Skin Cancer Flashcards
Tx for actinic keratosis (pre-squamous)
Diclofenac (topical NSAID)
Imiquimoid
Trichloroacetic acid (peel)
Tx of Basal cell carcinoma (albinos with severe peeling sunburns)
Imiquimod
Vosmedegib
5 FC
Tx of melanoma
Aldesleukin (IL2) Vemurafenib Trametinib sorafenib Interferon alfa Ipilimumab
only MAB used for skin cancer
ipilimumab (melanoma )
common sites for skin mets
GI, Lungs, Brain
basal cell clinical course
slow growing, greater ability to eb locally invasive (bone)–> but least likley to metastasize (reason is because it has a very fastidious strome that it can growht in and it carries this stroma with it as it locally invades–>less likley for distant mets)
when BCC does met. whats the tx
no stndardized tx.
–> cisplatin is the best we have
topical treatment of BCC in most sites
5 florouracil
topical tx of BCC is small and at low risk sites in pt’s who are bad candidates for conventional therapy
imiquimod-topical with limited systematization
advanced/metastatic BCC tx
vesmodegib
BCC especially reliant on
HedgeHog Signalling pathway–>vesmodegib is a SMO inhibitor
MOA for Imiquimod
immuno-stimulant
>activates TLR7 and TLR 8 (activating a TH1 respone in sentinel cells around the tumor)whilst inhibiting Adenosine receptors
>also activates NFkB-causing upreg of TNF and IL’s
>also negatuvely modulates GLI ligand-independent signalling
>adora’s?
what all does imiquimod treat
BCC, HPV, AL’s
define the mutations in most BCC
HH driven malignancy with an activating mutation in GLI oncogene–> which signals in a ligand-independent manner
HH signalling travels via a protein named
SMO-smoothened
consequence of upregulaiton of HH signalling–> what molecules wind up being over-produced
BCL2 (anti-apoptotic)
VEGF
angiopoetins
*therfore HHinihbition from imiquimod, vesmodigib reduces all of these
why must small molecule inhibitors work at or below SMO
pathway is ligand independent, so blocking PTCH! receptor is inneffective
Moa for Vismoedegib
oral smo inhibitor
BBW’s for SMOE
intrauterine fetal death
male-related teratogenicity
*must confirm no pregnancy and use 2 forms of BC
Targetted drugs for squamous cell
none
conventional drugs for squamous cell
cisplatin but not standard tx
first line theray for squamous
sxical xision
Immuntherapies for Melanoma
Aldesleukin
Interferon alpha
Ipilimumab
Signal transduction inhibitors for melanoma
sorafenib
trametinib
vemurafenib
chemotherapy for advanced melanoma
again these don’t work well
dacarbazine, lomustine, carmustine (20% but repsonse short lived)
also taxanes, platinums, vincas
how does aldesleukin work?
IL2 agonist whose effects are identical to endogenous IL2–> BINDS to IL3 surface receptor-creates a cytokine cascade-whereby TNF IL’s and IFN’s are rleased
induces proliferation of B, T, Macrphages and NK cells
aldesleukin
BBW’s with aldesleukin
Cardio, Pul, Renal, CNS deffieincies
*also contra in hepatic disease or post-trasnplant
what do you have to have before putting someone on Aldesleukin
Thallium Stress Test
formal PFT
*daily on tx CXR
unique side effect of aldesleukin
renail failure insufficiency by CAPILLARY LEAK SYNDROME
“all-dats-leakin”
what to do Tregs do
tone down host anti-tumor, viral response
- guards againts autimmunity in life
- but hinders our anti-cancer efforts
VLS (capillary leak syndrome)
hypotension, inc vasc, permeability, pulmonary edema, renal/liver failure
what causes VLA
CD122hiNK cells–> releaisng pro-inflamm cytokines (TNF)
or
IL2 binding to CD25 endothelial cells increasing permeability
Aldesleukin acivates which cell lines
CD4 and CD* (beefs up their antitumor response
Treg->accidentally beefs up host anti-antitumor repsone (BAD off target effect)
MOA for interferon alpha2b
works like endogenous interferon
BBW’s for interferon
worsening of auto-immune dz
cardiac dysfuntion
depression–> suicide
routine tests for interferon
CBC’s, CXR, ECG, LFT’s
CLTA4 recombinant antibody
Ipilimumab
many BBW’s but no D-D interxn potention
Ipilimumab
side effects of Ipilimumab
Severe and fatal immune-mediated adverse reactions
*can cause dermatitis/TEN
rash, dirrhea, tiredness, ithch
MOA for ipilimumab
bind CLTA4 on the t cell and PREVENTS CLTA4 from binding to B7 (CD80/CD86)
what does CTLTA4 do
negative regulator of t cell activation (thus blockade prevents t cells from being toned down…you can only turn them up, their proliferaiton and acitvation is augmented..and HOST MORE ABLE TO FIGHT OF TUMOR
THIS DRUG FIGHTS MELANOMA INDIRECTLY BY INCREASING T CELL MEDIATE ANTI-TUMOR RESPONSE
IPILUMUMAB
PROBLEM WITH IMMUNE THERAPY
UNWANTED IMMUNE-MEDIATED ADVERSE EFFECTS IN MANY ORGANS–> LIMITS CLINICAL UTILITY
HEMORRHAGE POSIBLE–>rash (severe-desquamative),hepatic dysfunction high LFT’s,, heme toxic
sorafenib
mutli-kinase inhibitor
sorafenib
what kinases does sorafenib inhibit
VEGF, PDGFR< cKIT, RAF
2 drugs that cause hand and foot syndrome
Sorafenib
Trametinib
routine tests required with sorafenib
CBC’s–> anemia and nutropenia, BM supressed
increased risk of brain/GI bleed
srafenib–> inhibits VEGF
effects of sorafenib mutli-kinase inhibition
- antiproliferation
1. antiangiogenic
recommended regimen for sorafenib right now
dacarbazine IV on day one
then sorafenib for 21 days
MOA for tremtinib
reversible MEK inihib.
how to remember tremetinib
treMEKinhib
treats BRAF V600E or V600K muts
tremetinib
severe skin toxiticities
tremetinib and sorafenib
routine test for tremetinib
LVEF must be monitored, CBC’s and LFT’s
side effects
cardiomyopathy, ILD, retinal pigment epithelial detachmet
retinal epithelial dettachment
tremetinib
requires genotyping for BRAF mutation
tremetinib and vemurafenib
order of signal transduciton
RTK–> cKIT, NRAS< BRAF<proliferation and survival
if MEK is mutant what will work
nothing or tremtinib?
if mek is mutant what wont work
vemurafenib–> downstream
works on BRAF V600E * not to be used in wild-type tumors
works only on mutant BRAF
vemurafenib
may cause paradoxical ERK activation of RAS driven growth if used un wild type tumors
vemurafenib
requires constituitively acitve BRAF mutation V600e
vemurafenib and trametinib
patients receiving this drug are at a higher risk for developing SCC (25% of patients)
vemurafenib
significant toxicities of vemurafeinib
skin-SJS and SCC possible
eye-uveitis, iritis, retinal vein occlusion
cardiac–> qt prolong
liver–>PGP and cyp interactions
monitoring required with vemurafenib
EKG, electrolytes, creatinine, lft’s
resistance to vemurafenib
alternative pathway selection (normal RAF, Araf, Craf, etc all have a greater presence if BRAF is inhibited)
causes pradoxical RAS-driven proliferation of pre-exisiting and unrecognized malignancies
vemurafenib
commonalities of toxicity in MEK/RAF inh.
liver, heart, eye, secondary malignancies
all three raf/mek inhibitors have the potential to cause
possibly severe rash (SJS-desquamative)
pregnancy
immune modulators C–>dont give
raf/mek inhibitors D–> teratogen associated
