on macrophages and tumor cells
(inhibitory signal to prevent cell killing)

121
Q

Pembrolizumab (MOA, indication)

A

MOA: binds PD-1 receptor on T-cells to prevent inhibitory signaling and lead to enhanced tumor cell killing
Indication: advanced metastatic melanoma, NSCLC

122
Q

Nivolumab (MOA, indication)

A

MOA: binds PD-1 receptor on T-cells to prevent inhibitory signaling and lead to enhanced tumor cell killing
Indication: advanced metastatic melanoma, NSCLC

123
Q

Atezolizumab (MOA, indication)

A

MOA: binds PD-L1 receptor on macrophages and tumor cells to prevent inhibitory signaling and lead to enhanced tumor cell killing
Indication: urothelial carcinoma

124
Q

What is a neo-antigen?

A

Neo-antigens are non-self antigens generally associated with tumor cells (created d/t mutations).
They make cells more susceptible to immune responses (non-self).
**Irradiation prior to immunotherapy enhances efficacy because it causes mutations which creates neo-antigens

125
Q

Blinatumomab (MOA, indication)

A

MOA: bispecific antibody that binds CD3 on T-cells and CD19 on B-cells to bring them closer together and cause lysis (eliminates all B-cells)
Indication: B-cell leukemia

126
Q

How are T-cells genetically modified in Adoptive T-cell Transfers (“tumor vaccines”)?

A

T-cells are removed from a patient and modified to overexpress chimeric antigen receptors (CARs) that will lead to an enhanced immune response when engrafted into the patient.
CAR = TCR + tumor cell receptor
(T-cell activated against whatever CAR binds to)

127
Q

Sipuleucel-T (MOA, indication)

A

Brand: Provenge (PAP-GM-CSF)
MOA: “tumor cell vaccine;” prostate tumor antigen (PAP) linked to immune cell activator (GM-CSF). APCs activated ex vivo with PAP-GM-CSF then reinfused to “stimulate patient’s own immune system to attack cancer”
Indication: refractory prostate cancer

128
Q

HPV vaccines (names and HPV types)

A

Quadrivalent (HPV4): Gardasil
Types 6, 11, 16, 18

Bivalent (HPV2): Cervarix
Types 16, 18

129
Q

Aldesleukin (MOA, indication)

A

Brand: Proleukin (IL-2)
MOA: T-cell driver; highly proinflammatory cytokine
Indication: (variety); used to replenish cells after chemo
SE: extremely non-specific -> hyperinflammatory effects (fever, malaise, anorexia)

130
Q

Aflibercept (MOA, indication)

A

MOA: fusion protein (VEGFR + Fc); binds VEGF ligand to prevent its binding to VEGFR
Indication: metastatic colon cancer in combination with 5-FU, leucovorin, irinotecan

131
Q

HDAC inhibitors (MOA, list)

A

MOA: inhibit histone deacetylases leading to re-expression of tumor suppressor genes which promote tumor cell death

  1. Romidepsin
  2. Vorinostat
  3. Belinostat
132
Q

Romidepsin (MOA, indication)

A

MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: T-cell lymphoma
Warnings: infections (reactivation of DNA viruses)

133
Q

Vorinostat (MOA, indication)

A

MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: recurrent T-cell lymphoma

134
Q

Belinostat (MOA, indication)

A

MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: refractory T-cell lymphoma

135
Q

Azacytidine (MOA, indication)

A

MOA: incorporates into DNA and covalently binds DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes
Indication: myelodysplastic syndrome (MDS)

136
Q

Decitabine (MOA, indication)

A

MOA: incorporates into DNA and covalently binds DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes
Indication: myelodysplastic syndrome (MDS)

137
Q

DNMT inhibitors (MOA, list)

A

MOA: incorporate into DNA and covalently bind DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes

  1. Azacytidine
  2. Decitabine
138
Q

What fusion characterizes acute promyelocytic leukemia (APL)?

A

Fusion of the retinoic acid receptor (RAR) and the promyelocytic leukemia (PML) genes
(fusion protein binds DNA and prevents expression of tumor suppressor genes)

139
Q

Tretinoin (MOA, indication)

A

MOA: differentiation agent; binds retinoic acid receptor (RAR) and induces differentiation and inhibits proliferation of leukemia cells
Indication: acute promyelocytic leukemia (APL)

140
Q

Bexarotene (MOA, indication)

A

MOA: agonist for retinoid X receptors (RXRs); increases differentiation, inhibits proliferation, and induces apoptosis
Indication: T-cell lymphoma

141
Q

Thalidomide (MOA, indication)

A

MOA: block effects of eFGF and VEGF (inhibition of angiogenesis); full MOA unknown
Indication: multiple myeloma (MM) in combination with dexamethasone
SE: potent teratogen!

142
Q

Pomalidomide (MOA, indication)

A

MOA: thalidomide analog; block effects of eFGF and VEGF (inhibition of angiogenesis); full MOA unknown
Indication: multiple myeloma (MM)
**REMS requirement

143
Q

Lenalidomide (MOA, indication)

A

MOA: thalidomide analog; block effects of eFGF and VEGF (inhibition of angiogenesis); full MOA unknown
Indication: MM, MDS, mantle cell lymphoma
Warnings: TLS, tumor flare reaction, hepatotoxicity, SPM
*available PO

144
Q

Carfilzomib (MOA, indication)

A

MOA: proteasome inhibitor; disruption of intracellular protein homeostasis leads to cell apoptosis
Indication: MM
*irreversible; lacks neuropathy SE of Bortezomib

145
Q

Bortezomib (MOA, indication)

A

MOA: proteasome inhibitor; disruption of intracellular protein homeostasis leads to cell apoptosis
Indication: MM
*reversible; neuropathy SE

146
Q

Vismodegib (MOA, indication)

A

MOA: binds and inhibits Smoothened from activating GLI1 in hedgehog signaling pathway (constitutively active in 90% of basal cell carcinomas)
Indication: basal cell carcinoma

147
Q

Sonidegib (MOA, indication)

A

MOA: binds and inhibits Smoothened from activating GLI1 in hedgehog signaling pathway (constitutively active in 90% of basal cell carcinomas)
Indication: basal cell carcinoma

148
Q

Venetoclax (MOA, indication)

A

MOA: BCL-2 inhibitor; frees pro-apoptotic proteins (BAK) from BCL-2 to initiate programmed cell death
Indication: chronic lymphocytic leukemia (CLL)
**1st FDA approved small molecule that inhibits protein-protein interaction!

149
Q

What is the first FDA approved small molecule that inhibits protein-protein interaction?

A

Venetoclax

BCL-2 inhibitor; prevents BCL-2 binding to pro-apoptotic proteins freeing them to initiate cell death

150
Q

Omacetaxine (MOA, indication)

A

MOA: inhibits initial elongation step of protein synthesis
Indication: CML (last line therapy)
*many adverse effects d/t nonspecific inhibition of protein translation

151
Q

Asparaginase (MOA, indication)

A

MOA: breaks down circulating asparagine, starving leukemic cells that are usually deficient in asparagine synthetase
Indication: childhood acute lymphoblastic leukemia

152
Q

Denosumab (MOA, indication)

A

MOA: binds RANKL and prevents its interaction with RANK on osteoclasts thereby inhibiting bone resorption
Indication: MM, advanced breast/prostate cancer
(mimics effect of natural RANKL binder- OPG)

153
Q

What is the natural binder of RANKL?

A

Osteoprotegerin (OPG)

-soluble decoy receptor that binds RANKL preventing its binding to RANK on osteoclasts

154
Q

Cause of Tumor Lysis Syndrome (TLS)?

A

Rapid and massive increase of URIC ACID in the blood that can occur after the first round of chemotherapy in which there is rapid lysis of tumor cells
-leads to severe renal function impairment (precipitation in renal tubules)

155
Q

Allopurinol (MOA, indication)

A

MOA: competitive inhibitor of xanthine oxidase thereby preventing metabolism of xanthine to uric acid
Indication: given PRIOR to chemotherapy for leukemia or lymphoma to prevent TLS caused by massive increase in uric acid levels

156
Q

Rasburicase (MOA, indication)

A

MOA: recombinant urate oxidase that breaks down uric acid to allantoin which is more soluble and can be renally excreted
Indication: prevention and treatment of hyperuricemia in subjects receiving chemotherapy
**higher mammals don’t express urate oxidase

157
Q

What drug is indicated for acute and delayed CINV?

A

Netupitant/Palonosetron (Akynzeo)

  • Netupitant: substance P/NK1 antagonist (acute and delayed phase)
  • Palonosetron: 5-HT3 antagonist (acute phase)
158
Q

Filgrastim (MOA, indication)

A

Brand: Neupogen
MOA: recombinant G-CSF that promotes the proliferation of granulocytes to reduce the period of neutropenia following chemotherapy
Indication: prophylaxis and treatment of chemotherapy-induced granulocytopenia
**Critical timing (1-4 days after chemo)

159
Q

Sargramostim (MOA, indication)

A

Brand: Leukine
MOA: recombinant GM-CSF that promotes proliferation of granulocytes to reduce neutropenia following chemotherapy
Indication: following induction of chemotherapy in AML, before/after bone marrow transplant

160
Q

Oprelvekin (MOA, indication)

A

Brand: Neumega
MOA: IL-11 stimulates megakaryocyte progenitors, increasing production of platelets
Indication: following chemotherapy to reduce thrombocytopenia; alternative to platelet transfusion

161
Q

Epoetin (MOA, indication)

A

Brand: Procrit
MOA: recombinant human EPO that stimulates erythroid progenitors, increasing production of erythrocytes
Indication: treatment of chemotherapy or malignancy-induced anemia

162
Q

Olaparib (MOA, indication)

A

MOA: PARP inhibitor (PARP functions to repair damaged DNA); without PARP or BRCA, cells can’t repair DNA and apoptose
Indication: breast cancer with BRCA 1/2 mutations

163
Q

Guidelines for tumor mass (number of cells)

A

10^9 cells = detected by imaging
10^10 cells = symptoms
10^12 cells = lethal

164
Q

Palbociclib (MOA, indication)

A

MOA: Cdk4/6 kinase inhibitor (prevent regulation of cell cycle initiation)
Indication: breast cancer
*non-specific for any cancer cell; targets dividing cells

165
Q

Most reactive site for alkylation of purine bases in DNA?

A

Guanine N7

166
Q

Which chemotherapeutic agents cause secondary malignancies in long-term cancer survivors?

A

Alkylating agents

monoadducts are mutagenic and carcinogenic

167
Q

Mechlorethamine (MOA, indication)

A

Brand: Mustine
MOA: rapidly alkylates all nucleophiles; extremely reactive (1 minute half life)
Indication: no longer used (extremely toxic)

168
Q

What are general side effects for all alkylators?

A

Myelosuppression
N/V
Carcinogenic
Teratogenic

169
Q

Bendamustine (MOA, indication)

A

Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy

170
Q

Chlorambucil (MOA, indication)

A

Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy

171
Q

Melphalan (MOA, indication)

A

Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy

172
Q

List chemo agents that are nitrogen mustard derivatives

A
  1. Mechlorethamine (Mustine)
  2. Bendamustine
  3. Chlorambucil
  4. Melphalan
  5. Cyclophosphamide
  6. Ifosfamide
173
Q

Cyclophosphamide (MOA, indication)

A

Nitrogen mustard derivative
MOA: prodrug, active metabolite crosslinks DNA (phosphoramide mustard, PM)
Indication: general chemotherapy
SE: mild bone marrow toxicity and hemorrhagic cystitis
(d/t high levels of ADH and d/t acrolein)

174
Q

What is the most useful alkylating agent?

A

Cyclophosphamide

nitrogen mustard derivative; prodrug with modest side effects compared to most alkylating agents

175
Q

Ifosfamide (MOA, indication)

A

Nitrogen mustard derivative
MOA: prodrug, active metabolite crosslinks DNA (phosphoramide mustard, PM)
Indication: general chemotherapy
SE: increased CNS toxicity d/t more dechloroethylated metabolites than Cyclophosphamide

176
Q

Mesna (MOA, indication)

A

MOA: reactive thiol with negatively charged sulfonate group; accumulates in urine and inactivates reactive intermediates (acrolein, eg)
Indication: administered with Cyclophosphamide to prevent hemorrhagic cystitis

177
Q

List chemo agents that are nitrosoureas

A
  1. Carmustine

2. Lomustine

178
Q

Carmustine (MOA, indication)

A

Nitrosourea
MOA: non-enzymatic conversion (chemical reaction) to electrophilic diazonium ion that crosslinks DNA
Indication: glioblastoma and brain tumors (highly lipophilic, crosses BBB)
Toxicity: myelosuppression delayed (3-4 weeks) and prolonged

179
Q

Lomustine (MOA, indication)

A

Nitrosourea
MOA: non-enzymatic conversion (chemical reaction) to electrophilic diazonium ion that crosslinks DNA
Indication: glioblastoma and brain tumors (highly lipophilic, crosses BBB)
Toxicity: myelosuppression delayed (3-4 weeks) and prolonged

180
Q

Busulfan (MOA, indication)

A

Alkyl Sulfonate
MOA: causes cross links between DNA strands; myeloablation toxicity used to kill all cells in bone marrow prior to BMT
Indication: given high-dose with Cyclophosphamide before a bone marrow transplant
Toxicity: Busulfan lung (pulmonary fibrosis)

181
Q

Dacarbazine (MOA, indication)

A

Alkylating agent (IV)
MOA: prodrug with enzymatic conversion to methyldiazonium ion that mono-alkylates DNA (does NOT crosslink)
Indication: general chemotherapy
SE: severe N/V, mild myelosuppression

182
Q

Temozolide (MOA, indication)

A 
Alkylating agent (PO)
MOA: prodrug that chemically reacts to form methyldiazonium ion that alkylates DNA (does NOT require enzymatic conversion like Dacarbazine)
Indication: glioblastoma and brain tumors (crosses BBB)
183
Q

What chemotherapeutic agents alkylate DNA via a diazonium ion?

A
  1. Carmustine
  2. Lomustine
  3. Dacarbazine
  4. Temozolide
184
Q

Toxicities of the Platinum drugs

A
  1. Cisplatin: dose-limiting nephrotoxicity, severe n/v, minimal myelosuppression
  2. Carboplatin: significant myelosuppression, minimal nephrotoxicity
  3. Oxaliplatin: dose-limiting acute sensory neuropathy, minimal nephrotoxicity
185
Q

Cisplatin (MOA, indication)

A

MOA: non-enzymatic conversion to active aquo form that covalently reacts with DNA to form intrastrand crosslinks
Indication: many solid tumors
Toxicity: nephrotoxicity, minimal myelosuppression

186
Q

Carboplatin (MOA, indication)

A

MOA: non-enzymatic conversion to active aquo form that covalently reacts with DNA to form intrastrand crosslinks
Indication: many solid tumors
Toxicity: myelosuppression, minimal nephrotoxicity

187
Q

Oxaliplatin (MOA, indication)

A

MOA: non-enzymatic conversion to active aquo form that covalently reacts with DNA to form intrastrand crosslinks
Indication: many solid tumors AND colorectal cancers
Toxicity: neuropathy, minimal nephrotoxicity

188
Q

Mechanisms of drug resistance to alkylating agents and platinum drugs

A
  1. Increased DNA repair enzymes (Guanine O-alkyl transferase)
  2. Increased free thiols (Glutathione)
  3. Increased glutathione S-transferase (GST)
    - neutralization of alkylating agents by glutathione
189
Q

Mitomycin C (MOA, indication)

A

DNA alkylator
MOA: aziridine-containing natural product that bifunctionally crosslinks similar to Mustine
Indication: general chemotherapy

190
Q

What chemotherapeutic agents alkylate DNA via an aziridine?

A
  1. Mechlorethamine (Mustine) and derivatives: Bendamustine, Chlorambucil, and Melphalan
  2. Mitomycin C
191
Q

Radium 223 dichloride (MOA, indication)

A

MOA: absorbed into bone and produces short range alpha radiation that damages DNA
Indication: treats bone metastases

192
Q

Procarbazine (MOA, indication)

A

MOA: unclear; inhibits DNA, RNA, and protein synthesis
Indication: general chemotherapy

193
Q

5-Fluorouracil (MOA, indication)

A

5-FU, fluorinated uracil analog
MOA: 5-FU converted to FdUMP which inhibits thymidylate synthase thereby depleting thymidine and inhibiting DNA synthesis (cell death)
Indication: blood cancers, myeloid cancers
**DPD deficiency d/t polymorphism can lead to life-threatening toxicity to 5-FU

194
Q

Drug interactions with 5-FU

A

Thymidine

  • 5-FU then thymidine = rescues cytotoxic effect
  • thymidine then 5-FU = enhanced cytotoxic effect

Leucovorate
-folate cofactor that increases 5-FU efficacy

195
Q

Fluorodeoxyuridine (MOA, indication)

A

Nucleoside version of 5-FU
MOA: 5-FU converted to FdUMP which inhibits thymidylate synthase thereby depleting thymidine and inhibiting DNA synthesis (cell death)
Indication: blood cancers, myeloid cancers

196
Q

Capecitabine (MOA, indication)

A

Orally active prodrug of 5-FU
MOA: 5-FU converted to FdUMP which inhibits thymidylate synthase thereby depleting thymidine and inhibiting DNA synthesis (cell death)
Indication: blood cancers, myeloid cancers

197
Q

Uracil analogs (MOA, list)

A

MOA: inhibition of thymidine synthase

  1. 5-Fluorouracil
  2. Fluorodeoxyuridine
  3. Capecitabine
198
Q

Cytosine analogs (MOA, list)

A

MOA: inhibition of DNA synthesis

  1. Cytosine arabinoside (Ara-C)
  2. Difluorodeoxycytidine (Gemcitabine)
199
Q

Cytosine Arabinoside (MOA, indication)

A

Ara-C, cytosine analog
MOA: mimics deoxycytidine except arabinose sugar instead of deoxyribose; competitive inhibitor of DNA polymerase and can be incorporated into DNA to inhibit further synthesis
Indication: meningeal leukemia and lymphoma
*Cytidine deaminase inactivates Ara-C

200
Q

Difluorodeoxycytidine (MOA, indication)

A

Gemcitabine, cytosine analog
MOA: inhibits ribonucleotide reductase and incorporates into DNA to inhibit further synthesis
Indication: meningeal leukemia and lymphoma
*greater potency than Ara-C

201
Q

Purine analogs (MOA, list)

A

MOA: interfere with purine nucleotide biosynthesis

  1. 6-Mercaptopurine
  2. 6-Thioguanine

MOA: incorporate into DNA/RNA to inhibit replication and transcription

  1. Fludarabine
  2. Nelarabine
  3. Cladribine
202
Q

6-Mercaptopurine (MOA, indication)

A

MOA: thio analog of adenine (nucleobase) that blocks the synthesis of purine nucleotides
Activating enzyme: HGPRT
Metabolizing enzyme: TPMT
**TPMT polymorphism increases risk of hematologic toxicity
**DDI with allopurinol (competition for xanthine oxidase blocks breakdown of MP and increases toxicity)

203
Q

6-Thioguanine (MOA, indication)

A

MOA: thio analog of guanine (nucleobase) that blocks the synthesis of purine nucleotides
Activating enzyme: HGPRT
Metabolizing enzyme: TPMT
**Allopurinol does NOT block breakdown of 6-TG

204
Q

Fludarabine (MOA, indication)

A

Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers

205
Q

Nelarabine (MOA, indication)

A

Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers

206
Q

Cladribine

A

Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers

207
Q

List the purine analog inhibitors of DNA/RNA synthesis

A

Arabino adenosine analogs

  1. Fludarabine
  2. Nelarabine
  3. Cladribine
208
Q

What reaction is DHFR responsible for?

A

Reduction of dihydrofolate to tetrahydrofolate

essential for folic acid use as a cofactor in nucleotide synthesis, etc

209
Q

List the DHFR inhibitors

A
  1. Methotrexate
  2. Pralatrexate
  3. Pemetrexed
210
Q

Methotrexate (MOA, indication)

A

MOA: DHFR inhibitor
*Leucovorin rescues normal cells from toxic effects of MTX (reverses effects of DHFR inhibition by increasing tetrahydrofolate in cells)

211
Q

Pralatrexate (MOA, indication)

A

MOA: DHFR inhibitor

*Selectively enters cells expressing RFC-1 (cancer cells generally have more folate transporters on surface)

212
Q

Pemetrexed (MOA, indication)

A

MOA: inhibits DHFR, thymidylate synthase, and glycinamide ribonucleotide formyltransferase
*decreased risk of drug resistance

213
Q

Leucovorin (MOA, indication)

A

MOA: stable folate cofactor that is converted to tetrahydrofolate intracellularly
Indications:
1. Rescues normal cells from MTX toxicity by reversing effect of DHFR inhibition
2. Enhances efficacy of 5-FU and Capecitabine (folate cofactor needed for uridine analog MOA- inhibiting thymidylate synthase)

214
Q

Hydroxyurea (MOA, indication)

A

MOA: inhibits ribonucleotide reductase; decreases production of deoxyribonucleotides needed for DNA synthesis
*cells halted in S-phase

215
Q

Actinomycin C (MOA, indication)

A

MOA: binds DNA and inhibits transcription by RNA polymerase and DNA replication
*non-cell cycle specific

216
Q

Camptothecin (MOA, indication)

A

Topoisomerase I inhibitor (intercalator)
MOA: binds Topo1 and forms a ternary drug-enzyme-DNA complex, blocking DNA religation (S-phase inhibition)
Indication: not used clinically d/t severe and unpredictable toxicity

217
Q

Topotecan (MOA, indication)

A

Topoisomerase I inhibitor (intercalator)
MOA: binds Topo1 and forms a ternary drug-enzyme-DNA complex, blocking DNA religation (S-phase inhibition)
*water soluble analog of camptothecin

218
Q

Irinotecan (MOA, indication)

A

Topoisomerase I inhibitor (intercalator)
MOA: binds Topo1 and forms a ternary drug-enzyme-DNA complex, blocking DNA religation (S-phase inhibition)

**UGT1A1 polymorphism increases toxicity of Irinotecan (enzyme responsible for metabolizing SN-38, active metabolite of irinotecan)

219
Q

Topoisomerase I inhibitors (MOA, list)

A

MOA: bind Topo1 and forms a ternary drug-enzyme-DNA complex, blocking DNA religation (S-phase inhibition)

  1. Camptothecin
  2. Topotecan
  3. Irinotecan
220
Q

Polymorphisms (4)

A
  1. BRCA1/2 (PARP inhibitor, olaparib)
  2. DPD (Uridine analog, 5-FU)
  3. TMPT (Purine analog, 6-MP)
  4. UGT1A1 (Topo1 inhibitor, Irinotecan)
221
Q

Major side effect of Topoisomerase II inhibitors?

A

Cardiotoxicity

-d/t free radical damage (heart tissue has low levels of neutralizing enzymes)

222
Q

Topoisomerase II inhibitors - Anthracyclines (MOA, list)

A

MOA: intercalate, form free radicals, and inhibit Topo2A (non-cell cycle specific, G2/M)

  1. Daunorubicin
  2. Doxorubicin
  3. Epirubicin
  4. Idarubicin
223
Q

Dexrazoxane (MOA, indication)

A

MOA: metal chelating agent that binds iron and blocks iron-oxygen induced toxicities
Indication: protects against anthracycline-induced cardiotoxicity (caused by iron-catalyzed free radicals)
*does not prevent chemo efficacy

224
Q

Mitoxantrone (MOA, indication)

A

(not an Anthracycline but related structure)
MOA: intercalation and inhibition of Topo2
*No free radical formation and cardiotoxicity

225
Q

Topoisomerase II inhibitors - Epipodophyllotoxins (MOA, list)

A

MOA: inhibit religation of double stranded breaks induced by Topo2 but does NOT intercalate (G2 block**)

  1. Etoposide
  2. Teniposide
226
Q

Topoisomerase inhibitors sensitive to GST?

A 
-Glutathione S-transferase neutralizes effectiveness
Topo1 inhibitors (Camptothecins)
Topo2 inhibitors (Anthracyclines only)
227
Q

Bleomycin (MOA, indication)

A

MOA: intercalates into DNA and generates free radical formation which lead to single and double strand breaks (G2/M phase specific)
Toxicity: pulmonary toxicity (d/t low levels of aminohydrolase)

228
Q

Erubulin (MOA, indication)

A

MOA: microtubule de-polymerizing agent (but not destabilizing); binds at ends and prevents elongation
*low rate of neurotoxicity

229
Q

Vinca Alkaloids (MOA, list)

A

Microtubule Destabilizers
MOA: bind + end of tubulin and inhibit assembly (polymerization); lead to metaphase and mitotic arrest
1. Vincristine
2. Vinblastine
3. Vinorelbine
*Toxicity: peripheral neuropathy, myelosuppression

230
Q

Taxanes (MOA, list)

A

Microtubule Stabilizers
MOA: bind - end of tubulin and inhibit shortening (depolymerization); decrease free tubulin and prevent microtubule formation at spindle
1. Paclitaxel
2. Doetaxel
3. Cabazitaxel
*Toxicity: myelosuppression, neurotoxicity (reversible)

231
Q

Epithilones (MOA, list)

A

Microtubule Stablizers
MOA: bind tubulin and inhibit tubulin depolymerization and promote microtubule stabilization
1. Epithilone
2. Ixabepilone
*Toxicity: same as Taxanes- neurotoxicity (reversible)

232
Q

What drugs are a poor substrate for MDR and PGP pumps?

A

Cabazitaxel, Epthilone, Ixabepilone

microtubule stabilizers

Therapeutics Fall 2016 (4 decks)

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