Download Vetenskaplig rapport, Dnr 120261 Utveckling av en ny målinriktad

Vetenskaplig rapport, Dnr 120261
Utveckling av en ny målinriktad behandling för SMARCB1-negativa tumörer
In this project, we identified a new drug combination for SMARCB1-negative tumors.
Two drugs (the proteasome inhibitor Bortezomib and the histone deacetylase inhibitor
suberoylanilide hydroxamic acid [SAHA, Vorinostat]) synergistically inhibit in vitro and in
vivo growth of human SMARCB1-negative tumor cells. This negative effect is accompanied
by increased apoptosis of tumor cells.
Based on our results we suggest the development of a diagnostic test for tumor patients with
suspected loss of SMARCB1 function to select those individuals that may respond to this
combination therapy. Since SMARCB1 protein levels are reduced or absent in the majority of
rhabdoid and other SMARCB1-negative tumors, such a test could be based on
immunohistochemistry of tumor tissue sections. Non-tumorigenic cells that are abundant in
such tissue sections (e.g. blood vessel cells) could serve as internal positive control.
Initially, we performed subcutaneous transplantations of human tumor cell lines into
immunodeficient mice and used this system as in vivo model for drug treatment studies.
To better understand the nature of the synergistic action of Bortezomib and SAHA in vivo and
to assess the effect of these drugs in immunocompetent animals, we started to develop a
suitable mouse model for SMARCB1-negative brain tumors by combining three mouse lines.
SMARCB1-negative tumors of the brain mainly affect infants and young children and are
classified as embryonal tumors. We therefore set out to delete the Smarcb1 gene in neural
stem/progenitor cells of the developing and early postnatal brain in mice that already lack one
Smarcb1 allele. This was done by crossing NesCreErtm animals (Tamoxifen-inducible Cre
recombinase expressed in Nestin-positive cells; obtained from Jonas Frisen, KI) with
Smarcb1+/- animals (obtained from Stephen Jones, University of Massachusetts Medical
School, USA) and Smarcb1fl/fl animals (obtained from Charles Roberts, Harvard Medical
School, USA). In this way we achieve a sequential inactivation of the two Smarcb1 alleles, as
is thought to occur during tumorigenesis in humans.
To this end, we have generated triple transgenic mice and are currently testing different
Tamoxifen doses to trigger an efficient deletion of Smarcb1 in Nestin-positive neural
stem/progenitor cells.
The next aim will be to monitor such animals for tumor development and to then investigate
cellular effects of Bortezomib and SAHA on developed tumors.
The application of Bortezomib as a novel cancer therapy for SMARCB1-negative tumors led
to various patent applications with Lund University Innovation:
Case Ref.
Country
Application No.
P012199PCT1
PCT
PCT/EP2012/059160 WO 2012/156463 A1 PCT Stage completed
Publication No.
Case Status
P012199PCTCN1 China
201280023500.6
CN 103619337A
Pending-Reply to Exam Report filed
P012199PCTEP1
12724105.7
2709629
Pending-Client's reply received
European Patent Office
P012199PCTKR1 Republic of Korea
10-2013-7032129
P012199US1
13/683,179
United States of America
Pending -Application filed
2014-0179618
Pending-Reply to Exam Report filed