5. Uveal melanoma: pathophysiology
Location
Iris
% 5-year mts.
%10-year mts
4%
7%
Ciliary body
19%
33%
Choroides
15%
25%
Conjuntival melanoma is related more with its
cutaneous counterpart
Predrag Jovanovic et al.
Int J Clin Exp Pathol 2013;6(7):12301244
8. Uveal melanoma prognosis
Monosomy of chromosome 3 is the
most frequent chromosome aberration
in uveal melanoma (50%)
Class 1: low grade tumors with low metastatic risk
Class 2: high grade tumors with metastatic risk
chracterized by down-regulation of genes on
chromosome 3 and up-regulation of genes on
chromosome 8q.
9. BAP1: BCRA-1 associated protein-1 and metastatic
development of uveal melanoma
The gene encoding BAP-1 is located on chromosome
3p21.1 and is mutated in 80% of metastatic uveal
melanoma. BAP-1 is a enzyme that forms part of a
tumor-suppressor complex. BAP-1 mutation is associated
to metastatic behaviour
11. Ipilimumab in metastatic uveal melanoma
Outcome after compassionate use (USA, Italy):
1-year overall survival over 30%.
More common dose: 3 mg/Kg
Median overall survival 6 months (Italian use)
Toxicity experience and response similar to cutaneous
12. Uveal melanoma: rational for treatment
GNAQ and GNA11 are mutated in a mutually exclusive pattern (83% uveal):
these mutations are implicated in the stimulus of MAPK pathway via MEK.
GNAQ/GNA11 signals also via PLC(phospholipase C) and PKC (protein
kinase C), enzymes implicated in proliferation, invasion,apoptosis via ERK
Cancer Letters 2006;235:1-10
13. Therapeutic targets
• MEK inhibitors: (no response in wild-type GNAQ/GNA11)
– Selumetinib compared with temozolamide; 9 weeks benefit for
selumetinib for PFS
– MEK162
• PAK inhibitors: sotrastaurin (AEB071)/ enzastaurin.
– G1 cell cycle arrest
– Inhibition of PKC in GNAQ-mutant resulted in the inhibition of the
MAPK pathway.
A combination of a MEK and proteinkinase inhibitor could be a
perfect therapeutic combination
14. Conclusions
• 1. Metastases from melanoma can spread to almost
•
•
•
•
every anatomical location.
2. Uveal melanoma is the most common primary
malignancy of the eye
3. GNAQ and GNA11 are mutated in 80% of uveal
melanoma in a mutually exclusive pattern
4. Ipilimumab achieves a 30% survival in the first year in
uveal melanoma
5. MEK inhibitors and PAK inhibitors are key for
developing targeted therapies.