Lecture 13 : Anti-cancer therapies Flashcards
(29 cards)
To what is due the decline of death rates for cancer ?
to improved diagnostic tools, health conditions or habits, not necessarily better cancer therapies.
What is the difference between conventional and targeted anticancer drugs ?
conventional : drug targets and kills proliferating cells, targets what is common to all cancer cells (not specific to a certain cancer type), surgery for example.
targeted : drug targets cancer cells (spares “normal” cells), targets a molecule or a process driven by it.
Three conventional anti-cancer therapies
surgery, radiotherapy, chemotherapy
Define the neoadjuvant therapy
therapy before surgery to shrink the tumor and make it easier to remove
(frequently given, works better)
Define adjuvant therapy
therapy after surgery to kill the remaining cancer cells.
Principle of radiotherapy and how does it work ?
Principle : damage the DNA of the cancer cells, to inhibit further proliferation.
Direct DNA damage : charged particles (protons or ions).
Indirect DNA damage : photons, formation of free radicals.
Long term effects : induce mutations in the normal cells, can lead to a cancer later if administered at a young age.
Exemple of radioresistance and what happened ?
Radiotherapy provides transient efficacy in glioblastoma due to radioresistance.
Some cancer cells are able to upregulate the DNA repair systems.
Principle of chemotherapy
Induce cancer cell death via apoptosis.
Chemotherapies may target different stages of the cell cycle, or affect the cancer cells independent of cell cycle.
History of chemotherapy
several chemotherapies introduced in the 40s.
first initial objective was to use it to kill and physically harm people, by inducing a bone morrow failure. (mustard gas)
Types of chemotherapies
Alkylating agents, platinum derivatives, antimetabolites.
Alkylating agents - fonctionnement
They attach alkyl groups covalently to the DNA bases.
They work by binding to DNA, crosslinking two strands and preventing cell duplication.
They are highly mutagenic, may cause secondary tumors after therapy (same mechanism as mustard gas).
Platinum derivatives - fonctionnement
Form DNA adducts by binding with the DNA. That causes various cellular responses such as DNA replication arrest, transcription inhibition, cell-cycle arrest, DNA repair and apoptosis.
Antimetabolites - fonctionnement
They interfere with the normal functioning of specific enzymes/macromolecules that participate in DNA replication.
(block processes, no sticking)
What was observed in cancer cells resistant to different anti-anticancer therapies ?
They were overexpressing P-glycoprotein, a drug export transporter on the plasma membrane.
(could expel the chemotherapy from the cell)
Name of the drug that induces apoptosis of CML (chronic myeloid leukemia) but not normal bone marrow cells ?
Gleevec (imatinib), a specific Abl inibitor.
Particularities of the NSCLC (non small cell lung cancer) and the two targeted drugs
EGFR is upregulated or mutated in more than 60% of NSCLCs.
2 targeted drugs : gefitinib (Iressa) and erlotinib (Tarceva), both inhibit the EGFR TK.
What is the specific mutation in the EGFR that confer sensitivity to EGFR inhibitors (Iressa) ?
mutations in the TK domain that may constitutively activate the tyrosine kinase of EGFR and promote uncessant downstream signaling (protect the cancer cells from apoptosis).
Definition of oncogene addiction (+link to EGFR)
The cell has become dependent on a main (driver) mutation whose product (generally, an oncogenic protein) is required to maintain cell homeostasis in metabolically corrupted cancer cells
-> cancer cells with a mutated EGFR (constitutively active) EGFR are more dependent on EGFR signaling than cancer cells with a wild-type EGFR
Above a certain threshold, perturbations to the system (cell) can lead to..
cell collapse :
- excessive genetic damage may lead to cell apoptosis.
- excessive toxic stress may lead to cell necrosis.
How to overcome primary drug resistance to the RTK inhibitor, because of constitutive activation of the pathway downstream (mutant RAS) ?
By targeting downstream signaling (slide 44)
How to identify patients amenable to targeted therapies ? 3 biomarkers (genes)
- prognostic (survival)
- predictive (response to therapy)
- pharmacodynamic (drug activity)
-> genetic profiles (mutations), gene expression signatures, proteomic profiles
Unsupervised stratification of cancers based on…
gene expression signatures
What is and does Poly(ADP-ribose) polymerase (PARP) ?
PARP recognizes SSB proteins bound to single-strand DNA breaks.
It binds DNA and catalyzes the synthesis of poly-ADP-ribose chains.
Poly-ADP-ribose chains trigger the recruitment of DNA repair enzymes.
Cells with mutant BRCA1 or 2 are dependant on what to avoid collapse ?
PARP
