Cancer Biology Exam 4
Rational Treatment 1
• Cancer incidence and mortality (haven't change very much despite having more
knowledge on cancer)
- For some cancers mortality has decreased due to better refrigeration techniques (stomach cancer) or
prevention techniques (pap smear, colonoscopies, vaccines)
- mortality has remained constant for others because of unhealthy habits like smoking (lung &
bronchus)
- Diagnosis of small & early stage tumors possible now → should they actually be treated? → Breast
cancer incidence has increased and mortality is staying the same
- Weinberg's therapy decisions:
Cancer type Ideal treatment
Low invasive/metastatic potential that will none (surgery could provoke more tumors
likely remain this way always or cause death)
highly aggressive tumors that probably none (unless treatment might symptoms get
metastasize already better)
intermediate tumors before metastasis treat
• Stratifying cancer using functional genomics
- functional genomics used to stratify breast cancers into those with poor and good prognosis: using
gene microarray analysis of gene expression of 70 genes associated with poor or good prognosis to
have them over or under-expressed→ good way to establish which tumors to treat more aggressively
or not
• Traditional therapies
1. Surgery → removal of tumor
2. Radiation → damages DNA (preferentially cancer cells bc they’re unable to repair their DNA unlike
normal cells)
3. Chemotherapy → damaging DNA or interfering w/ mitosis (cancer cells more sensitive than normal
cell bc thy proliferate more) → correct dose: hurts cancer cells but not patient
- Alkylating agents (create DNA that's difficult to replicate/repair causing apoptosis →
by creating intra- & interstrand adducts)
- Nucleoside analogs (create DNA that's difficult to replicate/repair → added to DNA
instead of normal nucleotides → create residues that are difficult to replicate)
- Synthetic compounds (diverse: forming complex with topoisomerase prevent
unwinding of DNA or disrupting proteasome disrupting signaling pathways)
- natural products: stabilize/destabilize microtubules disrupting cell division
- combination therapies used to prevent drug resistance
• Targeted therapies
, - Targets of inhibition: oncoproteins (Her2 receptor blocked fro ligand with monoclonal Ab) & downstream
signaling pathways (Kinases inhibitors)
- many cancers rely mainly on 1 specific oncogene → target oncogene cancer is addicted to
- Druggable target have catalytic clefts → Kinases (Tyrosine kinases major players in cancer)
- TF not targeted bc they have no catalytic cleft
- blockage of protein interactions
- → ex) Nutlin blocking Mdm2 and p53 binding = Mdm2 not able to inhibit p53
anymore = p53 apoptosis pathway active again
- Specificity to inhibit specific kinase very hard since their catalytic clefts are all very similar
• Rational drug design
- Modeling/drug design
- Drugs should: be targeted to proteins
contributing directly to disease (oncogenes),
target targets with synaptic cleft (druggable),
detailed structures of target protein informs
design , you can screen libraries for
compounds and find a hit to further modified
drug for more specificity
- Desired: high specificity with low IC50 (amount
of drug needed to inhibit 50% of activity)
- Drug candidates testing process: in vitro (cell
culture) → mice → humans
- Gleevec activity in cell culture: →
• In vivo drug testing
Mice testing:Testing: Human cancer cells are tested in immunocompromised mouse hosts as a next
step in drug testing à Presumption: Human tumor cells in immunocompromised mice will behave
similarly to tumor cells in human patients
• Issue → Interactions with immune response not considered
→ If cancer is not orthotopic (at original site), may not accurately represent what would
happen in patient
→ cancer cells grown in culture are often not like most cancers encountered in people
- Pharmacokinetics: drug accumulation and disappearance from plasma over time
- Pharmacodynamics: kinetics of drug activity
- → both can be tested in mice
- Look for toxic effects in body and if has high therapeutic index (destroys cancer living other
cells unharmed)→ if successful, human in vivo trials can be started
Human trials process:
Phase I : Purpose = discover unanticipated toxicities and tolerable levels of drugs in patients
Rational Treatment 1
• Cancer incidence and mortality (haven't change very much despite having more
knowledge on cancer)
- For some cancers mortality has decreased due to better refrigeration techniques (stomach cancer) or
prevention techniques (pap smear, colonoscopies, vaccines)
- mortality has remained constant for others because of unhealthy habits like smoking (lung &
bronchus)
- Diagnosis of small & early stage tumors possible now → should they actually be treated? → Breast
cancer incidence has increased and mortality is staying the same
- Weinberg's therapy decisions:
Cancer type Ideal treatment
Low invasive/metastatic potential that will none (surgery could provoke more tumors
likely remain this way always or cause death)
highly aggressive tumors that probably none (unless treatment might symptoms get
metastasize already better)
intermediate tumors before metastasis treat
• Stratifying cancer using functional genomics
- functional genomics used to stratify breast cancers into those with poor and good prognosis: using
gene microarray analysis of gene expression of 70 genes associated with poor or good prognosis to
have them over or under-expressed→ good way to establish which tumors to treat more aggressively
or not
• Traditional therapies
1. Surgery → removal of tumor
2. Radiation → damages DNA (preferentially cancer cells bc they’re unable to repair their DNA unlike
normal cells)
3. Chemotherapy → damaging DNA or interfering w/ mitosis (cancer cells more sensitive than normal
cell bc thy proliferate more) → correct dose: hurts cancer cells but not patient
- Alkylating agents (create DNA that's difficult to replicate/repair causing apoptosis →
by creating intra- & interstrand adducts)
- Nucleoside analogs (create DNA that's difficult to replicate/repair → added to DNA
instead of normal nucleotides → create residues that are difficult to replicate)
- Synthetic compounds (diverse: forming complex with topoisomerase prevent
unwinding of DNA or disrupting proteasome disrupting signaling pathways)
- natural products: stabilize/destabilize microtubules disrupting cell division
- combination therapies used to prevent drug resistance
• Targeted therapies
, - Targets of inhibition: oncoproteins (Her2 receptor blocked fro ligand with monoclonal Ab) & downstream
signaling pathways (Kinases inhibitors)
- many cancers rely mainly on 1 specific oncogene → target oncogene cancer is addicted to
- Druggable target have catalytic clefts → Kinases (Tyrosine kinases major players in cancer)
- TF not targeted bc they have no catalytic cleft
- blockage of protein interactions
- → ex) Nutlin blocking Mdm2 and p53 binding = Mdm2 not able to inhibit p53
anymore = p53 apoptosis pathway active again
- Specificity to inhibit specific kinase very hard since their catalytic clefts are all very similar
• Rational drug design
- Modeling/drug design
- Drugs should: be targeted to proteins
contributing directly to disease (oncogenes),
target targets with synaptic cleft (druggable),
detailed structures of target protein informs
design , you can screen libraries for
compounds and find a hit to further modified
drug for more specificity
- Desired: high specificity with low IC50 (amount
of drug needed to inhibit 50% of activity)
- Drug candidates testing process: in vitro (cell
culture) → mice → humans
- Gleevec activity in cell culture: →
• In vivo drug testing
Mice testing:Testing: Human cancer cells are tested in immunocompromised mouse hosts as a next
step in drug testing à Presumption: Human tumor cells in immunocompromised mice will behave
similarly to tumor cells in human patients
• Issue → Interactions with immune response not considered
→ If cancer is not orthotopic (at original site), may not accurately represent what would
happen in patient
→ cancer cells grown in culture are often not like most cancers encountered in people
- Pharmacokinetics: drug accumulation and disappearance from plasma over time
- Pharmacodynamics: kinetics of drug activity
- → both can be tested in mice
- Look for toxic effects in body and if has high therapeutic index (destroys cancer living other
cells unharmed)→ if successful, human in vivo trials can be started
Human trials process:
Phase I : Purpose = discover unanticipated toxicities and tolerable levels of drugs in patients
