Cellular signaling pathways affected in neurofibromatosis
The NF1 gene product neurofibromin is a tumor suppressor protein that
suppresses Ras function. The NF2 gene product Merlin (a.k.a. schwannomin)
is a tumor suppressor protein that suppresses PAK1 function.
Below is a simplified diagram showing some of the cellular signaling
pathways involved in neurofibromin and merlin function.
These signaling pathways also represent some of the candidate therapeutic
targets for the treatment of NF1 and NF2, in which the tumor suppressor
functions of neurofibromin and merlin, respectively, are disabled.
The ‘downstream signaling pathways’ are progressively becoming a focus as
effective, specific therapeutics for NF1 and NF2 are sought.
Cytokine receptors
EGFR, PDGFR, etc.
SOS, Grb2
Ras
Merlin (NF2)
Rac1,2
PI3 K
AKT
PAK1
Rho
mTOR
Neurofibromin (NF1)
C-Raf
MEK 1,2
ERK 1,2
……………………….Downstream Signaling Pathways………………………………..
© 2006 KHS/Children’s Tumor Foundation
Drugs in recent, current or planned (*) testing for NF
DRUG
Pirfenidone
DISORDER
NF1
Iressa
(gefitinib)
Gleevec
(imatinib)
Zarnestra
(Tipifarnib)
NF1/NF2
INDICATION
Plexiform
neurofibroma
Meningioma
NF1/NF2
Meningioma
Rapamycin
PEG-INTRON
(pegylated
interferon
alpha)
CELL TARGET
Fibrosis
PHASE
III
EGFR
II
PDGFR; BcrAbl, KIT/PI3
Plexiform
Farnesyl protein
neurofibroma
transferase
II
NF1
NF1
MPNST
Plexiform
neurofibroma
mTOR
Jak-Stat
II*
I
Erlotinib
Lovastatin
NF1
NF1
MPNST
Cognitive
function
EGFR
HMG CoA
Reductase
I
I
Simvastatin
NF1
Cognitive
function
HMG CoA
Reductase
I
Nexavar
(Sorafenib)
NF1
Plexiform
neurofibroma
Raf Kinase
I*
NF1
II
For fully updated information on current NF clinical trials please visit:
http://www.ctf.org/research/
© 2006 KHS/Children’s Tumor Foundation
Other drugs in development that target NF-relevant pathways
Below is a partial list of drugs that are currently in clinical testing for disorders
other than NF; but which may also be relevant to NF. This list is provided for
the purposes of highlighting examples (but is not all-inclusive) of some of the
potentially relevant signaling pathway targets for NF therapeutics.
This information was compiled from public resources including www.PhRMA.org)
Drug Candidate
Signal Transduction
target
Avastin (Bevacizumab)
VEGF
Erbitux (Cetuximab)
EGFR
In current testing for cancer
indications…
Various
Most advanced
status is …
Marketed
Head and neck; colorectal; various
Marketed
Sutent (Sunitinib)
PDGFR/VEGFR/c-Kit/ GIST. Kidney, breast, lung; enal cell
FLT-3
carcinoma; stomach cancer, liver,
breast, prostate
Velcade (Bortezomib)
Proteasome
Multiple myeloma; lung
Marketed
Marketed
Certican (Everolimus)
FKBP-12/mTOR
Breast; various
Phase 3
Depsipeptide (FK228)
HDAC/PAK-1
Phase 3
Enzastaurin HCl
(LY317615l)
Lapatinib
PKC-beta
Cutaneous T-cell lymphoma, renal
cell carcinoma, hormone refractory
prostate cancer
Glioblastoma; various
EGFR/ErbB2
Phase 3
Panitumumab
EGFR
Breast, head/neck, kidney, bladder,
lung, stomach.
Metastatic colorectal; kidney; lung.
Sarasar (Lonafarnib)
Farnesyl protein
transferase (FPT)
Gliomas; head and neck; breast;
CMML; myelodysplastic syndrome
Phase 3
Temsirolimus
HGF/Met/FKBP12/
mTOR
Metastatic breast cancer;
lymphoma; kidney cancer
Phase 3
Vatalanib
Metastatic colorectal
Phase 3
AEE788
AP23573
multi-VEGFR/
PDGFR/c-kit
VEGFR/ErbB2
mTOR
Glioblastoma multiforme; various
Glioblastoma; various
Phase 2
Phase 2
BMS-354825
Src-Abl
CML; various
Phase 2
CI-1040 (PD184352)
MEK1/2; ERK
Lung, breast, colon, cancer
Phase 2
CP-547,632
VEGFR
Phase 2
iCo-007
c-raf
Ovarian, peritoneal, fallopian tube
cancer
Not cancer - AMD/ocular diseases
INSM-120-101
(rhIGFBP-3)
MDX-214
IGFR/Erk
Phase II for mytotonic dystrophy.
Cancer safety trials ongoing.
Various
Phase 2
AML; mast cell leukemia
Phase 2
Various
Phase 2
lung
Phase 2
EGFR
Midostaurin (PKC412)
VEGFR/PDGFR/PKC/
c-Kit
Perifosine (KRX-0401)
Akt/JNK/MAPK
SAI-EGF
EGFR
Phase 3
Phase 3
Phase 2
Phase 2
Zactima (ZD6474)
EGFR
lung
Phase 2
17-AAG
B-Raf/HSP90
Von Hippel Lindau; various
Phase 2
AVE0005
VEGF
Safety - cancer
Phase 1
BMS-273291
VEGFR2
Safety - cancer
Phase 1
LErafAON - ETU
Raf-1
Safety - cancer
Phase 1
© 2006 KHS/Children’s Tumor Foundation