Molecular biology and therapeutics in musculoskeletal oncology.

Musculoskeletal oncology encompasses a broad array of diseases and treatment challenges. The most important issue facing a patient with a sarcoma is cure. Traditional cytotoxic chemotherapy has evolved empirically over the last several decades. While substantial improvements have been made in cure rates for pediatric patients with sarcoma, cure rates have plateaued at considerably less than 100% and chemotherapy for adult patients is far less effective. Starting with cytogenetic analysis and, more recently, the molecular dissection of tumors, it has become obvious that “sarcoma” is not a diagnosis per se but a group of diseases. Adult soft-tissue sarcoma alone comprises many different histologic subtypes. A better understanding of the biology of tumors at the molecular level has brought forth the possibility of targeted therapy, prompting the American Academy of Orthopaedic Surgeons (AAOS) and the Orthopaedic Research Society (ORS) to hold the Molecular Biology and Therapeutics in Musculoskeletal Oncology Research Symposium in September 2008. In contrast to the broad-spectrum drugs that are used in traditional chemotherapy, targeted therapy is biologically based and attempts to counteract the exact abnormality of the tumor cell. The types of abnormalities include overactive cell-surface receptors, which are part of the signaling cascades that drive growth; the secretion of proteins that stimulate angiogenesis; and the loss of function of tumor-suppressor genes that normally restrain growth. The types of therapeutics used include monoclonal antibodies, drugs that block overactive receptors, and gene-therapy techniques. The concept is that instead of using the same drugs for all patients with a particular stage of disease, the treatment would be personalized on the basis of the biologic abnormalities. The difficulties include the fact that there are many molecular abnormalities in any one tumor, with heterogeneity from one cell to the next; genetic instability leading to additional abnormalities over time; an overlap of biochemical pathways between normal physiologic processes and tumor growth; and a lack of therapeutics capable of reversing or blocking many of the molecular abnormalities found in tumors. Another limitation of the strategy is that blocking the effect of a molecular abnormality does not usually cure the patient in the traditional sense but can suppress tumor growth for some period of time. Fortunately, sometimes there are synergies when targeted, biologically based therapy is combined with cytotoxic chemotherapy, leading to a higher chance of cure. The AAOS-ORS Molecular Biology and Therapeutics in Musculoskeletal Oncology Research Symposium was held in Salt Lake City, Utah, in September 2008, to address these issues. In addition to the AAOS and ORS sponsorship, the symposium received grant support from the Orthopaedic Research and Education Foundation, the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; collaborative sponsorship from the Musculoskeletal Tumor Society and the WWWW Foundation, Inc. (QuadW); and industry support from the Musculoskeletal Transplant Foundation, Stryker, and Biomet. The organizers cast a wide net so as to include leaders in the field representing academia, the National Institutes of Health, the U.S. Food and Drug Administration, industry, leading cancer institutions, and cancer-related organizations, both from within and outside the traditional orthopaedic boundaries. A complete list of participants and their affiliations is included in the Appendix. The objectives of the symposium were to establish the state of the art of molecular biology and therapeutics in musculoskeletal oncology, identify barriers and potential solutions to advance the field, establish research priorities, and provide an educational forum that could foster collaborations for new and established investigators. The meeting was organized around the major diseases in musculoskeletal oncology; current topics in cancer biology, including genomic screening; and novel therapies. The following summary of the presentations and deliberations of the breakout sessions is provided as a record of the meeting and to guide prioritization of research funding.