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Gary J. Brenner, MD, Ph.D.
Harvard Medical School/Massachusetts General Hospital
Screening of EGFR inhibitor/apoptotic drug combination in NF2 schwannoma xenograft mouse model
Dr. Brenner will use a newly developed NF2 schwannoma xenograft (human
cells implanted into mouse) model to test a new candidate drug therapy
combination. Human tumor cells are implanted into the mouse sciatic
nerve and rapidly - within 3 months - the mouse generates human tumors.
Because of their location in the nerve these tumors can be monitored
over time using non-invasive bioluminescence imaging. Dr. Brenner will
treat these tumors with a two-drug combination: the FDA approved drug
Tarceva (erlotinib) to target EGFR; and HSV amplicon vectors encoding
an apoptotic protein, which should induce cell death. Preliminary
studies suggest HSV amplicon vectors would also be compatible with
clinical trials.
Abraham Jacob, MD
Ohio State University
Preclinical testing of a novel AKT inhibitor OSU-03012 using an NF2 vestibular schwannoma xenograft model
NF2 vestibular schwannomas can cause hearing loss, balance problems,
and can be fatal. Recent experiments done in our lab have found that
the signaling element AKT is activated in NF2 vestibular schwannomas
(when merlin function is normal, it inhibits AKT). The drug OSU-03012
created at Ohio State University blocks AKT and is already being
studied in breast cancer, leukemia, and prostate cancer. OSU-03012 will
now be tested in a vestibular schwannoma xenograft mouse model. The
drug will be dosed orally or via a subcutaneous slow-release pellet.
Tumor growth & response to treatment will be monitored via MRI
scans taken several times over the next 6 months, after which time the
tumors will be analyzed. This experiment may open the door to using
OSU-03012 in human trials.
Susan Lindquist, Ph.D.
Whitehead Institute of Technology
Screening for Inhibitors of Heat Shock Transcription Factor 1: a Novel Therapeutic Target in NF1
Although much effort is focused upon blocking individual signaling
pathways regulating tumor cell growth using highly specific drugs
(‘magic bullets’), the complex nature of NF1 mean it may require more
than one single drug. Targeting the heat shock stress response has the
potential to achieve a broad effect, since tumor cells need heat shock
response for normal function.
Our group has recently shown that heat shock transcription factor 1,
HSF1, the master regulator of the heat shock stress response is
critical for the initiation of tumors through the Ras pathway that is
central to NF1. We will conduct a small molecule screen to identify
candidate inhibitors of HSF1 function, which could be potential NF drug
therapies.
Andrea McClatchey, Ph.D.
Harvard Medical School/Massachusetts General Hospital
Screening of EGFR inhibitors in a transgenic NF2 tumorigenesis model
Amongst other functions, merlin, the protein encoded by the NF2 gene,
regulates the function of the Epidermal Growth Factor Receptor (EGFR).
NF2 tumor cells fail to shut off EGFR and this is thought to play a key
role in stimulating tumor growth. A number of drugs target EGFR
including the FDA-approved drugs Iressa (gefitinib) and Tarceva
(erlotinib), which have been used for treatment of other tumors types.
Dr. McClatchey’s laboratory will examine at whether EGFR-targeted drugs
are potential treatments of NF2 tumors. The drugs will be tested in a
transgenic mouse model that develops NF2 associated liver tumors very
rapidly in early life, making it a good model for preclinical drug
testing.
David Wiemer, Ph.D.
University of Iowa
Screening the natural product schweinfurthin as a candidate therapeutic
for NF1-associated malignancies using xenograft and transgenic mouse
models
The natural product schweinfurthin A inhibits growth of NF1 mouse
astrocytoma cells, apparently by inhibiting the Rho signaling pathway,
which is downstream of neurofibromin signaling. Schweinfurthin A
appears to have no effect on healthy astrocytes making it a potential
drug candidate. Schweinfurthin analogue will be tested in both
xenograft and spontaneous NF1 mouse tumor models. Effective doses will
be determined and he effects of schweinfurthin on the immune system and
its ability to cross into the blood-brain barrier will be monitored.
These studies will lay the groundwork for designing human trials of
schweinfurthin for NF1.
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