Pharm 2 lectures: cancer bio & cancer chemo Flashcards
What is anchorage dependence for proliferation?
Cells depend on their integrins (transmemb prots) interacting with ECM to proliferate
-Cancer cells dont follow this!
What are the 6 “hallmarks of cancer” according to the Weinberg model of tumor progression?
#1 Self sufficiency in growth signals: oncogenes #2 Sensitivity to negative signals: TSGs #3 Evasion of apoptosis #4 Acquisition of limitless proliferative capacity #5 Sustained angiogenesis #6 Tissue invasion and metastasis
Hallmark #1 self sufficiency in growth signals: oncogenes
deletion or point mutation in protooncogene (GFs, Rs, signaling enzs, TFs) coding seq can cause hyperactive protein to be made, amplification can cause prot to be overproduced, and chrom translocation near DNA regulatory seq can cause normal protein to be overproduced or fusion protein to be produced
RAS
point mutatiosn in ras can make it const active, causing cancer
Hallmark #2 Insensitivity to negative signals (TSGs)
TSGs inhibit cell growth, but if inactivated (via pt mutation, deletion in chrom, methylation at promotor, LOH, and transcr/posttranscr regulation), will end up allowing cells to prolif (brake pedals, causes apoptosis)
MDM2 significance w. p53 phosphorylation
When MDM2 phosphorylates p53 at a SPECIFIC SITE, it becomes tagged for proteasome degradation and expr is decr, causing decr apop, causing tumor growth.
(So INCREASED MDM2 activity phos/decr p53, causing cancer)
2 examples of TSGs
p53, Rb
Therapies targeting CDKs/cyclins?
Want to INACTIVATE cyclins/CDKs with INHIBITORS, so they don’t phosphorylate Rb. Rb stays bound to E2F, thus it continues to do what in normally does (Rb continues to prevent transcr of E2F since it’s bound)
Overall, how do CDK inhibitors work on Rb?
CDK inhibitors inhibit CDKs/cyclins from phosphorylating Rb, preventing it from being unbound to E2F, keeping it bound, and thus preventing an increase in proliferation
what are the 2 ways to init apoptosis?
Tx via caspase?
Extrinsic path where env signals/cytokines bind to death receptors, activating caspases causing cell death, and
Intrinsic path where there’s intracell oxidative stress that acitvates mito, acitv caspases, causing cell death
-Increase caspase activity to incr apop! (esp casp 8&9)
How do cancers have limitless prolif capacity (role of telomeres?)
Cancers prevent their telomeres from shortening w/ replications (eg inactivating p53 or Rb extends lifespan, mutations can activate telomerase and keep telomeres there)
Order of cell cycle phases
G0, can then go into G1 with growth signal
G1 (commits), S, G2, M
What are the checkpoints at each phase of cell cycle (3)
G1: dna dmg repaired
G2: checks that all chrom are repl, check for dna dmg
M: check that all chrom attached to spindle correctly at meta plate
Which CDKs are targets for drugs? (CDKs are prots that regulate cell cycle at each step, want to inhib to prevent cycle progression)
CDK4&6
How do telomerase inhibs work
TERG gene encodes telomerase RT, increasing telomerase expr, which keeps telomeres in cells, causing cancer (by decr apop)
-More telomerase activity means more aggro tumor!
What are 3 examples of pro-angiogenic factors
VEGF, FGF1, FGF2 (activated in tumors and signal cell endoth bv cell prolif)
Steps of angiogenesis
Signaling molecs (angiogen factors) bind to endoth cell and pericyte receptors, endoth grows, endoth degrades BM, invade ECM and forms tubes, pericytes/mesenchyme cells secrete Ang-1, binds to Tie-2 on endoth cells inducing vessel stabilization
Tx involving angiogenesis
- Suppress angiogenesis via antibodies which can bind/suppress VEGF
- TKIs can also inhib angio
- Akt/MTOR inhibs block signaling after VEGF binds
CSC Tx
Cancer Stem Cells can cause tumor relapse, want to target/destroy these
Reviewing 6 Hallmarks of cancer and examples
1: activate H-ras oncogene 2 lose Rb suppressor 3 produce IGF survival factors 4 turn on telomerase (keeps chrom integrity and inhib apop) 5 Produce VEGF inducer 6 inactivate E-cadherin
