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PHRM 864 > Exam One: Oncology > Flashcards

Exam One: Oncology Flashcards

1
Q

Neoplasm

A

a new growth, may be benign or malignant

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2
Q

Tumor

A

a nonspecific term meaning lump or swelling

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3
Q

Cancer

A

any malignant neoplasm

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4
Q

Are the “plasias” cancerous or non-cancerous

A

non-cancerous

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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

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6
Q

Metaplasia

A

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

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7
Q

Dysplasia

A

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

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8
Q

Anaplasia

A

a loss of structural differentiation (e.g. leiomyoma)

cells dedifferentiate (occurs frequently in tumors as well)

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9
Q

Are the “omas” cancerous or noncancerous?

A

cancerous

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10
Q

Epithelial Origin Cancers

A
  • carcinoma
  • adenocarcinoma
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11
Q

Carcinoma

A

malignant neoplasm of squamous epithelial cell origin (benign is papilloma)

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12
Q

Adenocarcinoma

A

malignant neoplasm derived from glandular tissue (benign is adenoma)

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13
Q

Sarcoma

A

malignant neoplasm with origin in mesenchymal tissues or its derivatives

bone, muscle, fat

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14
Q

Lymphoma and Leukemia

A

malignant neoplasms of hematopoietic tissues

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15
Q

Melanoma

A

type of cancer of pigment producing cells in the skin or the eye

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16
Q

Blastoma

A

malignancies in precursor cells, often called blasts, which are more common in children (nephroblastoma, medulloblastoma, and retinoblastoma)

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17
Q

Teratoma

A

a germ cell neoplasm made of several different differentiated cell/tissue types

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18
Q

Myeloid Leukemias

A

differentiate from the common myeloid progenitor

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19
Q

Lymphocytic Leukemias

A

differentiate from the common lymphoid progenitor

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20
Q

Lymphomas

A

differentiate from the small lymphocyte

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21
Q

Leukemia

A

cancer of the white blood cells of hematopoietic origin

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22
Q

Numerical Staging System: 0

A

in situ carcinoma, no sign of local invasion

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23
Q

Numerical Staging System: 1

A

microscopic invasion of surrounding tissue

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24
Q

Numerical Staging System: II

A

4-9 surrounding lymph nodes are involved

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25
Q

Numerical Staging System: IV

A

distant metastases are detected

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26
Q

What is numerical staging system mostly based on?

A

tumor size, location, number

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27
Q

Which type of tumors get staged?

A

Primarily only solid tumors

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28
Q

Does poorer outcomes mean lethality?

A

No

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29
Q

Primary Tumor Staging: TX

A

primary tumor cannot be evaluated

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30
Q

Primary Tumor Staging: T0

A

No evidence of primary tumor

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31
Q

Primary Tumor Staging: Tis:

A

carcinoma in situ

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32
Q

Primary Tumor Staging: T1, T2, T3, T4

A

size and/or extent of invasion of the primary tumor

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33
Q

Regional Lymph Nodes Staging: NX

A

regional lymph nodes cannot be evaluated

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34
Q

Regional Lymph Nodes Staging: N0

A

no regional lymph node involvement

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35
Q

Regional Lymph Nodes Staging: N1, N2, N3

A

degree of regional lymph node involvement (number and location of lymph nodes)

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36
Q

Distant Metastasis (M): MX

A

distant metastasis cannot be evaluated

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37
Q

Distant Metastasis (M): M0

A

no distant metastasis

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38
Q

Distant Metastasis (M): M1

A

distant metastasis is present

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39
Q

In situ

A

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

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40
Q

Localized

A

cancer is limited to the organ in which it began, without evidence of spread

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41
Q

Regional

A

cancer has spread beyond the primary site to nearby lymph nodes or tissues and organs

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42
Q

Distant

A

cancer has spread from the primary site to distant tissues or organs or to distant lymph nodes

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43
Q

Unknown

A

there is not enough information to determine the stage

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44
Q

Tumor Grade

A

description of a tumor assigned by a pathologist

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45
Q

Well Differentiated

A

the cells of the tumor and the organization of the tumor’s tissue resemble those of normal cells and tissue

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46
Q

Undifferentiated

A

tumors that have abnormal-looking cells and may lack normal tissue structures, tend to grow and spread at a faster rate

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47
Q

Tumor Grading: Gx

A

grade cannot be assessed

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48
Q

Tumor Grading: G1

A

well differentiated (low grade)

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49
Q

Tumor Grading: G2

A

moderately differentiated (intermediate grade)

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50
Q

Tumor Grading: G3

A

poorly differentiated (high grade)

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51
Q

Tumor Grading: G4

A

undifferentiated (high grade)

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52
Q

3 Characteristics of Cancer

A
  1. uncontrolled cellular growth
  2. tissue invasion
  3. metastasis

1 is seen in benign tumors
All three are seen in cancer

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53
Q

What is cancer?

A

unstable, atypical and loses normal cellular function

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54
Q

Hallmarks of Cancer

A
  • Sustaining Proliferative Signaling
  • Avoiding immune destruction
  • Enabling replicative immortality
  • Activating invasion and metastasis
  • Inducing or accessing vasculature
  • Genome instability and mutation
  • Resisting Cell Death
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55
Q

For many tumors, the growth of the ____ tumor is not going to be life threatening

A

primary

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56
Q

v-Src is an ______

A

oncogene

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57
Q

proto-oncogene

A

any gene in a healthy cell capable of promoting tumor growth

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58
Q

Some cancers can result of mutation or deletion of a single potent _____

A

tumor suppressor

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59
Q

Retinoblastoma

A

childhood retinal cancer

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60
Q

2 hit hypothesis

A

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

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61
Q

Is RB1 an oncogene or tumor suppressor?

A

tumor suppressor

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62
Q

is p16 an oncogene or tumor suppressor

A

tumor suppressor

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63
Q

Classification arrives from what?

A

tissue of origin

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64
Q

Do tumors of the same classification always have a unifying genetic driver?

A

not always

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65
Q

Time to cancer is decreased with increased ________?

A

mutation rate, such as exposure to carcinogens

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66
Q

most cancers are relatively ________ and have a variety of gene mutations

A

heterogenous

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67
Q

What mutation impacts NSCLC patients the most?

A

EGFR: mutations in the EGFR catalytic domain increase the intensity and duration of signaling in response to ligand

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68
Q

Targeting Oncogenic Mutations

A

activating mutations can predict susceptibility

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69
Q

Tumor Suppressor Mutations

A

loss of function mutations can predict susceptibility to chemotherapies

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70
Q

Is BRCA a tumor suppressor or oncogene

A

tumor suppressor

encode for proteins involved in the DNA repair (germline)

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71
Q

BRCA mutations in _______ increase susceptibility to what type of inhibitors?

A

breast cancer, PARP inhibitors

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72
Q

Olaparaib: Drug Class

A

PARP Inhbitor

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73
Q

Olaparib: Target

A

Poly ADP ribose polymerase (PARP)

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74
Q

Olaparib: Cell Cycle

A

non specific

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75
Q

Olaparib: MoA

A

works by trapping PARP to DNA at sites of DNA breakage –> unable to uncouple from DNA

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76
Q

Olaparib: Also in this Class

A

Rucaparib, niraparib, talazoparib, veliparib

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77
Q

G0/G1

A

cell is quiescent or accumulating “building block” required for division

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78
Q

S

A

Cell replicating DNA

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79
Q

G2

A

cell assembling machinery for chromosomal segregation and cytokinesis, double checks duplicate chromosomes for errors

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80
Q

M

A

mitosis

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81
Q

What determines when the cells move from one phase of the cycle to another

A

Cell Cycle Clock

82
Q

Cell cycle is driven by what?

A

cyclins paired with cyclin-dependent kinases

83
Q

R point of Cell Cycle

A

critical time point where cells decide whether or not to enter the cell cycle

84
Q

Cyclins of G1

A

D and CDK4/6

85
Q

Cyclins of G1 –>S

A

E and CDK2

86
Q

Cyclins of S and G2

A

A and CDK2 /CDC2

87
Q

Cyclins of M

A

B and CDC2

88
Q

G1 Common Chemos

A
  • kinase inhibitors
  • hormone inhibitors
  • inhibit mitogenic signaling
89
Q

S Common Chemos

A
  • anti-metabolites
  • anti-folates
  • Topo I inhibitors
  • inhibit DNA replication
90
Q

G2 Common Chemos

A
  • Topo II inhibitors
  • sister chromatids separation
91
Q

M Common Chemos

A
  • microtubule inhibitors
  • chromosome segregation
92
Q

Non cell cycle specific chemos

A
  • alkylators
  • intercalaters
93
Q

Is Kras a tumor suppressor or oncogene?

A

oncogene

94
Q

Is PI3K a tumor suppressor or oncogene?

A

oncogene

95
Q

Is p53 a tumor suppressor or oncogene?

A

tumor suppressor

96
Q

Is RB1 a tumor suppressor or oncogene?

A

tumor suppressor

97
Q

Which cyclin is the master regulator of the cell cycle initiation

A

Cyclin D + CDK4/6

98
Q

Palbociclib: Dug Class

A

kinase inhibitor

99
Q

Palbociclib: Target

A

CDK4/6

100
Q

Palbociclib: Cell Cycle

A

G1 (not targeted therapies because they target all replicating cells)

101
Q

Palbociclib: MoA

A

prevents interaction between cyclin D and CDK4/6

102
Q

Palbociclib: Adverse Reactions

A
  • neutropenia
  • N/V/D
  • fatigue
  • similar to traditional chemotherapies
103
Q

Palbociclib: Also in this drug class

A
  • ribociclib, abemaciclib
  • “-ciclib”
104
Q

Palbociclib: Indication

A

cancers arising due to BRCA1/2 mutations

105
Q

Loss of Control in Cancer

A
  • 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
Q

Loss of checkpoint results in what?

A

increased cell death with chemotherapy

107
Q

When normal cells are exposed to certain chemotherapy drugs that cause DNA damage

A
  • 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
Q

When tumor cells that have lost G1/S checkpoint control are treated with chemotherapy that causes DNA damage

A
  • 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
Q

Drugs that do not require cycling cells

A
  • effective against cancer cells resting in G0 and cells progressing through the cell cycle
  • alkylating angents
110
Q

Non-cell specific drugs efficacy

A

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
Q

Limitation of cell kill

A
  • 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
Q

How can you increase cell kill?

A

prolonged exposure (repeated administration or continuous infusion)

113
Q

Major dose-limiting toxicities of chemo

A

Hematopoietic
- infections (WBC granulocytes)
- hemostasis (platelets)
- anemia (RBC)

GI:
- N/V
- loss of appetite

114
Q

Norton-Simon Hypothesis

A
  • give as dose-intensive and early as possible
  • give chemo at shorter intervals
  • use combo of drugs with distinct mechanism of action
115
Q

As tumors grow, their _____ slows

A

doubling time

116
Q

When tumor burden is ________, remaining will re-enter _____.

A

decreased, exponential growth
(diminishing returns, resistance and/or intolerable side effects)

117
Q

Factors increasing efficacy of cytotoxic chemo

A
  • small tumor (or treatment after surgical removal)
  • early diagnosis
  • increased drug intensity
118
Q

Cancer chemo given as single agent results in either _______.

A

drug resistance or drug toxicity

119
Q

Advantages of combo chemo

A
  • no additive toxicities for drugs with non-overlapping
  • increased cell killing
120
Q

Changes in Drug Target or Function

A
  • 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
Q

Drug Resistance Mechanisms

A
  • 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
Q

Physiological changes that promote resistance

A
  • metastasis in drug protected anatomical sites (brain)
  • massive stromalization
  • changes in cell state such as EMT
122
Q

Cell survival mechanisms

A
  • activation of anti-apoptotic regulators
  • increased repair of damage caused by chemotherapies
123
Q

Glucocorticoid have anticancer effects in blood cancers including

A
  • ALL
  • multiple myeloma
  • lymphomas
124
Q

Corticosteroid treatment

A
  • used as palliative care to reduce inflammation, edema, and manage pain during chemotherapy
  • reduce hypersensitivity reactions, N/V, immune related adverse effects
125
Q

Hormonal therapies target

A
  • estradiol (breast, endometrial)
  • dihydrotestosterone (prostate)
  • produced in adrenal, ovary, testies, adipocytes
126
Q

where are steroid hormone receptors located

A
  • cytoplasm or nucleus
  • unbound hormones can only diffuse into target cells
127
Q

two major strategies to endocrine therapies

A
  • stop steroid function
  • decrease production of steroids
128
Q

Hormones produced in the pituitary

A

LH/FSH

129
Q

Hormones produced in the hypothalamus

A

GnRH

130
Q

Enzyme that converts androstenedione to estrone

A

CYP19/Aromatase

131
Q

Breast cancer is made up of at least _____ distinct diseases

A

4
- claudin low (mesenchymal)
- basal like (BRCA 1)
- HER2 amplification
- luminal A/B

132
Q

Tamoxifen: Target

A

ER

133
Q

Tamoxifen: Activation

A
  • prodrug metabolized by CYP2D6
134
Q

Tamoxifen: MoA

A
  • Selective Estrogen Receptor Modulator (SERMs)
  • binds to estrogen receptor in a tissue specific manner
135
Q

Tamoxifen: Effects

A

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
Q

Tamoxifen: Post or Premenopausal

A

both

137
Q

Tamoxifen: Indication

A
  • treatment of ER+/PR+ breast cancer (resected or metastatic)
  • first drug approved for breast cancer prevention in high risk patients
138
Q

Raloxifene

A
  • no endometrial hyperplasia compared to tamoxifen
  • indication is osteoporosis as it increases bone mass and blocks bone resorption better than tamoxifen
139
Q

Fulvestrant: MoA

A
  • binds to ER and inhibits DNA binding
  • rapid receptor degradation
140
Q

Fulvestrant: Effects

A
  • pure ER antagonist and has NO agonist effects
141
Q

Fulvestrant: post or premenopausal

A

postmenopausal women who have progressed on other antiestrogen therapy with ER+ metastatic breast cancer

142
Q

Aromatase Inhibitors:

A
  • blocks the conversion of androstenedione –> estrone and testosterone –> estradiol
  • blocks synthesis of estrogens but not androgens or progesterone
143
Q

Source of estrogen in postmenopausal women

A

adipocytes
- androstenedione produced in adrenal gland and released into circulation
aromatase converts

144
Q

Primary target of aromatase inhibitors

A

adipose tissue (not ovary)

145
Q

Anastrozole/Letrozole: Drug Class

A

non-steroidal aromatase inhibitors

146
Q

Letrozole: MoA

A

potent and selective competitive inhibitor of aromatase

147
Q

Letrozole: Indication

A

breast cancer in postmenopausal women
- first line therapy
- OR started 3-5 years of tamoxifen

148
Q

Letrozole: Toxicity

A

-minimal
- increases bone density loss

149
Q

Exemestane: MOA

A

steroidal aromatase inhibitor
- false substrate that aromatase converts
- intermediate binds irreversible at active site and inactivates it

150
Q

Exemestane: Indication

A

postmenopausal women who have progressed on antiestrogen therapy

151
Q

Exemestane: Toxicity

A
  • minimal
  • hot flashes
  • increased cholesterol
  • occasional peripheral edema and weight gain (build up of progesterones)
152
Q

Effects of LH

A

increases activity of the conversion of cholesterol to progesterone

153
Q

effects of FSH

A

can increase expression of aromatase

154
Q

Leuprolide:MoA

A

GnRH Analog
- downregulates pituitary GnRH receptors and pituitary desensitization to decrease estrogen and androgen production

155
Q

Leuprolide: Side Effects

A
  • transient worsening of symptoms related to initial agonist effects (tumor flare)
  • hot flashes
  • sexula dysfunction
156
Q

Leuprolide in Women: Indication

A

premenopausal women breast cancer

157
Q

what converts testosterone to dihydrotestosterone

A

5-alpha reductase

158
Q

Androgen Receptor signaling

A
  • cytoplasmic
  • amplified in prostate cancer
  • binding of AR to DHT leads to translocation to the nucleus and action of genes that drive cell
159
Q

Leuprolide in Men: MoA

A
  • chemical castration
  • leads to a decrease in LH production
160
Q

Leuprolide in Men: Indication

A

palliative treatment of advanced prostate cancer

161
Q

Leuprolide in Men: side effects

A
  • tumor flare ( initial agonist effects)
  • gynecomastia
  • sexual dysfunction
162
Q

Degarelix and Relugolix: indication

A

GnRH antagonist for advanced prostate cancer

will not result in flare

163
Q

Aberaterone: MoA

A
  • inihbits the function of 17-alpha hydroylase and C17,20 lyase
  • inhibits conversion of pregnenolone and progesterone to DHEA and androstenedione
164
Q

Abiraterone: Side effects

A
  • increased cholesterol levels
165
Q

Enzalutamide (Apalutamide, Darolutamide)

A

AR antagonist
- prevents AR translocation to the nucleus
- inhibits AR binding to DNA
- approved for both metastatic and non-metastatic prostate cancer

166
Q

Gefitinib: MoA

A
  • EGFR targeted kinase inhibitor, turns off signal to proliferate
  • type I
  • tumors have EGFR exon 19 or exon 21 (L858R) mutations
  • NSCLC
167
Q

Afatanib and Neratinib: Moa

A
  • EGFR targeted kinaase inhibitor
  • covalent inhibitor of all ErbB receptors
  • NSCLC
168
Q

T790 mutation

A
  • resitance to Gefitinib
  • use osimertinib (third generation covalent inhibitor)
169
Q

Lapatinib: MoA

A
  • small molecule tyrosine kinase inhibitor that blocks HER2 and EGFR
  • reversible inhibitor of both EGFR and HER2
170
Q

Lapatinib selectivity

A

HER2+ breast cancer

171
Q

Lapatinib toxicity

A
  • symptoms of CHF
172
Q

Tucatinib: MoA

A

small molecule kinase inhibitor that preferentially binds HER2

173
Q

tucatinib selectivity

A

treatment of HER2+ breast cancer

174
Q

FLT3 mutations

A

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
Q

Midostaurin

A
  • first generation FLT3 inhibitor (broad)
176
Q

Crenolanib

A
  • second generation FLT3 inhibitor
177
Q

Quizartinib

A

Type II specific for ITD mutations in FLT3

178
Q

Imatinib: MoA

A
  • 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
Q

Imatinib: resistance

A
  • need to be on Abl inhibitors for life, resistance is a lifelong battle
180
Q

Ponatinib: MoA

A
  • BRC-Abl inhibitor
  • effective against all major forms of BRC-Abl
  • inhibits mutation T315I
181
Q

Alectinib

A
  • ALK inhibitor (-lec)
  • ALK+ metastatic NSCLC who have progressed on crizotinib
182
Q

Dabrafenib

A
  • 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
Q

Trametinib

A

-inhibits kinase activity of MEK1 and 2
- combo with dabrafinib
- type II allosteric inhibito r
- RASH

184
Q

Acalabrutinib

A
  • second gen BTK inhbitor
  • Bcell lymphoma
  • targets Cys481
185
Q

Rapamycin Analogs: Target

A

mTOR1 (serine-threonine kinase)

186
Q

5-FU target

A

thymidine synthase

187
Q

5-FU Resitance

A
  • downregulation of activating enzymes that comver 5-FU to fdUMP
  • upregulation of thymidylate synthase
188
Q

5-FU Susceptibiility

A

5% of the population has gene polymorphisms that results in a deficincey of the enzyme DPD which breaks down 5-FU

189
Q

5-FU Drug resucue

A

thymidine

190
Q

5-FU drug synergy

A

Leucovorate
- stable folate cofactor
- higher tetrahydrofolate levels increases 5-FU by increasing the amount of the covalent ternary complex with thymidylate synthase

191
Q

Capecitabine

A
  • orally active prodrug of 5-FU
192
Q

Cytarabine MoA

A
  • 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
Q

Cytarabine Resistance

A
  • downregulation of activating enzymes
  • upregulation of cytidine deaminase
  • downregulation of transporter to move drug into cells
194
Q

Cytarabine Syngergy

A

-tetrahydrouridine
- cytidine deaminase inhibitor
- increase efficacy and decrease resistance

195
Q

6MP MoA

A

blocks synthesis of purine nucleotides

196
Q

6 MP drug interaction

A
  • xanthine oxidase
    -allopurinol
197
Q

Antifolates (DHFR inhibition)

A

inhibition of TMP synthesis
- also inhibits RNA and protein synthesis
- also inhibits purine and pyrimidine synthesis

198
Q

Methotrexate

A

inhibits DHFR and mimics folates

199
Q

MTX resistance

A
  • decreased polyglutamation results in decreased intracellular MTX ammumulation
200
Q

Overdose of MTX

A

leucovorin increases pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition

PHRM 864 (10 decks)

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