EHE Group Research Update

Transcription

1 THE EHE FOUNDATION THE EHE RARE CANCER CHARITY (UK)* THE EHE RARE CANCER FOUNDATION (AUSTRALIA)* * Currently awaiting registration EHE Group Research Update Dr Rubin s EHE research progress Genetic basis of EHE tumor progression: We have hypothesized that disease progression in EHE is due at least in part to the accumulation of genetic mutations that interact with the WWTR1-CAMTA1 gene fusion that is found in virtually all EHE s. We have performed a discovery phase of the project and identified candidate mutations that interact with WWTR1- CAMTA1. The overall goals of this project are to develop tools that predict disease progression and to develop therapies that prevent or target disease progression. In over to validate our findings from the discovery phase, we have assembled a validation cohort from patients worldwide including the USA, UK, and other countries. The EHE not-for-profit organizations have been instrumental in helping to obtain these samples. Therapeutic compounds that target TAZ-CAMTA1: TAZ-CAMTA1 is the protein encoded by the WWTR1-CAMTA1 gene fusion. We believe that TAZ-CAMTA1 is the central oncogenic driver that underlies all EHE biology. As a corollary, we believe that if we can inhibit TAZ-CAMTA1 then we can control EHE. In Q1 of this year we established a collaboration with Dr. Cigal Kadoch, Dana Farber Cancer Institute to develop drug screens for compounds that can inhibit TAZ-CAMTA1 directly. We developed a research game plan and have begun to execute it. Currently, we are optimizing expression of protein fragments that will be used to construct this assay and have begun initial steps at purification. Research model development: We have established two important collaborations with Jesse Boehm at the Broad Institute and Lou Stancato at Eli Lilly to establish human EHE-derived cell line and xenograft models. While no EHE cell lines or xenografts have been developed yet, these collaborations are ongoing. We are also working on a genetically engineered mouse model of EHE. The construction phase of this project began about a year ago. So far, a targeting vector has been constructed, mouse embryonic stem cells have been targeted and chimeric mice have been generated that harbor the targeted gene. We had hoped to establish germline transmission of the chimeric mice but initial attempts failed. We are currently expanding our chimera breeding with the hope of

2 germline transmission soon. We hope to be breeding and testing these mice by Q1/Q Ideally, we will have a sense of the success of this model by Q3/Q Hormonal influences on EHE behaviour: EHE is approximately four times more common in women and we would like to know why. The obvious hypothesis is that there is a hormonal influence. Our current plan involves screening tissue sections to determine whether there are hormone receptors on the surface of EHE cells. I have recruited a talented pathology resident, Dr. Hope Hastings, to help with this project. We have not been able to identify any hormone yet but we will examine many more candidates over the coming months. Post-doctoral research associate recruited: After a long and fruitful search including the review of over 100 applications, Dr. Kepeng joined the Rubin lab as a post-doctoral research associate in late October, After completing her PhD studies from the Chinese Academy of Sciences in 2002, Dr. Che joined the laboratory of Dr. Michael Gelb at the University of Washington where she worked on protein-related projects focused on measuring cell membrane proteins. In 2007 she moved to the Cleveland Clinic where she worked with Dr. Donald Jacobsen on Vitamin B12 and with Dr. Erik Pioro on proteins associated with amyotropic lateral sclerosis (ALS). She has extensive expertise in protein biochemistry, molecular biology, and mouse models of human diseases. She will be a valuable addition to the Rubin lab as she will focus her efforts on developing methods to identify new therapeutic compounds for EHE and to characterize a genetically engineered mouse EHE model. Dr Rubin s EHE Team; (left to right) Shuang Ma (Research Associate), Andrea Hallet (Technician), Brian Rubin, Ashley Kendig (Technician), Kepeng Che (Postdoctoral researcher)

3 New Immunotherapy Research Initiative Approved Professor Izhak Haviv, from the Faculty of Medicine at the Bar Ilan University in Israel, joined Jane Gutkovich and Hugh Leonard at the CTOS annual meeting in Lisbon in November where a meeting with members of the EHE advisory boards was held to allow Prof Haviv to present his project proposal. The meeting was attended by Dr Stachiotti from the Istituto Nazionale Tumori in Milan, Dr Ravi from MD Anderson Cancer Center in Houston, Dr Jonathan Trent from the Sylvester Comprehensive Cancer Center in Miami, and Dr David Thomas from Peter MacCallum Cancer Center, Australia. Also taking part by conference call was Dr Brian Rubin from the Cleveland Clinic. Dr Scott Okuno from the Mayo Clinic in Rochester, Minnesota, joined the meeting later due to a prior commitment. Prof Haviv s project relates to the possible application of personal vaccine immunotherapy to EHE. The initial proof of concept phase, presented at the CTOS meeting, if successful, will demonstrate the likely positive application of immunotherapy to EHE tumours, and could open up several different avenues of additional research. Prof Haviv presented his project and was able to discuss a number of aspects with the participants. Additions and small changes to the project were agreed. At the end of the meeting all present agreed that the project should be continued and that the EHE foundations should fund this research. Since the CTOS meeting in early November, the advisory board members and advisors of the three EHE foundations who were not present in Lisbon have also been contacted and the project discussed. Their support for the project has also been secured. At the end of the fourth quarter, protocols for the operational phase are being finalised, while the logistics of moving samples to Israel is under review. A critical part of the proof-of-concept phase will be the provision of blood samples from EHE patients. These samples will be taken at various hospitals that are assisting with the project, treated as per the agreed protocols, frozen and shipped to Israel where Prof Haviv s team will undertake the proof-of-concept laboratory analysis. At the same time as shipping samples, each patient s clinical records will also be required so that specific characteristics of a patient s EHE can be tied to the laboratory results, if required.

4 EHE CTOS meeting involving Jane Gutkovich, Dr. Silvia Stachiotti and Dr. Vinod Ravi (closest to furthest on the left), and Dr. Jonathan Trent, Prof Izhak Haviv and Dr. David Thomas (closest to furthest on the right). Bio-banking and Liquid Biomarkers under review Bio-banking is the process by which blood and tissue samples are collated, preserved and stored so that they are available for later research. This of course has to be undertaken with full ethical approval of the hospitals involved and full approval of every patient that takes part. The resultant store of samples can however be invaluable in the future should a new treatment or aspect of EHE need to be tested.

5 Liquid Biomarkers are different products, chemicals or compounds that may be measured in a patient s blood and can indicate when the level of progression of their EHE is changing. However, today we do not know what these bio-markers are. This is the research that needs to take place to hopefully identify such biomarkers for use in the future. Bio-banking may be critical in this process as banked samples may allow us to look back at development of the EHE in different patients and tie this to results of their blood analyses, and thus help confirm what the key biomarkers and processes may be. Quality of Life and PROMs At the CTOS meeting in Lisbon, Lonneke van de Poll, Professor of Cancer Epidemiology and Survivorship from the Netherlands Cancer Institute gave a well-received paper on results from their different Patient Reported Outcomes (Measures) (known as PROMs) research studies. This research engages directly with patients through patient-completed questionnaires to try and understand the impact on patients quality of life of their cancer diagnosis, treatment regimes, and all aspects of their cancer journeys. In later discussion with Prof van de Poll, we talked about the possibility of using EHE as an example of a very rare cancer, and our EHE Facebook group as a role model for engaging with patients worldwide who have the same disease. It transpired that Prof van de Poll was also in discussion with the Sarcoma Unit of the Royal Marsden Hospital in London, who are looking to undertake a PROM study of sarcoma patients in the UK and Holland. Prof van de Poll is keen to continue with an international aspect of the study, possibly using EHE as her target group. This will not only lead to potentially interesting research for EHE patients, but it will also increase our exposure on a number of fronts and so hopefully raise further awareness of EHE. We are continuing to evaluate the benefits of being involved in this project.