rhabdomyosarcoma conference at NCI

Our thanks to Javed Khan for hosting the NCI Targeting Rhabdomyosarcoma Workshop this week in Gaithersburg.  Highlights included the interaction of muscle biologists and those who study rhabdomyosarcoma.  

AACR 2015

The 2015 Annual AACR in Philadelphia meeting concludes today.  It was a particular honor for Dr. Keller to present with his career mentor, 2007 Nobel laureate Mario Capecchi at the session,  Modeling Human Sarcomas: Recent Advances in Organ Site Research.  On Sunday, Dr. Capecchi received the lifetime career award from the AACR.    

Mayo Clinic seminar

My thanks to hosts Drs. Aubrey Thompson and Al Copland for the opportunity to present our work at cc-TDI in their seminar series.  It was a very productive visit - with new collaborations formed, and special traction on the Xp11 RCC effort.  

Purdue Cancer Center seminar

My thanks to hosts Drs. Shihuan Kuang and Timothy Ratliff for the opportunity to present our work at the Purdue University Center for Cancer Research seminar series on February 26.  Purdue has exciting programs in muscle & non-muscle stem cell biology & physiology and tissue engineering, and cancer biology.  It was a pleasure to meet with these accomplished scientists and build new collaborations.  

NCI Targeting Rhabdomyosarcoma Workshop

reposted from http://ncifrederick.cancer.gov/events/Rhabdomyosarcoma/ 

NCI Shady Grove
8717 Grovemont Circle
Gaithersburg, MD 20877

Host Institute
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health

Background
Rhabdomyosarcoma (RMS) is the third most common extracranial solid tumor of childhood. Approximately 350 new cases are diagnosed in the United States each year accounting for 3 percent of childhood cancers. RMS is derived from primitive myoblasts and morphologically resembles early stages of prenatal skeletal muscle differentiation. However, a large percentage of RMS tumors occur in locations normally lacking skeletal muscle, with the head and neck, genitourinary tract and retroperitoneum being frequent sites of tumor localization. Development of RMS has been associated with genetic tumor predisposition syndromes including Li-Fraumeni syndrome, neurofibromatosis and Costello syndrome. Childhood RMS is subdivided into two major subtypes, embryonal and alveolar, which have distinct histological features and genetic alterations. Adult RMS is largely a third histological subtype, namely pleomorphic RMS. The alveolar RMS subtype carries a poorer prognosis and is strongly myogenin positive by immunohistochemistry. The embryonal RMS subtype carries a better prognosis and is strongly MYOD1 positive by immunohistochemistry. Treatment for RMS is typically multidisciplinary including surgical resection, chemotherapy and radiation therapy. Relapse-free survival rates with this aggressive treatment regimen approach 70-80% for patients with localized disease. However, the 5-year survival rate for patients with metastatic disease at diagnosis continues to be less than 30%. Improvement in these survival rates is dependent upon identification of RMS-specific molecularly targeted agents.

Recent next-generation sequencing efforts have highlighted several driver mutations in RMS. The drivers for ARMS include the PAX3-FOXO1 and PAX7-FOXO1chimeric transcription factors. In contrast, the drivers for ERMS include mutations in the FGFR4/RAS signaling pathway, loss of heterozygosity at 11p15 (leading to IGF2 overexpression) and chromosome 8 gains. The prognostic significance of these mutations is currently unknown. Of these drivers, only IGF1R has been targeted in clinical trials in RMS, through the use of therapeutic monoclonal antibodies. These agents, including cixutumumab, show limited single agent activity and efficacy is limited by tumor resistance to the targeted agent. Small molecule inhibitors of the RAS-MAP kinase pathway, receptor tyrosine kinases, and reactive oxygen species have been validated and tested in other cancer types. In addition, targeted agents directed against other chimeric transcription factors, such as EWS-FLI1, have been identified. Validation of these targeted agents in RMS is complicated by the lack of a universal pre-clinical animal model of ERMS or ARMS.

The purpose of this meeting is to bring together the leaders in rhabdomyosarcoma basic, genomic, translational and clinical research to share ideas, data, resources and plan for collaborative and synergistic approaches to decipher rhabdomyosarcoma biology and develop novel therapies.

Planning committee
Javed Khan, Fred Barr, Doug Hawkins, Stephen Skapek, Janet Shipley, David Langenau, Charles Keller, Mari Yohe

Funding Sources
Office of Rare Disease (ORDR; http://rarediseases.info.nih.gov/)
Center for Cancer Research (CCR; https://ccr.cancer.gov/)

AACR Pediatric Cancer Think-Tank

This week the AACR held a think-tank in Philadelphia on the critical issues in childhood cancer research and care delivery.   In attendance were 43 invitees from universities, pharmaceutical companies and patient advocacy groups.  Topics included prevention (yes, prevention!), improved care for hereditable cancer predispositions, making drugs available for children with cancer, and the promise of genomics in delivering personalized cancer care.  Charles presented on the topic that not only mutation but also cell of origin strongy influences response to treatment - and the types of epigenetic therapies that can be given.  

SARC SPORE meeting

We presented our research project in collaboration with Dr. David Langenau (MGH) at today's SARC clinical trial consortium SPORE meeting - we are grateful for this 2 year pilot project funding.  Differentiation as a therapy for rhabdomyosarcoma? possibly! 

upcoming lab participation & talks

AACR Pediatric Cancer Think Tank (October 2014)
Pablove Foundation Pediatric Soft Tissue Sarcoma Symposium Think Tank (November 2014)
AACR Recent Advances Sessions (April 2015)
AACR Special Conference on The Basic Science of Sarcomas (November 2015)

Children's Oncology Group Fall Meeting

This meeting was productive.  Our lab presented at the Soft Tissue Sarcoma Chemotherapy Breakout session on "Three novel target-therapy pairs for potential clinical trials within 18 months?", as well as at the CNS session on "Ad Hoc Preclinical Consortia to Support Trial Design".  Both presentations bridged scientific/drug discovery and the potential initiation of clinical trials.    

Cold Spring Harbor Laboratory

We are grateful to collaborator Chris Vakoc for the opportunity to present the lecture, "Rhabdomyosarcoma:  Developmental Origins & Therapeutic Opportunities" as the prelude to a collaboration made possible by generous rhabdomyosarcoma patient advocates in this community.  

Save the Date: Rhabdomyosarcoma & Soft Tissue Sarcoma Conference

The Pablove Foundation is hosting a scientific conference on rhabdomyosarcoma & soft tissue sarcoma November 6-8, 2014 in Los Angeles.  This is a by-invitation meeting for clinician-scientists and researchers from the US and abroad; however, the symposium on Saturday November 8 will be open to the public.  Registration information will likely be available late Summer/early Fall through the Pablove Foundation website.  
  
update:  the website is now open for registration.  

Banbury Conference on Rhabdomyosarcoma

This past week the Cold Spring Harbor Laboratory held a special Banbury Conference to critically examine scientific and translational progress in rhabdomyosarcoma.  Through the kind sponsorship of members of the community, an international group of clinicians, cancer scientists and muscle biologists met to discuss driving clinical & biological problems in pediatric, adolescent and young adult rhabdomyosarcoma.  From this meeting will come a "white paper" describing prioritizes areas for further development - and collaborative opportunities.  We are grateful to the CSHL Banbury staff, as well as the CSHL leadership, for making this very unique meeting possible.  

COG Spring meeting

The Fall COG meeting was held in St Louis this past week.  The soft tissue sarcoma session, and corresponding Ewing's-Rhabdomyosarcoma Biology session, were very productive.  

NBTS working group meeting

The community owes a great thanks to David Arons and his team at the National Brain Tumor Society who yesterday held the 2nd working group meeting on "Key Issues in Pediatric Brain Tumor Research: Availability of Drugs for Pediatric Brain Tumor and Pediatric Cancer Research".  This meeting brought together academics, the Children's Oncology Group leadership, pharmaceutical stakeholders and members of the advocacy community - and it is hoped that specific improvement outcomes will result.   

Banbury Conference on Rhabdomyosarcoma

stay tuned for additional information on an upcoming Banbury Meeting on Rhabdomyosarcoma, hosted by the Cold Spring Harbor Laboratory, May 13-16.

Rally Foundation 'Legacy Gift' Project

Matthew presented the Rally Foundation for Childhood Cancer Research's Legacy Gift project via a booth at the Children's Oncology Group meeting this week in Dallas, Texas.  This project's goal is to developing tissue resources for tumor cell culture and patient-derived xenografts of rare childhood cancers.  Autopsy-derived samples ("legacy gifts") are a major emphasis of this project... with a rationale that the most resistant tumor to develop better treatments. 
 
Please see also the Rally Foundation parent interview at

https://vimeo.com/76616638.  Have some tissues ready.  

 

Rhabdomyosarcoma Pico-Course for the Community

We’ve been having some conversations with families touched by rhabdomyosarcoma and undifferentiated sarcoma… they have requested that instead of a 2014 Nanocourse with a rhabdomyosarcoma project, that we first have a very focused rhabdomyosarcoma “pico-course” this August.  The invited group will be very small, but this one-week lab & community leadership internship is meant to be impactful.  

We did something very similar for brainstem gliomas last year, which resulted in a peer-reviewed manuscript submission of a roadmap to curing that cancer.

If you are interested in attending, please contact Charles via keller (at) ohsu.edu.  

Lausanne NCCR Conference

We are grateful to Michel Aguet and Ivan Stamenkovic for the opportunity to present Ken and Jinu's recent studies at the Lausanne National Center of Competence Research (NCCR) in Molecular Oncology Symposium.  This symposium addressed drug development in pharma as well as academics.

Ken and Simone at AACR

Ken and Simone had the opportunity to meet at the AACR meeting in D.C., pictured here in front of the poster for their collaborative studies.  We have really enjoyed this productive collaboration with Simone Hettmer, a pediatric oncologist at DFCI, and her research mentor, Amy Wager at the Joslin.  

Miles Alpern Levin Memorial Lectureship

We are grateful to NCI scientist, Dr. Javed Khan, who delivered the 2013 Miles Alpern Levin Memorial Lectureship today on. "The application of genomics to identify diagnostic biomarkers, drivers and therapeutic targets for pediatric cancers".   The recent results of deep sequencing for alveolar and embryonal rhabdomyosarcoma from Javed's laboratory are very provocative.