Exam One: Oncology Flashcards
1
Q
Neoplasm
A
a new growth, may be benign or malignant
2
Q
Tumor
A
a nonspecific term meaning lump or swelling
3
Q
Cancer
A
any malignant neoplasm
4
Q
Are the “plasias” cancerous or non-cancerous
A
non-cancerous
5
Q
Hyperplasia
A
an increase in organ or tissue size due to an increase in the number of cells
can be physiologic, compensatory, or pathologic
6
Q
Metaplasia
A
an adaptive, substitution of one type of adult tissue to another type of adult tissue
7
Q
Dysplasia
A
an abnormal cellular proliferation in which there is loss of normal architecture
8
Q
Anaplasia
A
a loss of structural differentiation (e.g. leiomyoma)
cells dedifferentiate (occurs frequently in tumors as well)
9
Q
Are the “omas” cancerous or noncancerous?
A
cancerous
10
Q
Epithelial Origin Cancers
A
- carcinoma
- adenocarcinoma
11
Q
Carcinoma
A
malignant neoplasm of squamous epithelial cell origin (benign is papilloma)
12
Q
Adenocarcinoma
A
malignant neoplasm derived from glandular tissue (benign is adenoma)
13
Q
Sarcoma
A
malignant neoplasm with origin in mesenchymal tissues or its derivatives
bone, muscle, fat
14
Q
Lymphoma and Leukemia
A
malignant neoplasms of hematopoietic tissues
15
Q
Melanoma
A
type of cancer of pigment producing cells in the skin or the eye
16
Q
Blastoma
A
malignancies in precursor cells, often called blasts, which are more common in children (nephroblastoma, medulloblastoma, and retinoblastoma)
17
Q
Teratoma
A
a germ cell neoplasm made of several different differentiated cell/tissue types
18
Q
Myeloid Leukemias
A
differentiate from the common myeloid progenitor
19
Q
Lymphocytic Leukemias
A
differentiate from the common lymphoid progenitor
20
Q
Lymphomas
A
differentiate from the small lymphocyte
21
Q
Leukemia
A
cancer of the white blood cells of hematopoietic origin
22
Q
Numerical Staging System: 0
A
in situ carcinoma, no sign of local invasion
23
Q
Numerical Staging System: 1
A
microscopic invasion of surrounding tissue
24
Q
Numerical Staging System: II
A
4-9 surrounding lymph nodes are involved
25
Numerical Staging System: IV
distant metastases are detected
26
What is numerical staging system mostly based on?
tumor size, location, number
27
Which type of tumors get staged?
Primarily only solid tumors
28
Does poorer outcomes mean lethality?
No
29
Primary Tumor Staging: TX
primary tumor cannot be evaluated
30
Primary Tumor Staging: T0
No evidence of primary tumor
31
Primary Tumor Staging: Tis:
carcinoma in situ
32
Primary Tumor Staging: T1, T2, T3, T4
size and/or extent of invasion of the primary tumor
33
Regional Lymph Nodes Staging: NX
regional lymph nodes cannot be evaluated
34
Regional Lymph Nodes Staging: N0
no regional lymph node involvement
35
Regional Lymph Nodes Staging: N1, N2, N3
degree of regional lymph node involvement (number and location of lymph nodes)
36
Distant Metastasis (M): MX
distant metastasis cannot be evaluated
37
Distant Metastasis (M): M0
no distant metastasis
38
Distant Metastasis (M): M1
distant metastasis is present
39
In situ
abnormal cells are present only in the layer of cells in which they developed
40
Localized
cancer is limited to the organ in which it began, without evidence of spread
41
Regional
cancer has spread beyond the primary site to nearby lymph nodes or tissues and organs
42
Distant
cancer has spread from the primary site to distant tissues or organs or to distant lymph nodes
43
Unknown
there is not enough information to determine the stage
44
Tumor Grade
description of a tumor assigned by a pathologist
45
Well Differentiated
the cells of the tumor and the organization of the tumor's tissue resemble those of normal cells and tissue
46
Undifferentiated
tumors that have abnormal-looking cells and may lack normal tissue structures, tend to grow and spread at a faster rate
47
Tumor Grading: Gx
grade cannot be assessed
48
Tumor Grading: G1
well differentiated (low grade)
49
Tumor Grading: G2
moderately differentiated (intermediate grade)
50
Tumor Grading: G3
poorly differentiated (high grade)
51
Tumor Grading: G4
undifferentiated (high grade)
52
3 Characteristics of Cancer
1. uncontrolled cellular growth
2. tissue invasion
3. metastasis
1 is seen in benign tumors
All three are seen in cancer
53
What is cancer?
unstable, atypical and loses normal cellular function
54
Hallmarks of Cancer
- Sustaining Proliferative Signaling
- Avoiding immune destruction
- Enabling replicative immortality
- Activating invasion and metastasis
- Inducing or accessing vasculature
- Genome instability and mutation
- Resisting Cell Death
55
For many tumors, the growth of the ____ tumor is not going to be life threatening
primary
56
v-Src is an ______
oncogene
57
proto-oncogene
any gene in a healthy cell capable of promoting tumor growth
58
Some cancers can result of mutation or deletion of a single potent _____
tumor suppressor
59
Retinoblastoma
childhood retinal cancer
60
2 hit hypothesis
most tumor suppressors can be expressed from either chromosome and thus will need to be homozygous deletion/mutation
heterozygous mutations can be inherited and show increased susceptibility to cancers
need two mutated genes for cancer to develop in retinoblastoma
61
Is RB1 an oncogene or tumor suppressor?
tumor suppressor
62
is p16 an oncogene or tumor suppressor
tumor suppressor
63
Classification arrives from what?
tissue of origin
64
Do tumors of the same classification always have a unifying genetic driver?
not always
65
Time to cancer is decreased with increased ________?
mutation rate, such as exposure to carcinogens
66
most cancers are relatively ________ and have a variety of gene mutations
heterogenous
67
What mutation impacts NSCLC patients the most?
EGFR: mutations in the EGFR catalytic domain increase the intensity and duration of signaling in response to ligand
68
Targeting Oncogenic Mutations
activating mutations can predict susceptibility
69
Tumor Suppressor Mutations
loss of function mutations can predict susceptibility to chemotherapies
70
Is BRCA a tumor suppressor or oncogene
tumor suppressor
encode for proteins involved in the DNA repair (germline)
71
BRCA mutations in _______ increase susceptibility to what type of inhibitors?
breast cancer, PARP inhibitors
72
Olaparaib: Drug Class
PARP Inhbitor
73
Olaparib: Target
Poly ADP ribose polymerase (PARP)
74
Olaparib: Cell Cycle
non specific
75
Olaparib: MoA
works by trapping PARP to DNA at sites of DNA breakage --> unable to uncouple from DNA
76
Olaparib: Also in this Class
Rucaparib, niraparib, talazoparib, veliparib
77
G0/G1
cell is quiescent or accumulating "building block" required for division
78
S
Cell replicating DNA
79
G2
cell assembling machinery for chromosomal segregation and cytokinesis, double checks duplicate chromosomes for errors
80
M
mitosis
81
What determines when the cells move from one phase of the cycle to another
Cell Cycle Clock
82
Cell cycle is driven by what?
cyclins paired with cyclin-dependent kinases
83
R point of Cell Cycle
critical time point where cells decide whether or not to enter the cell cycle
84
Cyclins of G1
D and CDK4/6
85
Cyclins of G1 -->S
E and CDK2
86
Cyclins of S and G2
A and CDK2 /CDC2
87
Cyclins of M
B and CDC2
88
G1 Common Chemos
- kinase inhibitors
- hormone inhibitors
- inhibit mitogenic signaling
89
S Common Chemos
- anti-metabolites
- anti-folates
- Topo I inhibitors
- inhibit DNA replication
90
G2 Common Chemos
- Topo II inhibitors
- sister chromatids separation
91
M Common Chemos
- microtubule inhibitors
- chromosome segregation
92
Non cell cycle specific chemos
- alkylators
- intercalaters
93
Is Kras a tumor suppressor or oncogene?
oncogene
94
Is PI3K a tumor suppressor or oncogene?
oncogene
95
Is p53 a tumor suppressor or oncogene?
tumor suppressor
96
Is RB1 a tumor suppressor or oncogene?
tumor suppressor
97
Which cyclin is the master regulator of the cell cycle initiation
Cyclin D + CDK4/6
98
Palbociclib: Dug Class
kinase inhibitor
99
Palbociclib: Target
CDK4/6
100
Palbociclib: Cell Cycle
G1 (not targeted therapies because they target all replicating cells)
101
Palbociclib: MoA
prevents interaction between cyclin D and CDK4/6
102
Palbociclib: Adverse Reactions
- neutropenia
- N/V/D
- fatigue
- similar to traditional chemotherapies
103
Palbociclib: Also in this drug class
- ribociclib, abemaciclib
- "-ciclib"
104
Palbociclib: Indication
cancers arising due to BRCA1/2 mutations
105
Loss of Control in Cancer
- leads to increase cell proliferation
- checkpoint controls are often lost as well
- cancer cells often do not fully repair damaged DNA, repair damaged mitotic spindles or finish replicating DNA before proceeding to next stage of cell cycle
106
Loss of checkpoint results in what?
increased cell death with chemotherapy
107
When normal cells are exposed to certain chemotherapy drugs that cause DNA damage
- cells halt in G1 until DNA repaired
- cells then proceed into S
- if cells proceed into S without repairing DNA, they apoptose
- preserves genomic integrity of daughter cells
108
When tumor cells that have lost G1/S checkpoint control are treated with chemotherapy that causes DNA damage
- cells dont halt in G1 and attempt to replicate DNA
- attempting to replicate damaged DNA can trigger apoptosis
- OR if the apoptotic response has been lost replicate damaged DNA and acquire lethal genetic damage that results in necrosis
109
Drugs that do not require cycling cells
- effective against cancer cells resting in G0 and cells progressing through the cell cycle
- alkylating angents
110
Non-cell specific drugs efficacy
most effective when tumor cells are progressing through the cell cycle, but are not dependent upon the cell being in a specific phase of the cell cycle
- alkylating agents and DNA intercalation
111
Limitation of cell kill
- with a phase specific agent
- number of cells killed by the agent will be limited to the number of cells present in the appropriate phase of the cell cycle
- higher drug doses may not result in greater tumor cell killing
112
How can you increase cell kill?
prolonged exposure (repeated administration or continuous infusion)
113
Major dose-limiting toxicities of chemo
Hematopoietic
- infections (WBC granulocytes)
- hemostasis (platelets)
- anemia (RBC)
GI:
- N/V
- loss of appetite
114
Norton-Simon Hypothesis
- give as dose-intensive and early as possible
- give chemo at shorter intervals
- use combo of drugs with distinct mechanism of action
115
As tumors grow, their _____ slows
doubling time
116
When tumor burden is ________, remaining will re-enter _____.
decreased, exponential growth
(diminishing returns, resistance and/or intolerable side effects)
117
Factors increasing efficacy of cytotoxic chemo
- small tumor (or treatment after surgical removal)
- early diagnosis
- increased drug intensity
118
Cancer chemo given as single agent results in either _______.
drug resistance or drug toxicity
119
Advantages of combo chemo
- no additive toxicities for drugs with non-overlapping
- increased cell killing
120
Changes in Drug Target or Function
- increased expression of drug target through gene amplification or expression (up-regulation of drug target making it harder to inhibit)
- emergence of mutant, structurally altered target
- emergence of cells bearing alterations in genes whose products are functionally redundant with drug target
120
Drug Resistance Mechanisms
- increased transport out of the cell through efflux pumps
- reduced transporter into the cell (decreased permeability)
- decreased activation of prodrug
- increased detoxification of drug molecule
121
Physiological changes that promote resistance
- metastasis in drug protected anatomical sites (brain)
- massive stromalization
- changes in cell state such as EMT
122
Cell survival mechanisms
- activation of anti-apoptotic regulators
- increased repair of damage caused by chemotherapies
123
Glucocorticoid have anticancer effects in blood cancers including
- ALL
- multiple myeloma
- lymphomas
124
Corticosteroid treatment
- used as palliative care to reduce inflammation, edema, and manage pain during chemotherapy
- reduce hypersensitivity reactions, N/V, immune related adverse effects
125
Hormonal therapies target
- estradiol (breast, endometrial)
- dihydrotestosterone (prostate)
- produced in adrenal, ovary, testies, adipocytes
126
where are steroid hormone receptors located
- cytoplasm or nucleus
- unbound hormones can only diffuse into target cells
127
two major strategies to endocrine therapies
- stop steroid function
- decrease production of steroids
128
Hormones produced in the pituitary
LH/FSH
129
Hormones produced in the hypothalamus
GnRH
130
Enzyme that converts androstenedione to estrone
CYP19/Aromatase
131
Breast cancer is made up of at least _____ distinct diseases
4
- claudin low (mesenchymal)
- basal like (BRCA 1)
- HER2 amplification
- luminal A/B
132
Tamoxifen: Target
ER
133
Tamoxifen: Activation
- prodrug metabolized by CYP2D6
134
Tamoxifen: MoA
- Selective Estrogen Receptor Modulator (SERMs)
- binds to estrogen receptor in a tissue specific manner
135
Tamoxifen: Effects
Antagonist
- blocks estrogen-dependent breast cancer cell proliferation
- hot flashes
Agonist
- incidence of endometrial cancer increased 3-fold
- preservation of bone density in postmenopausal women
136
Tamoxifen: Post or Premenopausal
both
137
Tamoxifen: Indication
- treatment of ER+/PR+ breast cancer (resected or metastatic)
- first drug approved for breast cancer prevention in high risk patients
138
Raloxifene
- no endometrial hyperplasia compared to tamoxifen
- indication is osteoporosis as it increases bone mass and blocks bone resorption better than tamoxifen
139
Fulvestrant: MoA
- binds to ER and inhibits DNA binding
- rapid receptor degradation
140
Fulvestrant: Effects
- pure ER antagonist and has NO agonist effects
141
Fulvestrant: post or premenopausal
postmenopausal women who have progressed on other antiestrogen therapy with ER+ metastatic breast cancer
142
Aromatase Inhibitors:
- blocks the conversion of androstenedione --> estrone and testosterone --> estradiol
- blocks synthesis of estrogens but not androgens or progesterone
143
Source of estrogen in postmenopausal women
adipocytes
- androstenedione produced in adrenal gland and released into circulation
aromatase converts
144
Primary target of aromatase inhibitors
adipose tissue (not ovary)
145
Anastrozole/Letrozole: Drug Class
non-steroidal aromatase inhibitors
146
Letrozole: MoA
potent and selective competitive inhibitor of aromatase
147
Letrozole: Indication
breast cancer in postmenopausal women
- first line therapy
- OR started 3-5 years of tamoxifen
148
Letrozole: Toxicity
-minimal
- increases bone density loss
149
Exemestane: MOA
steroidal aromatase inhibitor
- false substrate that aromatase converts
- intermediate binds irreversible at active site and inactivates it
150
Exemestane: Indication
postmenopausal women who have progressed on antiestrogen therapy
151
Exemestane: Toxicity
- minimal
- hot flashes
- increased cholesterol
- occasional peripheral edema and weight gain (build up of progesterones)
152
Effects of LH
increases activity of the conversion of cholesterol to progesterone
153
effects of FSH
can increase expression of aromatase
154
Leuprolide:MoA
GnRH Analog
- downregulates pituitary GnRH receptors and pituitary desensitization to decrease estrogen and androgen production
155
Leuprolide: Side Effects
- transient worsening of symptoms related to initial agonist effects (tumor flare)
- hot flashes
- sexula dysfunction
156
Leuprolide in Women: Indication
premenopausal women breast cancer
157
what converts testosterone to dihydrotestosterone
5-alpha reductase
158
Androgen Receptor signaling
- cytoplasmic
- amplified in prostate cancer
- binding of AR to DHT leads to translocation to the nucleus and action of genes that drive cell
159
Leuprolide in Men: MoA
- chemical castration
- leads to a decrease in LH production
160
Leuprolide in Men: Indication
palliative treatment of advanced prostate cancer
161
Leuprolide in Men: side effects
- tumor flare ( initial agonist effects)
- gynecomastia
- sexual dysfunction
162
Degarelix and Relugolix: indication
GnRH antagonist for advanced prostate cancer
will not result in flare
163
Aberaterone: MoA
- inihbits the function of 17-alpha hydroylase and C17,20 lyase
- inhibits conversion of pregnenolone and progesterone to DHEA and androstenedione
164
Abiraterone: Side effects
- increased cholesterol levels
165
Enzalutamide (Apalutamide, Darolutamide)
AR antagonist
- prevents AR translocation to the nucleus
- inhibits AR binding to DNA
- approved for both metastatic and non-metastatic prostate cancer
166
Gefitinib: MoA
- EGFR targeted kinase inhibitor, turns off signal to proliferate
- type I
- tumors have EGFR exon 19 or exon 21 (L858R) mutations
- NSCLC
167
Afatanib and Neratinib: Moa
- EGFR targeted kinaase inhibitor
- covalent inhibitor of all ErbB receptors
- NSCLC
168
T790 mutation
- resitance to Gefitinib
- use osimertinib (third generation covalent inhibitor)
169
Lapatinib: MoA
- small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR
- reversible inhibitor of both EGFR and HER2
170
Lapatinib selectivity
HER2+ breast cancer
171
Lapatinib toxicity
- symptoms of CHF
172
Tucatinib: MoA
small molecule kinase inhibitor that preferentially binds HER2
173
tucatinib selectivity
treatment of HER2+ breast cancer
174
FLT3 mutations
internal duplication tandem (ITD) in the tyrosine kinase domain
- ligand is a cytokine receptor important for hematopoeitic cell survival
- AML
- increased proliferation and decreased apoptosis
175
Midostaurin
- first generation FLT3 inhibitor (broad)
176
Crenolanib
- second generation FLT3 inhibitor
177
Quizartinib
Type II specific for ITD mutations in FLT3
178
Imatinib: MoA
- Type II Abl protein kinase inhibitor
- inhibition of the abl tyrosine kinase results in both reduced proliferation and enhanced apoptoitic cell death in CML and GIST
179
Imatinib: resistance
- need to be on Abl inhibitors for life, resistance is a lifelong battle
180
Ponatinib: MoA
- BRC-Abl inhibitor
- effective against all major forms of BRC-Abl
- inhibits mutation T315I
181
Alectinib
- ALK inhibitor (-lec)
- ALK+ metastatic NSCLC who have progressed on crizotinib
182
Dabrafenib
- second gen BRAF V600 inhibitor
- used in combo with trametinib for treatment of BRAFV600E/K mutant metastatic melanoma
- colorectal cancer has Ras and BRAF but do not respond
- activation of Wild Type remains a problem
183
Trametinib
-inhibits kinase activity of MEK1 and 2
- combo with dabrafinib
- type II allosteric inhibito r
- RASH
184
Acalabrutinib
- second gen BTK inhbitor
- Bcell lymphoma
- targets Cys481
185
Rapamycin Analogs: Target
mTOR1 (serine-threonine kinase)
186
5-FU target
thymidine synthase
187
5-FU Resitance
- downregulation of activating enzymes that comver 5-FU to fdUMP
- upregulation of thymidylate synthase
188
5-FU Susceptibiility
5% of the population has gene polymorphisms that results in a deficincey of the enzyme DPD which breaks down 5-FU
189
5-FU Drug resucue
thymidine
190
5-FU drug synergy
Leucovorate
- stable folate cofactor
- higher tetrahydrofolate levels increases 5-FU by increasing the amount of the covalent ternary complex with thymidylate synthase
191
Capecitabine
- orally active prodrug of 5-FU
192
Cytarabine MoA
- Ara-CTP is a competitive inhibitor of DNA polymerase alpha
- cytidine deaminase converts cytarabine to arabinoside
- decreased levels of cytidine deaminase in the CNS makes cytarabine toxic in leukemia and lymphoma ( brain and spinal cord)
193
Cytarabine Resistance
- downregulation of activating enzymes
- upregulation of cytidine deaminase
- downregulation of transporter to move drug into cells
194
Cytarabine Syngergy
-tetrahydrouridine
- cytidine deaminase inhibitor
- increase efficacy and decrease resistance
195
6MP MoA
blocks synthesis of purine nucleotides
196
6 MP drug interaction
- xanthine oxidase
-allopurinol
197
Antifolates (DHFR inhibition)
inhibition of TMP synthesis
- also inhibits RNA and protein synthesis
- also inhibits purine and pyrimidine synthesis
198
Methotrexate
inhibits DHFR and mimics folates
199
MTX resistance
- decreased polyglutamation results in decreased intracellular MTX ammumulation
200
Overdose of MTX
leucovorin increases pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition
