Homework 1 Flashcards
ECOG
What? physical status of the patient
0: fully active
4: completely disabled
Aggressive treatment requires higher ECOG score to tolerate the treatment
NCCN
National Comprehensive Cancer Network
1st Line Therapy for Metastatic Pancreatic Adenocarcinoma
First:
- if jaundice present –> metal stent
- genetic testing for inherited mutations
- molecular profiling for tumor tissue
Second:
- Good PS: clinical trial (preferred) or systemic therapy
- Poor PS: palliative and supportive care and consider single agent chemotherapy or targeted therapy
2nd Line Therapy for Metastatic Pancreatic Adenocarcinoma
No disease progression (after 4-6 months of chemotherapy)
- Folfirinox
- modified Folfirinox
- Nalirifox
- Gemcitabine + paclitaxel
Disease Progression:
- Gemcitabine
- Capecitabine
- continious infusion of 5-FU
3rd Line Therapy for Metastatic Pancreatic Adenocarcinoma
re-biopsy
radiation therapy
Is it reasonable to have the same drug as both the 1st line and 2nd line drug regimen?
YOU WANT TO AVOID THE SAME DRUG IN BOTH 1st and 2nd LINE
- when you give the drug the 1st time, the cancer cells have never seen the drug
- the weaker cancer cells are killed (tumor shrinkage) but some of the cancer cells survive and form resistance
Biomarkers for PD1/PDL-1 Drugs
- used to determine if certain patients are likely to benefit from immunotherapy
Examples:
- increased PDL1
- unstable MSI/dMMR
- increased TMD
CTLA-4 Inhibitor
Ipilimumab (Yervoy)
PD1/PDL-1 Interaction
Cancer cell expresses MHC and PDL-1 on the surface of the cell
PDL-1 on cancer cell interacts with PD1 on the T-cell
- PDL1 binds to PD1 on T-cell sending signal to the T-cell stating it is a good molecule
Should doctor order a test for PD1 or PDL-1 in tumor sample?
PDL-1
PD-1 Blockers
Pembrolizumab (Keytruda)
Nivolumab (Opdivo)
Cemiplimab (Libtayo)
PDL-1 Blockers
Atezolizumab (Tecentriq)
Avelumab (Bavencio)
Durvalumab (Imfinzi)
BRAC1
Olaparib
Niraparib
Talazoparib
Rucaparib
KRAS
Binimetinib
Trametinib
Cobimetinib
CDK4 and CDK6 Inhibitors
Palbociclib
Ribociclib
Abemaciclib
PARP Inhibitor to treat BRCA1 Mutation Cancers
When DNA is broken or damaged, the body can repair the DNA by both BRCA-mediated and PARP
In a patient with BRCA-mutated cells, the patient can no longer repair the DNA via the BRCA-mediated pathway; however, it can still repair the DNA via the PARP pathway (accuracy is low)
If we give PARP inhibitors, both the BRCA-mediated and PARP pathways for DNA repair are blocked and the cell (cancer) will die
Even if we give a PARP inhibitor that blocks PARP in good cell, the cell can still repair the DNA by the BRCA-mediated pathway as the BRCA cell is not mutated in a good cell
SYNTHETIC LETHALITY
BRCA1 Mutations Gain or Loss of Function
most of the patients are loss of function
HSB3
SOS –> KRAS
Salirasib
membrane bound KRAS
Lonafarnib & Tipifarnib
soluble KRAS
Vemurafenib
RAF inhibitor
Trametinib
MEK1/2 inhibitor
Perifosine
AKT inhibitor
Deltarasin
soluble KRAS to the membrane bound KRAS
AMG 510
- small molecule that specifically and irreversible inhibits KRAS G12C mutation by locking KRAS in inactive (GDP) state
- normal KRAS is a ball that does not have clear binding pockets
- when G12C mutation occurs, it forms a disulfide bond binding pocket that allows AMG 510 to bind into the pocket through C cysteine
CDKN2A/B Loss
CDK2NA and CKD2NB encodes for tumor suppressors involved within the CDK4/6 and MDM2 pathways
This tumor suppression leads to disrupted cell progression and proliferation
Melanoma Patients with NRAS Mutation
Ribociclib + Binimetinib (Mektovi)
