Intro to Neoplasia Flashcards
terminology
___ - new growth (benign or malignant)
___ - nonspecific lump or swelling
___ - any malignant neoplasm
- neoplasm
- tumor
- cancer
terminology - the ‘plasias’
hyperplasia - increase in the ___ of cellls
___ - adaptive substitution of one type of adult tissue to another
dysplasia - abnormal cellular proliferation with a loss of normal ___
anaplasia - loss of structural ___ (occurs frequently in tumors)
- number
- metaplasia
- architecture
- differentiation
terminology - the ‘omas’
carcinoma - malignant neoplasm of ___ epithelial cell origin (benign is ___ )
adenocarcinoma - malignant neoplasm of ___ tissue
sarcoma - malignant neoplasm of ___ tissues (bone muscle fat)
lymphoma and leukemia - malignant neoplasm of ___ tissues
melanoma - cancer of ___ producing cells ( ___ ) in the skin or eye
blastoma - malignancies in ___ cells ( ___) which are more common in children
teratoma - ___ cell neoplasm made of several different differentiated cell tissue/types
- squamous, papilloma
- glandular
- mesenchymal
- hematopoietic
- pigment, melanocytes
- precursor, blasts
- germ
a 6 month old boy is determined to have a systemic malignancy originating from precursor cells of the nervous system. The pathology report would state?
A) adenocarcinoma
B) neuroblastoma
C) leukemia
D) metastatic sarcoma
neuroblastoma
blood cancers: leukemias and lymhomas
leukemia is a cancer of the ___ blood cells of hematopoietic origin
white
general pathological staging of carcinomas
0: in situ - no sign of local invasion
I: microscopic invasion
II: 4-9 surrounding __ are involved
III: 10 or more are involved
IV: distant ___ are detected
Largely based on tumor ___ , ___ and ___ . Primarily only solid tumors get staged
- lymph nodes
- metastases
- size, location, number
T or F: staging does not always mean lethality
T
staging is simply a means to understand/stratify for treatments. While stages 3 and 4 usually mean poorer outcomes, it does not always mean lethality
stage 3 testicular cancer has a cure rat of > 70%
specific clinical staging system
TNM staging system
- Primary Tumor (T) (1-4, increasing in severity)
- Regional Lymph Nodes (N) (1-3, increasing in severity)
- Distant Metastasis (1, yes or no)
X = cannot be evaluated
0 = no evidence
Tis = tumor in situ, not cancer but could be potentially
Summary Staging
used by SEER program. Groups cancer into 5 main categories
1) ___ : abnormal cells are only in layer in which they developed
2) ___ : limited to the organ in which it began without spreading
3) ___: spread past primary site to nearby lymph nodes, tissues, and organs
4) ___ : cancer has spread from primary site to distant tissues, organs, or lymph nodes
5) unknown: not enough info
- in situ
- localized
- regional
- distant
as opposed to stage, tumor grading
grade - ___ of tumor assigned by a pathologist
- well-differentiated (G1) = looks like normal cells
- undifferentiated (G4) and poorly differentiated (G3) - abnormal looking cells that may lack normal structure, grow ___ than G1
very commonly seen in primary tumors in lethal locations
description
faster
cancer has 3 properties
1) uncontrolled cellular growth ( ___ tumors as well)
2) tissue ___
3) metastasis
cancer is unstable, atypical, and loses normal cellular function
- benign
- invasion
T or F
for many tumors, the growth of the primary tumor is not going to be life threatening
T
it’s the metastasis
Tumor Viruses: Is Cancer Contagious?
- RSV is a ___ that integrates into the genome and encodes for v-Src
- v-Src is an ___
- any gene in a healthy cell capable of promoting tumor growth is a ____
RSV = Rous Sarcoma Virus
- retrovirus
- oncogene
- proto-oncogene
Genetic Basis of Cancer
some cancers can result from mutation or deletion of a single potent ___
- these mutations run in families
Retinoblastoma
- childhood retinal cancer
- ___ hypothesis
- assumption that hereditary retinoblastoma has a single deletion already
- tumor suppressor
- 2 hit
RB1 is a ___
- most tumor suppressors can be expressed from either chromosome and will need to be ___ deletion/mutation
- ___ mutations can be inherited and families show ___ susceptibility to cancers
- also called a loss of ___
tumor suppressor
- homozygous
- heterozygous, increased
- heterozygosity
mechanism of cancer progression
T or F: often, just one mutation is enough to cause cancer on its own
FALSE
often, one mutation isnt sufficient to cause cancer on its own
most players can broadly be classified as ___ or ___ depending on whether they prevent or promote cancer.
doesnt tell much about molecular mechanisms
tumor suppressors, oncogenes
introduction to chemotherapy
tumors of the same classification can have a unifying ___ driver, but often do not
- 100% of chronic myelogenous leukemia (CML) have bcr-abl translocation
- non small cell lung cancer (NSCLC) is a very heterogeneous collection of cancers
treatmenrs are often determines empirically and often only affect a subset of patients with the same cancer classification
genetic
genetic basis of cancer
cancers often take 20 years or more to develop
- NSCLC in nonsmokers: median 888 mutations
- NSCLC in smokers: median 15,659 mutations
___ decrease time to develop cancer by increasing mutation rates
carcinogens
genomics age - the beginning of targeted therapies
most cancers are relatively ___ and have a variety of gene mutations
- we can use this info to predict efficacy of therapies
heterogeneous
targeting oncogenic mutations
activating mutations can predict susceptability to targeted therapy
- 15-30% of NSCLC patients have an ____ mutaion
- mutations in catalytic domain ___ the intensity and duration of signaling in response to ligand
- activating mutations also increase the susceptibility to inhibitor almost 10-fold
- EGFR
- increase
tumor suppressor mutations
___ of function mutations can predict susceptibilty to chemotherapies
“Synthetic Lethality”
loss
BRCA1 and BRCA2 are ___
- encode for proteins involved in DNA ___
- nonfunctional mutant alleles of BRCA 1/2 are inheritied as ___ mutations. Prevalent in Ashkenazi Jewish ancestry.
- BRCA mutations in breast cancer increase susceptibility to ___ inhibitors
tumor suppressors
- repair
- germline
- PARP
Olaparib
Poly ADP ribose polymerase (PARP) inhibitor
- primarily for cancers with ___ mutations
- works by ___ PARP to DNA (unable to uncouple)
- also in this class: rucaparib, niraparib, talazoparib, veliparib
- BRCA1/2
- trapping
Intro to Chemo
- 5 year survival rates are 69%
- only a few cancers are typicaly curable by chemo - Hodgkin’s disease, childhood leukemias and lymphonas, testicular cancer
- breast, colorectal, and bladder cancer respond well to the combo of surgery and chemo
- despite many advances, many common cancers such as lung, pancreatic, and brain cancers are typically resistant to chemotherapy
chemo therapies are relatively ___ agents that are generally toxic to cells
non-specific
cell cycle
G0 - not in the cycle yet
G1- accumulating building blocks required for division
S - Cell ___ DNA
G2 - Cell assembling machinery for chromosomal ___ and cytokinesis
M - mitosis
driven by ___ paired with cyclin-dependent kinases
___ point is the critical time point when cells decide whether or not to enter the cell cycle
- replicating
- segregation
- cyclins
- R (restriction)
inhibition of cyclin dependent kinases
cell cycle checkpoints - decision point where cell decides to proceed through the cell cycles
- G1 to S - signal? building blocks? unrepaired DNA damage?
- S to G2 - genome been replicated? errors?
- G2 to M - sister chromatid arms separated? mchinery assembled?
cell cycle checkpoints and common chemotherapies
G1 - mitogenic signaling
- ___ and ___ inhibitors
S - DNA replication
- anti- ___
- anti - ___
- ___ inhibitors
DNA damaging agents (non-cell cycle specific)
- ___ and ___
G2 - sister chromatid separation
- ___ inhibitors
M - chromosome segregation
- ___ inhibitors
- kinase, hormone
- metabolites, folates, topo1
- alkylators, intercalaters
- topo2
- microtubule
- proteins driving cell cycle can act as ____
- proteins halting cell cycle act as ___
- ___ is a tumor suppressor known as the gardian of the genome
- cyclin ___ and ____are master regulators of cell cycle initiation
- oncogenes
- tumor suppressors
- p53
- D, Cdk4,6
Palbociclib
___ kinase inhibitor
- arent targeted therapies bc they target all replicating cells
- SE: neutropenia, nausea, fatigue, diarrhea, vomiting (similar to traditional chemos)
- approved for ___ mutations
- CDK4/6
- BRCA 1/2
would not work in someone with a Rb mutation bc thats downstream
which of the following is potentially true of a tumor suppressor gene?
A) allows unrestricted cell growth and proliferation
B) promotes different phases of the cell cylce
C) produces proteins that block the activity of cyclins
D) is often overexpressed in cancer
produces proteins that block the activity of cyclins
why are common chemos selective for cancer cells?
T or F: tumors that are very slow growing and cycle once every few months are still susceptible to chemo
True
their rapid growth isnt what makes the drugs selective necessarily
Loss of Control in Cancer
tumor cells have lost cell cycle control mechanisms
- increased cell proliferation
- ___ controls are often lost
cancer cells often do not:
- fully repair damaged ___
- repair damaged mitotic ___
- finish ___ DNA before proceeding to next stage
opportunity: loss of checkpoint control results in ___ cell death with chemo
- checkpoint
- DNA
- spindles
- replicating
- increased
Normal Cells response to DNA damage
when normal cells are exposed to chemo that causes DNA damage
- cells halt in ___until DNA repaired
- Cell then proceeds into S
- if cells proceed to S without repairing DNA, they ___
- preserve genomic intergrity of daughter cells
- G1
- apoptose
Cancer cell response ot DNA damage
when tumor cells have lost G1/S checkpoint control are treated with chemo that causes DNA damage
- cells do not halt ___ and attempt to replicate damaged DNA
- replicating damaged DNA can trigger apoptosis
- OR, if apoptotic response has been lost, cells replicate damaged DNA and acquire lethal genetic damage that result in ___
- G1
- necrosis
cell cycle and when therapies are effective
drugs that do not require cycling cells - G0 and cells progressing through the cell cycle
- DNA ___ agents can damage DNA independent of cell cycling
drugs that are more effective against cycling cells at many phases of the cell cycle are called cell cycle ___
- most effective when tumor cells are progressing through the cycle
- not dependent upon the cell being in a specific phase
- some efficacy against cells resting in G0, but more effective against cells progressing though cycle
- ___ agents and DNA ___ agents
- alkylating
- non-specific
- alkylating, intercalation
Phase Specificity
Phase-specific (schedule-dependent) drugs
- most effective against tumor cells in a specific phase of the cell cycle
limitation of cell kill
- higher drug ___ may not result in greater tumor cell killing
- cells have to be in sensitive state
- increased cell kill requires prolonged ___ : repeated administration and continuous infusion
- doses
- exposure
side effects are a huge problem
chemo kills rapidly dividing cells
major dose limiting toxicities
- ___ - WBC (infections), platlets (hemostasis), RBC (anemia)
- GI - N/V, loss of appetite
hematopoietic
a chemo that interferes with DNA synthesis is
a) S phase specific
b) G1 phase specific
c) cell cyc;e non-specific
d) M-phase specific
S phase specific
which phase pf the cell cycle do you think is targeted by palbociclib (CDK4/6 inhibitor)?
a) G1
b) S
c) G2
d) M
G1
considerations of chemo
- chemo kills a constant ___ , not a constant ___ of tumor cells
- it is impossible to kill all tumor cells with a single dose of drug. Like antibiotics, it will select for cells resistant to drug
- as tumors grow, their doubling times ___ (most agents work on cycling cells)
- diminishing returns due to ___ and intolerable SE
Norton-Simon hypothesis
- give as dose-intensive and ___ as possible
- give chemo at ___ intervals
- use combination of drugs with distinct MOA
dose dense has been made possible with ___
- fraction, number
- slows
- resistance
- early
- shorter
- GM-CSF
efficacy of cytotoxic chemotherapy
- ___ relationship between tumor size and curability
- cell killing must be greater than cell growth
- smaller tumors, earlier diagnosis, and increased drug intensity increase success rates
- inverse
not all tumors will respond equally to chemotherapy and it may not be possible in some cases for kill > growth
designing combination chemo
a drug that is ineffective when used alone is often not approved for combo studies, but this is changing
- individual drugs in combo should be used at ___ doses
- use drugs with different MOA or different cell cycle
max
combination chemo
advantages of combo therapy
- no additive toxicity for drugs with ___ toxicities
- increased cell killing
non-overlapping
drug resistance
altered drug metabolism
1) ___ pumps - PgP, MRP
2) reduced transport into the cell - loss of drug importer, decreased membrane permeability
3) decreased activation of ___
4) increased detoxification of drug molecule
efflux
prodrug
changes in drug target or function
1) ___ of drug target via gene amplification or expression makes it harder to inhibit
2) emergence of mutant, ___ altered target
3) emergence of cells bearing alterations in genes whose products are functionally redundant with the drug target - cells can rewire pathways to ___ the need to drug target
1) upregulation
2) structurally
3) bypass
physiological changes that promote resistance
refuge of cancer cells in drug protected ___ sites (example: brain, cannot cross BBB)
massive ___
- pancreatic carcinomas develop highly desmoplastic stroma that impedes drug transport
changes in cell state such as EMT (epithelial mesenchymal transition)
- ___ cell cycle, increases drug ___ pumps and increases ___ proteins
- anatomical
- stromalization
- slows, efflux, anti-apoptotic
cell survival mechanisms
1) activation of ___ regulators - increase in proteins that help cancer cells bypass cell death
___ of damage caused by chemo - most common is the repair of drug-DNA adducts or DNA damage
1) anti-apoptotic
2) repair
what is the most common reaso for resistance to multiple chemotherapies at once
a) decreased activation of prodrugs
b) drug transport out of cells
c) cell cycle changes
d) mutations in drug targets
b) drug transport out of cells
limitations of chemo
resistance - surviving tumor cells can proliferate and regrow with selective ___
toxicity - not huge differences between cancer cells and normal cells
advantage
chemo toxicity
chemo relies on general priciple tumor cells are more sensitive to drugs than normal cells
___ therapeutic index
narrow
