A Roadmap for Sarcoma Research

This article gives an overview of the report of the National Cancer Institute’s Sarcoma Progress Review Group (PRG) that was published in January 2004. The report represents a collaborative effort of scientists, clinicians, industry representatives, patient advocates, and other professionals. The Sarcoma PRG, chaired by Dr. Karen Antman and Dr. Todd Golub, was charged with developing a roadmap for the next 5 years of sarcoma research. In "The Challenges of Sarcoma" section of the report, the PRG noted:

Since the 1950s, limb-sparing surgery, radiation therapy, and chemotherapy have improved sarcoma survival rates or reduced recurrence rates. Today, surgery—often coupled with radiation therapy—is usually the primary treatment for sarcoma, although some rhabdomyosarcomas and Ewing sarcomas can be cured with only radiation and chemotherapy. Most patients who die from sarcoma have chemotherapy-resistant metastatic disease. Only a few chemotherapy drugs are effective, and the rarity and heterogeneity of sarcoma make testing new agents challenging. Given the lack of a uniform standard of care, the difficulty in diagnosis, and the lack of new treatments (with the exception of imatinib for GIST, considered by many to be a model for tailored molecular therapy), most sarcoma patients have been underserved by the medical and research communities.

In the main body of the report, the PRG developed and discussed six high-priority recommendations for implementation by the NCI.

Priority 1: Sarcoma Research Consortium (SRC)

Create a dedicated, sarcoma-specific organizational structure—the Sarcoma Research Consortium (SRC)—to serve as a focal point for sarcoma clinical trials and related clinical- and laboratory-based research and to enhance networks of investigators and centers committed to sarcoma research. In partial support of this recommendation, the PRG noted that,

Sarcomas are a heterogeneous and uncommon group of malignancies. Optimal treatment requires close collaboration among multiple disciplines with special expertise in the diagnosis and treatment of sarcomas. The current decentralized system does not support the effective interaction between experts or collaboration among interested researchers. Resources for studying the many subtypes of sarcoma are fragmented, resulting in a few small, inadequately powered studies. Centrally coordinated initiatives and strong networks will facilitate multidisciplinary research and data sharing, streamline the research process, and produce more reliable results per funding dollar spent. The resulting system also will be a model for studying other rare cancers and rare diseases.

The PRG recommended that the SRC would consist of a national, multidisciplinary group of investigators to provide leadership for sarcoma research, Sarcoma Centers of Excellence, and a common infrastructure to support and accelerate sarcoma research. Further, the PRG recommended that the SRC would establish a national clinical trial agenda and oversee the conduct of such trials and that it would partner with NCI and other institutes in the conduct of sarcoma research, including efforts to increase the accuracy of sarcoma incidence and mortality data.

Priority 2: Research Focus

Fund and foster research focused on key areas of sarcoma biology most likely to advance the field. The PRG explicitly included the following areas in this priority: the developmental biology of mesenchymal tissues, mutational targets in growth signaling pathways, downstream targets of fusion proteins, cellular checkpoints and apoptotic pathways in the sarcoma context, and immunobiology of human sarcomas.

Priority 3: Animal Models

Develop sarcoma-specific animal model systems (including new models and metastatic models). In partial support of this recommendation, the PRG noted, "Most patients who die from sarcomas die from metastatic disease, but research in metastasis is hindered by the dearth of models specifically addressing sarcoma metastasis."

Priority 4: Sarcoma Profiling to Identify Targets for Therapy

Fund and foster comprehensive approaches to sarcoma profiling and target discovery. Two approaches specifically discussed in the report are: (1) comprehensive sarcoma profiling (genome, transcriptome, and proteome) to identify novel therapeutic targets, new markers for diagnosis, susceptibility, and prognosis, for prediction of treatment response and definition of intermediate endpoints; and (2) high-throughput screens and functional genomic approaches to identify novel therapeutic targets and critical pathways regulating sarcoma growth and survival.

Priority 5: A Sarcoma Toolkit

Develop a centrally available toolkit of core reagents and access to technology platforms for sarcoma research including cell lines, model systems, annotated tissue banks, biomarkers, and imaging. In discussing this priority, the PRG noted that, "Current resources are inadequate for current or planned research endeavors. The toolkit will enable new technology to define novel and valid biomarkers, imaging, and surrogate markers to take advantage of the unique biology of sarcoma subsets and encourage rational, targeted, and timely clinical development."

Priority 6: Clinical Trials

Design prospective clinical trials whose principal objective is to compare early surrogate (intermediate) markers to conventional endpoints. Such trials should be tightly linked to appropriate tissue banking and incorporate novel statistical methodologies appropriate to sarcomas. These trials should be conducted concurrently with a series of innovative therapeutic trials.

Closing Remarks

Finally, it is worth mentioning that the report also contains five appendices, the first two of which cover such topics as the "Translation of Therapeutic Targets and Experimental Models to Clinical Settings," "Innovative Clinical Trials," "Optimizing Existing Care," "Better Diagnosis and Prognostication," and "Better Communication and Outcomes." Significant progress could be made in all of the areas cited in the report if these priorities are actually funded and implemented by the NCI.

A copy of the complete 92-page report can be downloaded as a PDF document by clicking on the following title, A Roadmap for Sarcoma Research.