Module 3 - Oncology Flashcards
1
Q
6 essential characteristics of cancer
A
- enabling replicative immortality
- inducing angiogenesis
- resisting cell death
- sustaining proliferative signaling
- evading growth suppressors
- activating invasion and metastasis
2
Q
neoplasm definition
A
a new growth, may be benign or malignant
3
Q
neoplasia definition
A
a process of expansion d/t defects in the molecular controls that regulate cellular proliferation and/or death
4
Q
cancer terminology definition
A
any malignant neoplasm
5
Q
tumor definition
A
nonspecific term meaning lump or swelling
6
Q
hyperplasia definition
A
increase in organ/tissue size d/t an increase in the NUMBER of cells
7
Q
metaplasia definition
A
an adaptive substitution of one type of tissue to another type of tissue
8
Q
dysplasia definition
A
an abnormal cellular proliferation in which there is loss of normal architecture
9
Q
anaplasia definition
A
a loss of structural differentiation
10
Q
desmoplasia definition
A
the formation and proliferation of connective tissues and cells
11
Q
carcinoma definition
A
malignant neoplasm of epithelial cell origin
12
Q
adenoma definition
A
epithelial neoplasm which produces or is derived from GLANDULAR tissue
13
Q
papilloma definition
A
benign tumor of surface epithelium in which neoplastic cells grow outward in finger-like fibrovascular stalks
14
Q
teratoma definition
A
a germ cell neoplasm made of several differentiated cell/tissue types (that are not normally present at the site)
15
Q
sarcoma definition
A
malignant neoplasm with origin in mesenchymal tissues or its derivatives (connective tissues- muscles, nerves, bones, etc)
16
Q
lymphoma and leukemia definition
A
malignant neoplasms of hematopoietic tissues; leukemia: bone marrow
lymphoma: lymphatic system
17
Q
blastoma definition
A
cancer caused by malignancies in precursor cells (blasts)
18
Q
melanoma definition
A
cancer of pigment (melanin) producing cells, melanocytes
19
Q
Which type of cell diagnoses Hodgkin’s Lymphoma?
A
Reed-Sternberg cells
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.
21
Q
What does HER2 stand for?
A
Human Epidermal Receptor-2
proto-oncogene
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
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)
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.
25
TNM Staging System (abbreviation meaning)
T: primary tumor
N: regional lymph nodes
M: distant metastasis
(0-4 each based on extent)
26
How does Rous Sarcoma Virus (RSV) lead to tumor formation?
RSV is a retrovirus that encodes a protein (v-Src) that mimics the eukaryotic protein Src. These proteins drive proliferation and tumor progression (oncogenes).
27
Which type of cancer is not a hormone-responsive disease?
```
Ovarian cancer
(although ovaries are hormone-producing organs)
```
28
What hormones are primarily targeted in the treatment of hormone-dependent cancers?
estradiol (breast, endometrial)
| dihydrotestosterone (prostate)
29
What is the starting point for steroid hormone biosynthesis?
Cholesterol
30
What are the two major classes of anti-estrogen therapy?
1. Aromatase inhibitors (stop estrogen production)
| 2. SERMs (stop estrogen function)
31
Tamoxifen MOA
SERM (prodrug activated by CYP2D6)
- in mammary gland: binds ER and blocks estrogen-dependent cell proliferation
- in bone: activates ER to treat osteoporosis
32
Tamoxifen indication
prevention/treatment for ER+/PR+ breast cancer
* *effective in BOTH pre- and post-menopausal women
* *less effective with CYP2D6 variant
33
Estrogen agonist/antagonist effects
```
Agonist effects:
-increases incidence of endometrial cancer
-preservation of bone density
-blood clots
Antagonist effects:
-hot flashes
```
34
Where are Tamoxifen and Raloxifene estrogen receptor (ER) agonists vs antagonists?
Antagonist: breast, brain, uterus (raloxifene)
Agonist: blood, bone, uterus (tamoxifen)
35
What do SERM and SERD stand for?
SERM: Selective Estrogen Receptor Modulator
SERD: Selective Estrogen Receptor DownModulator
36
Where is the principle source of estrogen in postmenopausal women?
Adipocytes
37
Aromatase inhibitor MOA
MOA: inhibit enzyme that produces estrogen
(androgens and progesterone not affected)
Use: estradiol suppression in POSTMENOPAUSAL women
38
Non-steroidal Aromatase Inhibitors (list, MOA, indication)
Letrozole and Anastrozole
- competitive inhibitors of aromatase
- treatment of ER+ breast cancer in postmenopausal women
39
Steroidal Aromatase Inhibitors (list, MOA, indication)
Exemestane
- suicide inhibitor of aromatase (mimics androstenedione)
- treatment of ER+ breast cancer in postmenopausal women
40
medrooxyprogesterone acetate (Provera) MOA and indication
MOA: progesterone agonist that suppresses estrogen production and induces differentiation of endometrium
Indication: prevention of endometrial cancer in postmenopausal women
41
LHRH analogs in women (list, MOA, indication)
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
42
LHRH analogs SE in women
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)
43
Fulvestrant MOA and indication
SERD; pure ER antagonist
MOA: binds to ER and degrades receptor
Indication: ER+ metastatic breast cancer in post-menopausal women
44
Difference between SERM and SERD
SERMs and SERDs bind and modulate estrogen receptors
| SERDs also degrade estrogen receptors
45
List SERM and SERD drugs
SERM: tamoxifen, raloxifene
SERD: fulvestrant
46
Which hormonal therapies can be used to treat breast cancer in premenopausal women?
1. LHRH agonists (goserelin, luprolide)
| 2. Tamoxifen (SERM)
47
Which hormonal therapies can be used to treat breast cancer in postmenopausal women?
1. tamoxifen (SERM)
2. nonsteroidal aromatase inhibitors (anastrozole, letrozole)
3. steroidal aromatase inhibitor (exemestane)
4. pure anti-estrogen; SERD (fulvestrant)
5. progestin (megestrol acetate)
48
LHRH analogs in men (list, MOA, indication)
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
49
LHRH analogs in men SE
Acute administration: surge of LH/FSH (agonist/flare effect); transient worsening of sx
Chronic administration: potent loss of testosterone; gynecomastia, sexual dysfunction ("feminization")
50
LHRH antagonists (list, MOA, indication)
Abarelix, Degarelix
MOA: blockade of GnRH receptors decreases testosterone production; immediate effects vs LHRH agonists (avoids tumor flare)
Indication: treatment of prostate cancer
51
Androgen Antagonists (list, MOA, indication)
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
52
Androgen Antagonists SE
- Gynecomastia, hot flashes, impotence (reversible upon d/c)
- Acute hepatotoxicity (flutamide; rare, fatal)
- Diarrhea (flutamide)
53
Abiraterone (indication, MOA, SE)
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
54
5-alpha-reductase inhibitors
finasteride, dutasteride
- may delay growth of benign prostate tumors
- prolonged use may select for more aggressive AR-independent tumors
55
What is the goal of endocrine (hormonal) therapies?
To prolong progression (not curative)
| -all patients that initially respond will develop resistance
56
Which breast cancer treatment is administered as an IM injection once per month?
Fulvestrant (SERD)
57
Types of kinase inhibitors
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)
58
List the first generation EGFR inhibitors and their MOA
Erlotinib and Gefitinib
| MOA: small molecule TYPE 1 competitive inhibitors of EGFR tyrosine kinase (turn off proliferative signal)
59
Indication of Erlotinib and Gefitinib?
Treatment of EGFR-mutant metastatic NSCLC
| require positive Cobas EGFR Mutation Test
60
What does EGFR stand for?
Epidermal Growth Factor Receptor
61
What does NSCLC stand for?
Non-Small Cell Lung Cancer
62
Where do tyrosine kinase inhibitors bind?
diffuse through membrane and bind intracellularly on the tyrosine kinase domain
63
What mutation causes resistance to Erlotinib and Gefitinib?
T790M mutation
64
What is the second generation EGFR inhibitor and its MOA/indication?
Afatinib
MOA: forms covalent bond with Cys797 on EGFR
Indication: EGFR-mutant NSCLC
(does not benefit patients with T790M mutation)
65
What is the third generation EGFR inhibitor and its MOA/indication?
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
66
What does HER2 stand for?
Human EGF Receptor 2 (ErbB2)
| proto-oncogene genomically amplified in breast and gastric cancers
67
Lapatinib MOA/indication
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)
68
Herceptin (brand)
trastuzumab (generic)
69
What is a side effect of blocking HER2?
Decrease in cardiac function (reversible)
70
What does VEGFR stand for?
Vascular Endothelial Growth Factor Receptor
| critical to tumor angiogenesis
71
Which drugs target cMET and what are their indication?
Crizotinib and Cabozantinib
MOA: Type II kinase inhibitors of cMET
Indication: treatment of lung cancers in which cMET is amplified
72
What does HGF stand for?
hepatocyte growth factor
| -ligand of cMET (amplified in some lung cancers)
73
What cancer is associated with the BCR-Abl fusion protein?
chronic myelocytic leukemia (CML)
74
How does the BCR-Abl protein result in malignancy?
*Abl protein is a tyrosine kinase
| BCR-Abl protein's kinase activity is constitutively active (very common in CML)
75
What stem cell factor is associated with GIST and what does GIST stand for?
c-Kit
(tyrosine kinase)
Gastrointestinal Stromal Tumor
76
Gleevec (brand)
imatinib (generic)
77
What does CML stand for?
chronic myelocytic leukemia
| associated with BCR-Abl fusion protein
78
What is the MOA and indication of Imatinib?
(Gleevec)
MOA: type II small molecule inhibitor of Abl tyrosine kinase (also inhibits c-Kit)
Indication: treatment of CML and GIST
79
What is the MOA and indication of Ponatinib?
MOA: type II tyrosine kinase inhibitor effective against all major mutant forms of BCR-Abl, including T315 gatekeeper mutation
Indication: treatment of CML
80
What are the BCR-Abl inhibitors that are indicated in the treatment of CML?
1. Imatinib
2. Nilotinib
3. Ponatinib
4. Dasatinib
5. Bosutinib
81
What cancer is associated with the ELM4-ALK fusion protein?
Occurs in 6% of non-small cell lung cancers (NSCLC)
82
How does the ELM4-ALK protein result in malignancy?
ALK is a tyrosine kinase that becomes constitutively active when fused to ELM4
(results in NSCLC)
83
What does ALK stand for?
Anaplastic Lymphoma Kinase
| tyrosine kinase similar to EGFR that may inappropriately fuse to ELM4 gene and cause NSCLC
84
Crizotinib MOA and indication
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
85
Sorafenib MOA and indication
general kinase inhibitor
MOA: inhibits RAF, VEGFR, and p38 MAPK
Indication: advanced renal cell carcinoma, or hepatocellular carcinoma
86
Vemurafenib (indication, MOA, SE)
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
87
Dabrafenib (indication, MOA)
Indication: Braf V600E/K mutant metastatic melanoma (in combo with Trametinib)
MOA: second generation Braf-V600 inhibitor
88
Trametinib (indication, MOA, SE)
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
89
PI3K
Phosphoinositide 3-Kinase
| lipid kinase that leads to downstream activation of PKB (needed for cancer cell survival)
90
Idelalisib (indication, MOA)
Indication: relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma
MOA: PI3K inhibitor (first approved lipid kinase inhibitor)
91
Braf inhibitors (indication, list)
Indication: Braf-mutant melanoma
1. Sorafenib
2. Vemurafenib
3. Dabrafenib (in combo with Trametinib)
92
What is the only approved Type III allosteric inhibitor and what is its indication?
Trametinib
| Indication: Braf V600 mutant melanoma in combination with Dabrafenib (if no prior Braf inhibitor therapy)
93
Ibrutinib (indication, MOA)
Indication: B-cell leukemia
MOA: covalent kinase inhibitor of BTK (downstream from BCR)
94
List two general tyrosine kinase inhibitors that are indicated for renal cell carcinoma
Sunitinib
| Pazopanib
95
What two kinase inhibitors are indicated for the treatment of metastatic thyroid cancer and what do they inhibit?
Cabozantinib: RET (also c-MET and VEGFR)
Vandetanib: RET (also EGFR and VEGFR)
96
What is the order of the proteins in the RAS pathway?
RAS -> RAF -> MEK -> MAPK
97
Which drugs are Rapalogs (Rapamycin Analogs) and what do they target?
1. Sirolimus
2. Temsirolimus
3. Everolimus
4. Deforolimus
Inhibit mTOR (mammalian target of rapamycin)
98
What is mTOR?
mammalian target of Rapamycin
| serine-threonine kinase
99
What is the MOA of Sirolimus?
mTOR inhibitor
| MOA: inhibits immune response by blocking IL-2 signaling transduction
100
Temsirolimus (indication, MOA)
Indication: treatment of renal cell carcinoma
MOA: mTOR inhibitor
101
Everolimus (indication, MOA)
Indication: treatment of renal cell carcinoma and prevention of organ transplant rejection
MOA: mTORC1 inhibitor
102
What are the covalent kinase inhibitors?
1. Afatinib (EGFR, NSCLC)
2. Osimertinib (EGFR, NSCLC)
3. Ibrutinib (BTK, B-cell leukemia)
103
What are the driver mutations in lung cancer?
EGFR, KRAS, EML4-ALK, cMET
104
What is the substem nomenclature associated with the humanization of monoclonal antibodies?
```
(all monoclonal antibodies, stem is -mab)
mouse = -o
chimeric = -xi
humanized = -zu
fully human = -u
```
105
Trastuzumab (indication, MOA)
Brand: Herceptin
Indication: treatment of HER2+ breast cancer
MOA: humanized mAb that binds to HER2 and activates the immune system (induces ADCC)
106
Pertuzumab (indication, MOA)
Indication: treatment of HER2+ breast cancer in combination with trastuzumab (Herceptin)
MOA: humanized mAb that binds to HER2 and inhibits dimerization*
107
Cetuximab (indication, MOA, SE)
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
An acneiform rash is a side effect associated with which class of drugs
EGFR inhibitors: cetuximab, panitumumab
| predictive of better clinical outcome
109
Panitumumab (indication, MOA, SE)
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
Rituximab (indication, MOA)
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
Where is the CD20 protein expressed?
- normal B lymphocytes
| - immature pre-B cells
112
What are the second generation anti-CD20 antibodies and what are they used to treat?
Ofatumumab and Obinutuzumab
| -treat chronic lymphocytic leukemia (CLL)
113
Bevacizumab (indication, MOA)
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
Ramucirumab (indication, MOA)
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
TDM1 (MOA, indication)
Ado-Trastuzumab Emtansine: trastuzumab linked to mertansine (ADC)
MOA: Trastuzumab binds HER2, Mertansine inhibits microtubule activity (cytotoxic)
Indication: HER2+ metastatic breast cancer
116
Brentuximab vedotin (MOA, indication)
ADC: anti-CD30 Ab linked to MMAE
MOA: Ab binds CD30 on Reed-Sternberg cells, MMAE inhibits microtubules (cytotoxic)
Indication: Hodgkin's Lymphoma
117
What cell surface receptors act as brakes or checkpoints on the immune system to prevent T-cell attack?
CTLA-4 and PD-1
| use Ab binding to prevent inhibitory signaling interaction with T-cells and thereby allow activation of T-cells
118
Ipilimumab (MOA, indication)
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
What antibodies were designed to bind to inhibitory brake receptors that prevent T-cell activation?
CTLA-4: Ipilimumab
PD-1: Pembrolizumab, Nivolumab
PD-L1: Atezolizumab
120
Which type of cells is PD-1 vs PD-L1 expressed on?
PD-1: on T-cells
PD-L1: on macrophages and tumor cells
(inhibitory signal to prevent cell killing)
121
Pembrolizumab (MOA, indication)
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
Nivolumab (MOA, indication)
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
Atezolizumab (MOA, indication)
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
What is a neo-antigen?
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
Blinatumomab (MOA, indication)
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
How are T-cells genetically modified in Adoptive T-cell Transfers ("tumor vaccines")?
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
Sipuleucel-T (MOA, indication)
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
HPV vaccines (names and HPV types)
Quadrivalent (HPV4): Gardasil
Types 6, 11, 16, 18
Bivalent (HPV2): Cervarix
Types 16, 18
129
Aldesleukin (MOA, indication)
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
Aflibercept (MOA, indication)
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
HDAC inhibitors (MOA, list)
MOA: inhibit histone deacetylases leading to re-expression of tumor suppressor genes which promote tumor cell death
1. Romidepsin
2. Vorinostat
3. Belinostat
132
Romidepsin (MOA, indication)
MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: T-cell lymphoma
Warnings: infections (reactivation of DNA viruses)
133
Vorinostat (MOA, indication)
MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: recurrent T-cell lymphoma
134
Belinostat (MOA, indication)
MOA: HDAC inhibitor that leads to reexpression of tumor suppressor genes
Indication: refractory T-cell lymphoma
135
Azacytidine (MOA, indication)
MOA: incorporates into DNA and covalently binds DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes
Indication: myelodysplastic syndrome (MDS)
136
Decitabine (MOA, indication)
MOA: incorporates into DNA and covalently binds DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes
Indication: myelodysplastic syndrome (MDS)
137
DNMT inhibitors (MOA, list)
MOA: incorporate into DNA and covalently bind DNMT enzymes preventing methylation and resulting in reactivation of tumor suppressor genes
1. Azacytidine
2. Decitabine
138
What fusion characterizes acute promyelocytic leukemia (APL)?
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
Tretinoin (MOA, indication)
MOA: differentiation agent; binds retinoic acid receptor (RAR) and induces differentiation and inhibits proliferation of leukemia cells
Indication: acute promyelocytic leukemia (APL)
140
Bexarotene (MOA, indication)
MOA: agonist for retinoid X receptors (RXRs); increases differentiation, inhibits proliferation, and induces apoptosis
Indication: T-cell lymphoma
141
Thalidomide (MOA, indication)
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
Pomalidomide (MOA, indication)
MOA: thalidomide analog; block effects of eFGF and VEGF (inhibition of angiogenesis); full MOA unknown
Indication: multiple myeloma (MM)
**REMS requirement
143
Lenalidomide (MOA, indication)
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
Carfilzomib (MOA, indication)
MOA: proteasome inhibitor; disruption of intracellular protein homeostasis leads to cell apoptosis
Indication: MM
*irreversible; lacks neuropathy SE of Bortezomib
145
Bortezomib (MOA, indication)
MOA: proteasome inhibitor; disruption of intracellular protein homeostasis leads to cell apoptosis
Indication: MM
*reversible; neuropathy SE
146
Vismodegib (MOA, indication)
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
Sonidegib (MOA, indication)
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
Venetoclax (MOA, indication)
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
What is the first FDA approved small molecule that inhibits protein-protein interaction?
Venetoclax
| BCL-2 inhibitor; prevents BCL-2 binding to pro-apoptotic proteins freeing them to initiate cell death
150
Omacetaxine (MOA, indication)
MOA: inhibits initial elongation step of protein synthesis
Indication: CML (last line therapy)
*many adverse effects d/t nonspecific inhibition of protein translation
151
Asparaginase (MOA, indication)
MOA: breaks down circulating asparagine, starving leukemic cells that are usually deficient in asparagine synthetase
Indication: childhood acute lymphoblastic leukemia
152
Denosumab (MOA, indication)
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
What is the natural binder of RANKL?
Osteoprotegerin (OPG)
| -soluble decoy receptor that binds RANKL preventing its binding to RANK on osteoclasts
154
Cause of Tumor Lysis Syndrome (TLS)?
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
Allopurinol (MOA, indication)
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
Rasburicase (MOA, indication)
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
What drug is indicated for acute and delayed CINV?
Netupitant/Palonosetron (Akynzeo)
- Netupitant: substance P/NK1 antagonist (acute and delayed phase)
- Palonosetron: 5-HT3 antagonist (acute phase)
158
Filgrastim (MOA, indication)
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
Sargramostim (MOA, indication)
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
Oprelvekin (MOA, indication)
Brand: Neumega
MOA: IL-11 stimulates megakaryocyte progenitors, increasing production of platelets
Indication: following chemotherapy to reduce thrombocytopenia; alternative to platelet transfusion
161
Epoetin (MOA, indication)
Brand: Procrit
MOA: recombinant human EPO that stimulates erythroid progenitors, increasing production of erythrocytes
Indication: treatment of chemotherapy or malignancy-induced anemia
162
Olaparib (MOA, indication)
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
Guidelines for tumor mass (number of cells)
10^9 cells = detected by imaging
10^10 cells = symptoms
10^12 cells = lethal
164
Palbociclib (MOA, indication)
MOA: Cdk4/6 kinase inhibitor (prevent regulation of cell cycle initiation)
Indication: breast cancer
*non-specific for any cancer cell; targets dividing cells
165
Most reactive site for alkylation of purine bases in DNA?
Guanine N7
166
Which chemotherapeutic agents cause secondary malignancies in long-term cancer survivors?
Alkylating agents
| monoadducts are mutagenic and carcinogenic
167
Mechlorethamine (MOA, indication)
Brand: Mustine
MOA: rapidly alkylates all nucleophiles; extremely reactive (1 minute half life)
Indication: no longer used (extremely toxic)
168
What are general side effects for all alkylators?
Myelosuppression
N/V
Carcinogenic
Teratogenic
169
Bendamustine (MOA, indication)
Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy
170
Chlorambucil (MOA, indication)
Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy
171
Melphalan (MOA, indication)
Mustine derivative
MOA: aryl groups added to decrease nucleophilicity of nitrogen (reduced reactivity, longer half life)
Indication: general chemotherapy
172
List chemo agents that are nitrogen mustard derivatives
1. Mechlorethamine (Mustine)
2. Bendamustine
3. Chlorambucil
4. Melphalan
5. Cyclophosphamide
6. Ifosfamide
173
Cyclophosphamide (MOA, indication)
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
What is the most useful alkylating agent?
Cyclophosphamide
| nitrogen mustard derivative; prodrug with modest side effects compared to most alkylating agents
175
Ifosfamide (MOA, indication)
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
Mesna (MOA, indication)
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
List chemo agents that are nitrosoureas
1. Carmustine
| 2. Lomustine
178
Carmustine (MOA, indication)
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
Lomustine (MOA, indication)
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
Busulfan (MOA, indication)
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
Dacarbazine (MOA, indication)
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
Temozolide (MOA, indication)
```
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
What chemotherapeutic agents alkylate DNA via a diazonium ion?
1. Carmustine
2. Lomustine
3. Dacarbazine
4. Temozolide
184
Toxicities of the Platinum drugs
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
Cisplatin (MOA, indication)
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
Carboplatin (MOA, indication)
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
Oxaliplatin (MOA, indication)
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
Mechanisms of drug resistance to alkylating agents and platinum drugs
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
Mitomycin C (MOA, indication)
DNA alkylator
MOA: aziridine-containing natural product that bifunctionally crosslinks similar to Mustine
Indication: general chemotherapy
190
What chemotherapeutic agents alkylate DNA via an aziridine?
1. Mechlorethamine (Mustine) and derivatives: Bendamustine, Chlorambucil, and Melphalan
2. Mitomycin C
191
Radium 223 dichloride (MOA, indication)
MOA: absorbed into bone and produces short range alpha radiation that damages DNA
Indication: treats bone metastases
192
Procarbazine (MOA, indication)
MOA: unclear; inhibits DNA, RNA, and protein synthesis
Indication: general chemotherapy
193
5-Fluorouracil (MOA, indication)
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
Drug interactions with 5-FU
Thymidine
- 5-FU then thymidine = rescues cytotoxic effect
- thymidine then 5-FU = enhanced cytotoxic effect
Leucovorate
-folate cofactor that increases 5-FU efficacy
195
Fluorodeoxyuridine (MOA, indication)
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
Capecitabine (MOA, indication)
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
Uracil analogs (MOA, list)
MOA: inhibition of thymidine synthase
1. 5-Fluorouracil
2. Fluorodeoxyuridine
3. Capecitabine
198
Cytosine analogs (MOA, list)
MOA: inhibition of DNA synthesis
1. Cytosine arabinoside (Ara-C)
2. Difluorodeoxycytidine (Gemcitabine)
199
Cytosine Arabinoside (MOA, indication)
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
Difluorodeoxycytidine (MOA, indication)
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
Purine analogs (MOA, list)
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
6-Mercaptopurine (MOA, indication)
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
6-Thioguanine (MOA, indication)
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
Fludarabine (MOA, indication)
Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers
205
Nelarabine (MOA, indication)
Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers
206
Cladribine
Purine Analog
MOA: arabino adenosine analog (nucleotide) that inhibits DNA polymerase and ribonucleotide reductase which prevents replication and transcription
Indication: blood cancers
207
List the purine analog inhibitors of DNA/RNA synthesis
Arabino adenosine analogs
1. Fludarabine
2. Nelarabine
3. Cladribine
208
What reaction is DHFR responsible for?
Reduction of dihydrofolate to tetrahydrofolate
| essential for folic acid use as a cofactor in nucleotide synthesis, etc
209
List the DHFR inhibitors
1. Methotrexate
2. Pralatrexate
3. Pemetrexed
210
Methotrexate (MOA, indication)
MOA: DHFR inhibitor
*Leucovorin rescues normal cells from toxic effects of MTX (reverses effects of DHFR inhibition by increasing tetrahydrofolate in cells)
211
Pralatrexate (MOA, indication)
MOA: DHFR inhibitor
| *Selectively enters cells expressing RFC-1 (cancer cells generally have more folate transporters on surface)
212
Pemetrexed (MOA, indication)
MOA: inhibits DHFR, thymidylate synthase, and glycinamide ribonucleotide formyltransferase
*decreased risk of drug resistance
213
Leucovorin (MOA, indication)
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
Hydroxyurea (MOA, indication)
MOA: inhibits ribonucleotide reductase; decreases production of deoxyribonucleotides needed for DNA synthesis
*cells halted in S-phase
215
Actinomycin C (MOA, indication)
MOA: binds DNA and inhibits transcription by RNA polymerase and DNA replication
*non-cell cycle specific
216
Camptothecin (MOA, indication)
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
Topotecan (MOA, indication)
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
Irinotecan (MOA, indication)
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
Topoisomerase I inhibitors (MOA, list)
MOA: bind Topo1 and forms a ternary drug-enzyme-DNA complex, blocking DNA religation (S-phase inhibition)
1. Camptothecin
2. Topotecan
3. Irinotecan
220
Polymorphisms (4)
1. BRCA1/2 (PARP inhibitor, olaparib)
2. DPD (Uridine analog, 5-FU)
3. TMPT (Purine analog, 6-MP)
4. UGT1A1 (Topo1 inhibitor, Irinotecan)
221
Major side effect of Topoisomerase II inhibitors?
Cardiotoxicity
| -d/t free radical damage (heart tissue has low levels of neutralizing enzymes)
222
Topoisomerase II inhibitors - Anthracyclines (MOA, list)
MOA: intercalate, form free radicals, and inhibit Topo2A (non-cell cycle specific, G2/M)
1. Daunorubicin
2. Doxorubicin
3. Epirubicin
4. Idarubicin
223
Dexrazoxane (MOA, indication)
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
Mitoxantrone (MOA, indication)
(not an Anthracycline but related structure)
MOA: intercalation and inhibition of Topo2
*No free radical formation and cardiotoxicity
225
Topoisomerase II inhibitors - Epipodophyllotoxins (MOA, list)
MOA: inhibit religation of double stranded breaks induced by Topo2 but does NOT intercalate (G2 block**)
1. Etoposide
2. Teniposide
226
Topoisomerase inhibitors sensitive to GST?
```
-Glutathione S-transferase neutralizes effectiveness
Topo1 inhibitors (Camptothecins)
Topo2 inhibitors (Anthracyclines only)
```
227
Bleomycin (MOA, indication)
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
Erubulin (MOA, indication)
MOA: microtubule de-polymerizing agent (but not destabilizing); binds at ends and prevents elongation
*low rate of neurotoxicity
229
Vinca Alkaloids (MOA, list)
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
Taxanes (MOA, list)
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
Epithilones (MOA, list)
Microtubule Stablizers
MOA: bind tubulin and inhibit tubulin depolymerization and promote microtubule stabilization
1. Epithilone
2. Ixabepilone
*Toxicity: same as Taxanes- neurotoxicity (reversible)
232
What drugs are a poor substrate for MDR and PGP pumps?
Cabazitaxel, Epthilone, Ixabepilone
| microtubule stabilizers
