Lecture 1 - Concepts of Chemotherapy Flashcards
How is cancer defined, categorized and staged?
cancer: any malignant neoplasm
defined as “the plasias” and the “omas”
numerical staging system
characterized by: uncontrolled cellular growth (benign tumors), tissue invasion and metastasis (cancer)
cancer is unstable, atypical, and loses normal cellular function
Cancer is a disease of progression
cell with mutation –> hyperplasia –> dysplasia –> in situ cancer –> invasive cancer
Numerical staging system
0: in situ carcinoma, no sign of local invasion (not outside of tissue it was originally diagnosed in)
I: microscopic invasion of surrounding tissue
II: 4-9 surrounding lymph nodes are involved
III: 10 or more surrounding lymph nodes are involved
IV: distant metastases are detected
largely based on tumor size, location and number; primarily only solid tumors get staged
stages 3-4 usually means poorer outcomes, it does not always mean lethality
Specific clinical staging system - TNM staging system
primary tumor (T)
regional lymph nodes (N)
distant metastasis (M)
Primary tumor (T)
TX: primary tumor cannot be evaluated
T0: no evidence of primary tumor
Tis: carcinoma in situ - no spreading to neighboring tissue yet
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 (# + location of lymph nodes)
Distant metastasis (M)
MX: distant metastatis cannot be evaluated
M0: no distant metastasis
M1: distant metastasis is present
Summary staging
insitu
localized
regional
distant
unknown
In situ
abnormal cells are present only in the layer of 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
Unknown
there is not enough info to determine the stage
The “plasias”
hyperplasia
metaplasia
dysplasia
anaplasia
Hyperplasia
an increase in organ or tissue size due to an increase in the number of cells
can be physiologic, compensatory, or pathologic
Metaplasia
an adaptive, substitution of one type of adult tissue to another type of adult tissue
Dysplasia
an abnormal cellular proliferation in which there is loss of normal architecture; transforms cell into abnormal version of itself
Anaplasia
a loss of structural differentiation
cells dedifferentiate
occurs frequently in tumors
The “omas”
carcinoma
adenocarcinoma
sarcoma
lymphoma and leukemia
melanoma
blastoma
teratoma
Carcinoma
malignant neoplasm of squamous epithelial cell origin
Adenocarcinoma
malignant neoplasam derived from glandular tissue
Sarcoma
malignant neoplasm with origin in mesenchymal tissues or its derivatives e.g. bone, muscle, fat
Lymphoma and leukemia
malignant neoplasms of hematopoietic tissues (blood tissues)
Melanoma
a type of cancer of pigment producing cells (melanocytes) in the skin or the eye (uveal melanoma)
Blastoma
malignancies in precursor cells, often called blasts, which are more common in children (nephroblastoma, medulloblastoma, and retinoblastoma)
from developing cells
Teratoma
a germ cell neoplasm made of several different differentiated cell/tissue types
from reproductive cells
Leukemia is a cancer of
the white blood cells of hematopoietic origin
comes from multipotential hematopoietic stem cell (hemocytoblast) - myeloid leukemias and lymphocytic leukemias –> lymphomas
What are the “hallmarks” of cancer?
avoiding immune destruction
enabling replicative immortality
activating invasion & metastasis
inducing or accessing vasculature
genome instability & mutation
resisting cell death
sustaining proliferative signaling
Become familiar with tumor nomenclature
neoplasm: meaning a new growth, may be benign or malignant
tumor: a nonspecific term meaning lump or swelling
Tumor grading
description of a tumor
well-differentiated: if the cells of the tumor and the organization of the tumor’s tissue resemble those of normal cells and tissue, these grow at a slower rate than tumors that are undifferentiated or poorly differentiated, which have abnormal looking cell/lack normal tissue structures
GX: grade can’t be assessed
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated
G4: undifferentiated
Some infections can cause cancer
RSV causes cancer - it integrates into the genome
Differentiate oncogenes vs. tumor suppressors
oncogene: gene capable of causing cancer
proto-oncogene: any gene in a healthy cell capable of promoting tumor growth
tumor suppressor: slow down cell division or tell cells to die at the right time
tumor suppressors prevent cancer, oncogenes promote cancer
v-Src is an
oncogene
Kras is a
oncogene
RB1 is a
tumor suppressor
P16 and P53 are a
tumor suppressor
P53 is the guardian of the genome
BRCA1 and BRCA2 are
tumor suppressors
they encode for proteins involved in DNA repair
Most tumor suppressors need to be
homozygous deletion/mutation
heterozygous mutations can be inherited and families show increased susceptibility to cancers “loss of heterozygosity”
2-hit hypothesis
hereditary retinoblastoma has a single deletion already
How will genome sequencing change personalized cancer treatment?
most cancers have a variety of gene mutations
screen pt to find specific type of mutation, can then target that specific mutation
Targeting oncogenic mutations
EGFR mutation - tyrosine kinase which acts as oncogene, promotes growth
Tumor suppressor mutations
loss of function mutations can predict susceptibility to chemotherapies
“synthetic lethality” - when you lose a tumor suppressor, there’s still other pathways being utilized; ex. BRCA and PARP
BRCA mutations in breast cancer increase susceptibility to
PARP inhibitors
normal cell: PARP1 and BRCA lead to repair
cells with BRCA mutation: PARP1 is still able to lead to repair
cells with drug-induced PARP1 inhibition: cancer drug inhibits PARP1, BRCA can still repair the DNA
cells with BRCA mutation and PARP1 inhibition: cancer drug targets and inhibits PARP1, BRCA mutation leads to no repair and cell death
PARP inhibitor
olaparib: primarily for cancers with BRCA1/2 mutations; traps PARP to DNA –> unable to uncouple from DNA
CDK4/6 inhibitors
ribociclib, palbociclib, abemaciclib
directly inhibit kinase, prevent phosphorylation of Rb1 and prevent cells from dividing quickly
Palbociclib
Cdk4/6 kinase inhibitor
not a targeted therapy because they target all replicating cells
approved for cancers arising dur to BRCA1/2 mutations
Importance of cell cycle in chemotherapy
chemo to target DOGMA
central DOGMA of biology: DNA transcribed to RNA, RNA translated to protein
cell cycle driven by cyclins paired with cyclin-dependent kinases
R point is the critical time point when cells decide whether or not to enter the cell cycle
controlled by cyclin D
Cell cycle checkpoints
G1 phase: mitogenic signaling
S: DNA replication
G2: sister chromatid separation
M: mitosis, chromosome segregation
G0: rest phase
Understand how chemotherapies target cancer growth and cancer survival
loss of checkpoint control results in increased cell death with chemotherapy
Kinetics of cancer cell proliferation (rate of tumor growth, growth fraction, doubling time) and kinetics of cancer cell killing by chemotherapy
when tumor cells have lost G1/S checkpoint control, the cells do not halt in G1 and attempt to replicate damaged DNA, this triggers apoptosis or the damaged DNA is replicated and lethal genetic damages are acquired, resulting in necrosis
Drugs that do not require cycling cells
DNA alkylating agents - effective against cancer cells resting in G0 and cells progressing through the cell cycle
Drugs that are more effective against cycling cells at many phases of the cell cycle (non-specific)
alkylating agents and DNA intercalation agents - most effective when the tumor cells are progressing through the cell cycle; not dependent upon the cell being in a specific phase of the cell cycle
Phase specific drugs
most effective against tumor cells in a specific phase of the cell cycle
# of cells killed by the agent will be limited to the # of cells present in the apporpriate phase of the cell cycle; higher drug doses may not result in greater tumor cell killing
increased cell kill requires prolonged exposure - repeated administration or continuous infusion
Major mechanisms of drug resistance in cancer chemotherapy
chemo kills a constant fraction, not # of tumor cells
it will select for cells resistant to drug, undergo cycles of chemo to kill more fraction of tumor cells
give as dose-intensive and early as possible and at shorter intervals (longer intervals lead to more time for growth of the tumors)
Drug resistance - altered drug metabolism
- increased transport of drugs out of the cell through efflux pumps - PgP and MRP
- reduced transport into cell - loss of drug importer, decreased membrane permeability
- decreased activation of prodrug
- increased detoxification of drug molecule
Drug resistance - changes in drug target or function
- increased expression of drug target through gene amplification or expression - upregulation of a drug target makes it harder to inhibit
- emergence of mutant, structurally altered target - mutants that are active but don’t bind the drug
- emergence of cells bearing alteration in genes whose products are functionally redundant with the drug target - cell can reqire pathways to bypass need for drug target
Drug resistance - physiological changes that promote resistance
refuge of cancer cells in drug-protected anatomical sites - metastasis to brain where drugs don’t cross BBB
massive stromalization - pancreatic carcinomas develop highly desmoplastic stroma that impedes drug transport
changes in cell state such as EMT - slows cell cycle, increases drug effluc pumps and increases anti-apoptotic proteins
Most common dose-limiting toxicities resulting from cancer chemotherapy
hematopoietic - WBC (granulocytes) - infections, platelets - hemostasis, RBC - anemia
gastrointestinal, N/V, loss of appetite
Principles of combination chemotherapy
use combo of drugs with distinct mechanism of action to help to prevent resistance
also more effective to target different site in the cycle
CHOP: cyclophoshamide, doxorubicin, vincristine, prednisone
advantages: no additive toxicity for drugs with non-overlapping toxicities and increased cell killing
