Archives for October 2022

An Update from Memorial Sloan-Kettering Cancer Center – Investigating the Early Molecular Mechanisms of WWTR1::CAMTA1 and YAP1::TFE3 Gene Fusions in Driving the Pathogenesis of EHE

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The EHE community, which includes cancer patients and their families from around the world, benefits from the world-class innovative research that takes place at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City (US). In 2019, MSKCC received a $1 million private donation to establish an International Center of Expertise in EHE and since that time, significant knowledge of the disease has been gained and research questions continue to be explored.

To expand upon research initiated as part of the EHE Center of Expertise, The EHE Foundation together with the EHE Rare Cancer Foundation Australia (EHE-RCFA) provided a research grant in 2021 to Cristina Antonescu, MD and Fabio Vanoli, PhD to further investigate the early molecular mechanisms of WWTR1::CAMTA1 and YAP1::TFE3 gene fusions in driving the pathogenesis (the origination and development) of EHE. The research under this specific grant has concluded and Dr. Vanoli recently provided a summary of their research to date:

“Epithelioid hemangioendothelioma (EHE) is a malignant tumor originating from the inner layer of cells covering blood vessels. It affects all ages, but has a distinctive prevalence in young adults. EHE has a ubiquitous presentation, with common sites including liver, lung, and soft tissue. Most tumors have an indolent growth and do not cause symptoms; however, a subset is aggressive, especially in the multifocal setting or pleural involvement. Besides surgical procedures for localized, unifocal lesions, there are no effective therapies, either cytotoxic or targeted, available for EHE patients.

Like many other sarcomas affecting young adults, EHE is characterized at the molecular level by a consistent structural aberration, namely a chromosomal translocation. A translocation occurs when two genes, located on different chromosomes, are fused together creating a new gene able to induce cancer formation. In EHE the two genes that are commonly fused together are WWTR1 and CAMTA1. How the two genes, once fused together, cause the initiation and development of the tumor remains unknown, in part because of the lack of faithful EHE models (e.g., cancer-derived cell line) that allow us to further our understanding of EHE pathogenesis.

The aim of our work at MSKCC is to generate these models and study the mechanism underlying cellular transformation and tumor development. Our approach uses the latest CRISPR-Cas9 modern techniques of genome editing in a human naïve wild type cell line (lacking any other genetic aberrations) to generate a new cell line containing the translocation that fuses together the WWTR1 and CAMTA1 genes. Our methodology, which we successfully developed for the first time in 2017 to model another sarcoma relevant translocation, presents several advantages compared to the more classic strategies. The most relevant is the possibility to induce the expression of the translocation product in a timely regulated matter allowing the study of the early steps of tumorigenesis.

Another important aspect we are addressing is the choice of the appropriate cell type in which the translocation is generated. It is now well known that the same translocation can generate different tumor types depending on the tissue/cell that has been targeted. We are currently investigating the effect of the translocation in endothelial progenitors, the presumed cell of origin of EHE, and we will expand our analysis to more differentiated blood vessel cells.  It is pivotal to use the appropriate cell type not only to characterize the mechanism leading to tumorigenesis, but also to evaluate the response to potential therapeutic approaches.

The final goal of our work is to utilize these cell lines as pre-clinical models for drug screening and identification of not yet available targeted therapies to benefit patients with EHE.”

Cristina Antonescu, MD is a co-Investigator of this research and is the Attending Pathologist, Director Bone and Soft Tissue Pathology, Co-Director of Sarcoma Center, Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC) New York, NY.

Fabio Vanoli, PhD is a co-Investigator of this research and is an Assistant Lab Member in the Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC) New York, NY.

The EHE Foundation and EHE-RCFA are grateful to Drs. Vanoli and Antonescu and we look forward to continued advancements in EHE research from their lab.

The EHE Foundation Funds Fellowship Travel Grants

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In June, the EHE Foundation provided two Fellowship Travel Grants supporting young investigators’ participation in a workshop entitled “YAP/TAZ and TEAD: At the Crossroads of Cancer.” The workshop is hosted annually by the Telluride Science Research Center (TSRC) and this year was co-led by notable EHE researchers and advocates – John Lamar, PhD, Albany Medical Center and Guy Weinberg, MD, University of Illinois (retired).

The 2022 Fellowship Travel Grant recipients were:

  • Caleb Seavey, MD, PhD, Cleveland Clinic (US) – Dr. Seavey is a research fellow at the Lerner Research Institute and has been working in Dr. Brian Rubin’s Lab since 2019. Dr. Seavey’s presentation at the TSRC was entitled Loss of CDKN2A in epithelioid hemangioendothelioma enhances tumorigenicity and imparts cellular immortality, thereby facilitating the generation of the first cell lines of this disease.
  • Karin Schlegelmilch, PhD, The Francis Crick Institute (UK) – Dr. Schlegelmilch is a senior postdoctoral fellow in Dr. Erik Sahai’s lab. Her presentation entitled Modelling therapy resistance in cancer highlighted her research on the role of YAP signaling in the development of resistance to targeted therapy in melanoma which may shed light on mechanisms relevant for other types of cancer, such as EHE.

Dr. John Lamar, co-leader of the workshop, said “Karin and Caleb made major contributions to the workshop. They both gave outstanding presentations and actively contributed to the discussions. We are so glad they attended and grateful that The EHE Foundation supported these young researchers that helped make our workshop a success.”

The workshop was founded by Guy Weinberg in 2017 and brings together knowledgeable experts in the Hippo-YAP/TAZ and EHE fields to share their research during scientific presentations and talk science during group hikes and other social events. In addition to hosting recognized experts in these fields who have long-standing track records of successful research, Dr. Weinberg also believes in the value of having younger scientists attend the workshop; in his words, “…this advances and assures continued interest in important research relevant to EHE.”

The EHE Foundation has contributed specifically to this approach by funding the attendance of such ‘young faculty’ as Karin and Caleb through fellowship stipends. These efforts promote participation of talented young scientists and nurture the next generation of EHE researchers.

An important message from Jenni Kovach, President, The EHE Foundation Board of Directors

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I am writing today to share an organizational change to The EHE Foundation. After four years as a part-time contractor, Medha Deoras-Sutliff has ended her engagement with the foundation to pursue other opportunities. Medha will continue to provide her services to the foundation until the end of November to ensure a smooth transition. 

Medha came into the foundation at a time when we were experiencing much change and growth. She has been instrumental in building capacity, strengthening our fundraising efforts, expanding support to the EHE community, and improving our day-to-day operations. Having never heard of EHE prior to her role with us, Medha quickly became and will continue to be part of the EHE family.

As we plan to move forward, we will be hiring a full-time Executive Director that will concentrate on foundation management and development (both grants and fundraising efforts). We will be posting the position soon and hope to have someone hired by the end of the year. 

In the meantime, please join me in thanking Medha for her tremendous work and dedication she has provided to the foundation and to our community.