Intro to Cancer Therapeutics

Question 1

Epochs of Cancer treatment

Answer 1

Surgery, Radiation, Cytotoxic chemotherapy, combination chemotherapy, growth factor antagonism, specific immune therapy

Question 2

adjuvant

Answer 2

systemic therapy given after surgery as an aid to achieving cure

Question 3

neo-adjuvant

Answer 3

pre-operative therapy

Question 4

single most conceptual advance in cancer therapy

Answer 4

combination of local and systemic therapy

Question 5

Systemic therapies are usefully classified as

Answer 5

chemotherapy (poisons that inhibit mitosis or induce apoptosis)
Signal transduction inhibitors
Immune therapy

Question 6

Central dogma

Answer 6

DNA – RNA – protein

Question 7

Most pharmacology impacts

Answer 7

proteins (then intermediary metabolism) - least DNA and RNA

Question 8

Where does protein regulation come at protein level

Answer 8

Protein-Protein interactions
Glycosylation
Phosphorylation
Proteolysis
Degradation (Ubiquitin)

Question 9

Where do you regulate DNA to regulate proteins

Answer 9

Promoter
	•Transcription factors
	•Constitutive Expression
	•Silencing by Methylation
Chromatin

Question 10

how do you regulate RNA to regulate protein

Answer 10

Alternate splicing
iRNA
shRNA

Question 11

Pathologic alterations of DNA

Answer 11

Viral Insertion
Translocation
Mutation
	Gain-of-function
	Loss-of-function
	Silent

Question 12

Phases of mitosis

Answer 12

prophase
prometaphase
metaphase
anaphase
telophase

Question 13

possible outcomes of mitotic arrest

Answer 13

(unattached kinetochores) – >
chronic arrest
adaptation, mitotic death

survival, apoptosis

Question 14

Cancers are diseases of rapid/slow growth

Answer 14

Diseases of slow accumulation from failure to response to apoptotic signals

Question 15

2 pathways of apoptosis

Answer 15

Intrinsic

FAS-mediated

Question 16

Intrinsic apoptotic pathway

Answer 16

tbid - Cyto C –> casp 9 + apaf-1 –> apoptosome –> cleaved casp 9 –> cleaved casp 3 –> casp 7, apoptosis

Question 17

FAS mediated pathway

Answer 17

Fas-ligand + receptor –> cleaved casp 8 – casp 3– casp 7, PARP – apoptosis

Question 18

most drugs work where

Answer 18

proteins

Question 19

fundamental, highly regulated process important both for neoplasia and sensitivity to chemotherapy

Answer 19

apoptosis

Question 20

what is cancer

Answer 20

dysregulated growth characterized by 
loss of orientation and contact inhibition
failure to respect anatomic boundaries
immune evasion
promotion of angiogenesis

Question 21

what does cancer arise from

Answer 21

Arises from unbalanced growth promoting signals (“oncogenes”) with growth inhibitors (“tumor suppressors”)

Question 22

human cancers are complex “organs” with

Answer 22

malignant cells, stromal cells, vasculature & immune infiltrates. They typically have very high interstitial pressure, low oxygen tension and low pH

Question 23

how are cancers currently classified

Answer 23

Currently cancers are classified by tissue type of origin:
• Epithelial (carcinoma) ca. 70% of all cancers, named by anatomic site
• Stromal (sarcoma)
• Hematologic (leukemia, lymphoma, plasma cell dyscrasia)
• Germ Cell Tumors

Question 24

cancer classification smart way

Answer 24

Soon, cancers will be classified on the basis of biology: 
What is driving proliferation
What is inhibiting apoptosis
What is promoting invasion
What is promoting immune evasion
etc.

Question 25

order of drug testing

Answer 25

biochemical assays
in cell culture
at least 2 non-human species
Phase 1 - dose safety
Phase 2 - effective?
Phase 3 - compare

Question 26

monoclonal antibodies - name

Answer 26

mab

Question 27

proteasome inhibitors - name

Answer 27

omib

Question 28

tyrosine kinase inhibitors - name

Answer 28

nib

Question 29

mTor inhibitors

Answer 29

limus

Question 30

antiandrogens

Answer 30

amide

Question 31

nucleoside analogs

Answer 31

abine

Question 32

Phase I clinical trials usually include

Answer 32

pharmacokinetics

pharmacodynamics

Question 33

pharmacokinetics

Answer 33

the characterization of the distribution, metabolism and excretion of drugs: How the body affects the drug

Question 34

pharmacodynamics

Answer 34

the characterization of how the drug interacts with a living system: How the drug affects the body

Question 35

aim of phase I clinical trials

Answer 35

dose limiting toxicity (DLT)

Question 36

how many in phase I clinical trials

Question 37

grades of toxicity

Answer 37

grade 1 events have no physiologic or clinical consequence
Grade 2 events are physiologically relevant
Grade 3 events are potentially associated with major morbidity (hospitalization, intensive treatment, etc.)
Grade 4 events are life threatening

CTAE v4.0

Question 38

Phase II clinical trials goal

Answer 38

Scientific and statistical goal is to define the rate of “benefit” in a defined population

Question 39

phase II number of patients

Answer 39

30-60

Question 40

Prognostic factors

Answer 40

tumor size and nodal status (now)

PMN:Lymphocyte ration
Performance Status
Inflammatory markers such as acute phase reactants:
	low albumin
	high ferritin
	high platelets
	elevated c-reactive protein
	Erythrocyte sedimentation rate (ESR)
	elevated beta-2 microglobulin
	elevated IL-6
Age
Particular genetic lesions

Question 41

Phase III goal

Answer 41

formally compare two or more treatments (or strategies) using a definitive end-point such as survival time

Question 42

Phase III number of people

Answer 42

300-1200

Question 43

phase III requires what skill

Answer 43

equipoise (Lucky you test)

Question 44

All treatment arms in a phase 3 trial must be defensible as _______.

Answer 44

reasonable