Funding a research into rhabdomyosarcoma
Over the past year the Chris Lucas Trust has generously continued its long-term
support for the ICR to provide funding towards Dr. Janet Shipley’s Research Team.
The aim of this research is to find new therapeutic targets which could potentially
help to improve cure rates, reduce side effects and improve function and quality of
life for children and young adult patients diagnosed with rhabdomyosarcoma. This
will be achieved through furthering understanding of the molecular biology
underlying these tumours, with links to national and international groups involved in
the clinical management of patients.
I am writing now to provide a short update on the progress made in 2010/11 ahead
of Joanna Selfe starting in the senior researcher role supported by the Chris Lucas
Trust. This has been written in conjunction with Dr Janet Shipley.
May 2011
Progress on the key achievements from our previous research supported by
the Chris Lucas Trust through funding Dr. Edoardo Missiaglia, a senior
scientist is:
We organised the genomic, gene expression and microRNA profiling of
around 100 rhabdomyosarcoma samples in collaboration with Professor Olivier
Delattre at Institut Curie. This data has been invaluable in underpinning a number of
studies.
Genomic and gene expression analysis of rhabdomyosarcoma cell lines
provided new insights (publication 1). This has identified cell line models with
particular features suitable for studying the effects of modulating the expression of
particular genes that may be therapeutic targets.
The profiling data of tumours has also provided support and cell line
models for the rhabdomyosarcoma biological component of the EU Consortium
Innovative Therapy for Childhood Cancers (ITCC) and the Kids Cancer Kinome
(KCK) project. This has led to the investigation of a number of potential therapeutic
targets for treatment of rhabdomyosarcoma (KCK website:
http://www.kidscancerkinome.org/).
The gene profiling data was analysed using computer-based
bioinformatic approaches in conjunction with analysis of the fusion gene status of
rhabdomyosarcomas. 70% of the alveolar subtype are associated with fusion genes
(either PAX3-FOXO1 or PAX7-FOXO1). Our work showed that the 30% of alveolar
cases without fusion genes are clinically and biologically more similar to the
embryonal subtype which strongly suggests that they should be treated differently
from the alveolar fusion gene positive cases. This has implication for the future
design of clinical trials (publications 2 and 3).
Edoardo’s bioinformatics work using the various profiling data for
rhabdomyosarcomas has also underpinned other collaborative studies (such as our
investigations of the SHH signalling with Simone Fulda (publication 6); the MYCN
gene and PDGFRs with Roberto Tonelli, Italy and Monika Ehnman, Sweden,
respectively (manuscripts in preparation)).
MicroRNAs play an important role in regulating the expression of genes. As
rhabdomyosarcomas resemble undeveloped muscle cells which can move and
grow, we investigated microRNAs that we showed caused rhabdomyosarcoma cells
to resemble fully developed muscle cells which do not have the ability to grow
(publications 4 and 5). This represents a potential therapeutic approach.
Edoardo integrated gene expression data with microRNA data to determine
possible roles for microRNAs in the cancer processes underlying
rhabdomyosarcomas. This provides a basis for further investigations.
Since Edoardo Missiaglia moved to the Swiss Bioinformatics Institute over a
year ago, we have kept in touch. He has continued with projects formally
through support from the Chris Lucas Trust in addition to spending his spare
time with analyses. We have also benefitted from additional bioinformatic
expertise from his new colleagues. This work has been mainly focussed on
the project below:
Following on from our study of the significance of fusion gene status in
the alveolar subtype of rhabdomyosarcoma Edoardo’s bioinformatics work has
determined clinically significant gene expression patterns and the impact of PAX3-
FOXO1 and PAX7-FOXO1 fusion genes on these patterns. This has allowed us to
propose a new robust and simple clinico-molecular approach to stratify patients for
particular treatments (manuscript in preparation).
Rebecca Allen, a new graduate who had
previously undertaken work experience in
the laboratory, joined us as a Scientific
Officer in September 2010 supported by the
Chris Lucas Trust. She has been learning
various techniques and contributing to
rhabdomyosarcoma projects in the lab.
She is now focussed mainly on the
following:
Further investigation of microRNAs
identified in the bioinformatic analyses and
those affected by the fusion gene protein. As
these or the genes they affect may have
therapeutic potential, we are keen to capitalize on our findings and explore the
effects of modulating their levels in cells.
Rebecca has been working with Joanna Selfe, an experienced scientist in the
group. Joanna has just started to be supported by the Chris Lucas Trust from
May 2011. She will be involved in supervising the functional work on
microRNAs and will investigate key candidate genes indicated from Edoardo’s
bioinformatic analyses as potential biomarkers and/or therapeutic targets.
Publications:
1. Missiaglia E, Selfe J, Hamdi M, Williamson D, Schaaf G, Fang C, Koster J,
Summersgill B, Messahel B, Versteeg R, Pritchard-Jones K, Kool M, Shipley J.
Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes
frequently altered in primary tumors: an approach to identify candidate genes
involved in tumor development. Genes Chromosomes Cancer. 2009 48(6):455-67.
2. Williamson D, Missiaglia E, de Reyniès A, Pierron G, Thuille B, Palenzuela G,
Thway K, Orbach D, Laé M, Fréneaux P, Pritchard-Jones K, Oberlin O, Shipley J*,
Delattre O* (*joint last) ‘Fusion Gene Negative’ Alveolar Rhabdomyosarcoma are
Clinically and Molecularly Indistinguishable from Embryonal Rhabdomyosarcoma. J
Clin Oncol. 2010 28(13):2151-8.
Editorial article: Diagnosing alveolar rhabdomyosarcoma: morphology must be
coupled with fusion confirmation. Wexler LH, Ladanyi M.J Clin Oncol. 2010
28(13):2126-8.
Research Highlight: Fusion gene status crucial in RMS Nat Rev Clinical
Oncology 7, 356 (July 2010)
Press coverage: http://f1000medicine.com/article/s7r0n21t2xh8mvc/id/2890959
http://www.healthcanal.com/public-healthsafety/
6733.htmlhttp://www.medicalnewstoday.com/articles/183913.php
3. Williamson D, Missiaglia E, de Reyniès A, Pierron G, Thuille B, Palenzuela G,
Thway K, Orbach D, Laé M, Fréneaux P, Pritchard-Jones K, Oberlin O, Shipley J,
Delattre O. Correspondence: Reply to J.R. Anderson et al. J Clin Oncol. 2010
28(29): 589-590.
4. RaoPK, Missiaglia E, Shields L, Hyde G, Yuan B, Chris Shepherd C, Shipley
J, Lodish H. Distinct roles for miR-1 and miR-133a in the proliferation and
differentiation of rhabdomyosarcoma cells. FASEB J. 2010 24(9):3427-37.
5. Missiaglia E, Shepherd CJ, Patel S, K, Thway K, Pierron G, Pritchard-Jones
K, Renard M, R Sciot R, Rao R, Oberlin O, Delattre O, Shipley J. MicroRNA-206
expression levels correlate with clinical behaviour of rhabdomyosarcomas. Br J
Cancer. 2010 102(12):1769-77.
6. Zibat A, Missiaglia E, Rosenberger A, Pritchard-Jones K, Shipley J, Hahn H,
Fulda S. Activation of the sonic hedgehog (SHH) pathway confers a poor prognosis
in embryonal and fusion gene negative alveolar rhabdomyosarcoma. Oncogene.
2010 29(48):6323-30.
We remain extremely grateful to the Chris Lucas Trust for their generous support
over the last year and continued pledge for funding both the roles of Rebecca Allen
and Joanna Selfe.
