Intro to Neoplasia, Pathology and Chemotherapy Flashcards
What is the median age of Cancer diagnosis?
67
Neoplasm
new growth, may be benign or malignant
Tumor
nonspecific term meaning lump or swelling
Cancer
any MALIGNANT neoplasm
Hyperplasia
an increase in organ or tissue size due to an increase in the number of cells
Metaplasia
an adaptive, substitution of one type of adult tissue to another type of adult tissue
Dysplasia
an abnormal cellular proliferation is which there is a loss of normal architecture
Anaplasia
a loss of structural differentiation. Cells differentiate
Carcinoma
malignant neoplasm of squamous epithelial cell origin
Adenocarcinoma
adeno=gland
malignant neoplasm derived from glandular tissue
Sarcoma
malignant neoplasm with origin in mesenchymal tissues or its derivatives
example: bone, muscle, fat
Lymphoma and Leukemia
malignant neoplasms of hematopoietic tissues
Melanoma
type of cancer of pigment producing cells in the skin or the eye
Blastoma
malignancies in precursor cells, often called blasts, which are more common in children
Teratoma
a germ cell neoplasm made of several different differentiated cell/tissue types
Myeloid leukemias
common myeloid progenitor
Lymphocytic leukemias
common lymphoid progenitor
Lymphomas
small lymphocyte–>T lymphocyte and B lymphocyte–> plasma cell
Stage 0
In situ carcinoma, no sign of local invasion
Stage 1
microscopic invasion of surrounding tissue
Stage 2
4-9 Surrounding Lymph nodes are involved
Stage 3
10 or more surrounding lymph nodes are involved
Stage 4
Distant metastases are detected
What is the numerical staging system based on?
largely based on tumor size, location, and number
Primary tumor
T
TX
Primary tumor cannot be evaluated
T0
No evidence of primary tumor
Tis
Carcinoma In Situ: Abnormal cells are present but have not spread to neighboring tissue; although not cancer, CIS may become cancer and is sometimes called preinvasive cancer
T1, T2, T3, T4
Size and/or extent of invasion of the primary tumor
Regional Lymph Nodes
N
NX
Regional lymph nodes cannot be evaluated
N0
No regional lymph node involvement
N1, N2, N3
Degree of regional lymph node involvement
Distant Metastasis
M
MX
Distant metastasis cannot be evaluated
M0
No distant metastasis
M1
Distant metastasis is present
In situ
abnormal cells are present only in the layer of the cells in which they developed
Localized
cancer is limited to the organ in which it began, without evidence of spread
Regional
cancer has spread beyond the primary site to nearby lymph nodes or tissues and organs
Distant
cancer has spread from the primary site to distant tissues or organs or to distant lymph nodes
G1
Well differentiated (low grade)
G4
Undifferentiated (high grade)
Cancer is a disease of progression
Cell with mutation–>Hyperplasia–>Dysplasia–>In situ cancer–> Invasive cancer
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
For many tumors the growth of the primary tumor is not going to be life threatening
Cells from a primary tumor can sit in an organ for very long periods of time before metastasizing
Metastasized cells are considered a tumor from the PRIMARY SITE
v-Src
ONCOGENE: gene that can cause cancer
RSV encodes a protein (v-Src) that is similar to the eukaryotic protein Src
any gene in a healthy cell capable of promoting tumor growth–> proto-oncogene
Tumor Suppressor
RB1
Most tumor suppressors can be expressed from either chromosome, and will need to be homozygous deletion/mutation
Heterozygous mutations can be inherited and families show increased susceptibility to cancers
Also called “loss of heterozygosity”
Genetic Basis of Cancer
Cancers often take 20 years or more to develop, although the time to cancer is decreased with increased mutation rate, such as through exposure to carcinogens
Carcinogen-induced cancers have very high mutation rates
Targeting Oncogenic mutations
Activating mutations can predict susceptibility to targeted therapy
15-30% of NSCLC patients have an EGFR mutation
Mutations can be identified using sequencing technologies
Mutations in EGFR catalytic domain increase the intensity and duration of signaling in response to logand
Tumor Suppressor Mutations
Loss of function mutations can predict susceptibility to chemotherapies
“Synthetic lethality”
Kill tumor cell while keeping healthy tumor in tact
BRCA 1 and BRCA2
Tumor suppressors
The BRCA1 and 2 gene encode for proteins involved in DNA repair
The nonfunctional mutant alleles of BRCA1/2 are inherited as germline mutations
BRCA mutations in breast cancer increase susceptibility to PARP inhibitors
Olaparib
PARP inhibitor: binds to DNA when it is bound it recruits additional modifiers
For cancers with BRCA1/2 mutations it works by “trapping” PARP DNA–> unable to uncouple from DNA
Chemotherapy
target the central dogma
G0/G1
Cell is quiescent or accumulating building blocks required for division
CDK 4/6
G1: kinase inhibitors and hormone inhibitors
S
cell replicating DNA
CDK1
Anti-metabolites, Antifolates, Topol inhibitors
G2
Cell assembling machinery for chromosomal segregation and cytokinesis
Topo2 inhibitors
M
mitosis
chromosome segregation
Microtubule inhibitors
R-point
restriction point is the critical time point when cells decide whether or not to enter the cell cycle
G1 to S
Is there a signal telling cell to proceed through cycle?
Are there sufficient quantities of the required nucleotide “building block?”
Is there unrepaired DNA damage?
S to G2
Has the genome been replicated?
Are there any errors?
G2 to M
Have sister chromatid arms been separated?
Has the machinery required for chromosomal segregation and cytokinesis been assembled?
P16
Tumor suppressor
TP53
Tumor suppressor
RAS
Oncogene
Palbociclib
Cdk4/6 kinase inhibitor
Aren’t exactly “targeted therapy” because they target all replicating cells
Adverse reactions: neutropenia, nausea, fatigue, diarrhea, vomiting
Approved for cancers arising due to BRCA1/2 mutations
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
When tumor cells that have lost G1/S checkpoint control are treated with chemotherapy that causes DNA damage
Cells don’t halt in G1 and attempt to replicate damaged DNA
Attempting to replicate damaged DNA can trigger apoptosis
OR, if the apoptotic response has been lost cells replicate damaged DNA and acquire lethal genetic damage that results in necrosis
Drugs that are more effective against cycling cells at many phases of the cell cycle are called cell cycle non-specific
These drugs are more effective when the tumor cells are progressing through the cell cycle, but they are not dependent upon the cell being in a specific phase of the cycle
Alkylating agents and DNA intercalation agents
Phase-specific
drugs are most effective against tumor cells in a specific phase of the cell cycle
DNA synthesis (S phase) or Mitosis (M phase)
Major dose-limiting toxicities of chemotherapy
Hematopoietic: WBC-infections, platelets-hemostasis, RBC-anemia
Gastrointestinal, N/V, loss of appetite
Combination chemotherapy
use combinations of drugs each of which is at least partially effective against a particular tumor
a drug that is ineffective when used alone is often not approved for combination studies, although this is changing
individual drugs in combination should be used at max doses
use drugs with different mechanism of action or different cell cycle specificities
CHOP
C: cyclophosphamide
H: Doxorubicin
O: Vincristine
P: Prednisone
Drug resistance
Many tumors initially sensitive to chemotherapy become resistant
Changes in drug targets/function
increased expression of drug target through gene amplification
emergence of a mutant, structurally altered target
emergence of cells with alterations in genes where the downstream effects are functionally redundant with the drug target
cells can rewire the pathway to bypass the need for drug target
