New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents
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Published OnlineFirst August 28, 2012; DOI: 10.1158/1078-0432.CCR-12-0875 Clinical Cancer CCR New Strategies Research New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents Katherine A. Janeway1 and Robert G. Maki2 Abstract The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However, many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. Clin Cancer Res; 18(21); 5837–44. Ó2012 AACR. Background cancers (Fig. 1). The most common sarcomas that arise in Sarcomas represent a family of rare cancers of bone and children are aneuploid sarcomas, such as osteogenic sarco- soft tissue accounting for less than 1% of cancer in adults ma as well as those with specific translocations, such as and approximately 15% of pediatric cancer (1). They are Ewing sarcoma and alveolar rhabdomyosarcoma (ARMS). biologically heterogeneous, with more than 50 histologic In adults, the most common sarcomas are usually aneu- subtypes identified in soft tissue and more than 20 in bone, ploid, including leiomyosarcoma, and undifferentiated in keeping with the multiple types of connective tissue that pleomorphic sarcoma (UPS, formerly termed MFH, malig- comprise the scaffolding of the human body (2). nant fibrous histiocytoma), whereas other sarcomas that KIT Given their heterogeneity, a number of approaches have have specific genetic changes, such as mutation in SS18-SSX been used to characterize them, including histology (e.g., gastrointestinal stromal tumor (GIST) or the the 3 classes of liposarcoma), genetics (aneuploid sarcomas translocations seen in synovial sarcoma, are collectively vs. those with driver mutations or specific chromosomal somewhat less common. translocations), anatomic primary site, or whether they are In this commentary, we highlight the hurdles that face more prevalent in children or adults. In general, while clinical investigations into sarcomas more common in children who get sarcomas will most typically receive multi- children and adults, as well as new therapeutic options, modality therapy with surgery, chemotherapy, and radia- some of which have been decades in the making. Tantaliz- tion, in adults, the use of chemotherapy in the primary ing recent discoveries place us on the cusp of a new era disease setting is not as widespread, given the more limited linking tumor genetics to specific therapeutics for at least a benefit observed with the use of adjuvant systemic therapy few of the histologies discussed herein, but the ballast in many subtypes (3). otherwise hindering more rapid clinical research may prove The biology of sarcomas is interesting due to the involve- difficult to jettison. ment of particular signaling pathways in specific sarcoma subtypes (4, 5), many of which have parallels in other Sarcomas more common in children The most common histologies of sarcoma treated in children include osteogenic sarcoma, Ewing sarcoma, rhab- domyosarcoma (alveolar and embryonal subtypes, primar- Authors' Affiliations: 1Deparment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 2Departments of Medicine, ily), and less commonly other sarcomas, such as synovial Orthopaedics, and Jack Martin Fund Division of Pediatric Hematology- sarcoma and desmoplastic small round cell tumor, which as Oncology, Mount Sinai School of Medicine, New York a group are termed nonrhabdomyosarcoma soft tissue Prior presentation: Presented in part at the American Association for sarcomas. New therapeutics stand to impact upon the way Cancer Research Annual Meeting, Chicago, IL, April 2012. we treat each of the most common childhood sarcoma Corresponding Author: Robert G. Maki, Departments of Medicine, Ortho- diagnoses (Table 1). paedics, and Jack Martin Fund Division of Pediatric Hematology-Oncol- ogy, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1208, Osteosarcoma. Outcomes for newly diagnosed patients New York 10029. Phone: 212-241-7022; Fax: 212-360-6921; E-mail: with osteosarcoma had not changed in over 20 years (6). [email protected] The lack of progress reflects the dearth of effective newer doi: 10.1158/1078-0432.CCR-12-0875 agents, save for the immunotherapeutic mifamurtide, Ó2012 American Association for Cancer Research. which is now approved outside the United States and www.aacrjournals.org 5837 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst August 28, 2012; DOI: 10.1158/1078-0432.CCR-12-0875 Janeway and Maki Target Neoplasm Sarcoma subtype VEGF GIST Breast carcinoma RTK Ewing sarcoma Others RAS- Desmoid tumor? RAF Colorectal carcinoma Angiosarcoma MEK VEGF Solitary fibrous tumor? Thyroid carcinoma Alveolar soft part sarcoma? Others Clear cell sarcoma? ERK Autocrine, Akt paracrine loops Dermatofibrosarcoma Multiple myeloma protuberans Golgi Tenosynovial giant cell tumor TOR TOR PEComa (perivascular Renal carcinoma epithelial cell tumor) Endoplasmic ALK, BRAF, other ALK(ϩ) non-small cell reticulum intracellular kinases ALK lung cancer, anaplastic Inflammatory large cell lymphoma, myofibroblastic tumor malignant melanoma p53-HDM2 interaction Dedifferentiated Acute leukemias? liposarcoma HDACs, ?hsp90 Cutaneous T-cell Synovial sarcoma lymphoma p53 Nuclear hormone HDM2 receptors Breast carcinoma Endometrial stromal HDACs Prostate carcinoma sarcoma ER CDKs Dedifferentiated Chronic leukemias? liposarcoma CDK4 © 2012 American Association for Cancer Research Figure 1. Schematic of clinically useful targets in sarcomas versus other forms of cancer. MEK, mitogen-activated protein/extracellular signal–regulated kinase; ERK, extracellular signal–regulated kinase; RTK, receptor tyrosine kinase. referenced later. The challenge in identifying new agents RANKL and its receptor RANK are members of the with activity in osteosarcoma is a function of the complex tumor necrosis factor family of receptors and ligands biology of this disease, challenges in detecting radiographic with the physiologic function of regulating bone turn- responses in tumors with calcified stroma and deficiencies over. Osteosarcoma expresses both RANK and RANKL in risk stratification. While there have been no research and in osteosarcoma, RANK–RANKL interaction activates discoveries pointing to a single essential pathway in oste- downstream signaling and modulates gene expression osarcoma, preclinical studies have identified new agents (10, 11). Interfering with RANK–RANKL interaction in with potential clinical activity. vivo decreases osteosarcoma growth and metastatic tumor Two agents of significant interest are antidisialoganglio- burden (12–14). These data will hopefully build on a side (GD2) antibody and receptor activator of NF-kB clinical trial in giant cell tumor of bone (GCTB), in which (ligand; RANKL) antibody denosumab. GD2 is a cell surface interruption of RANKL signaling by virtue of denosumab sialic acid–containing glycosphingolipid expressed normal- led to rapid and sustained radiological changes with ly in central nervous system, peripheral nerves, and mela- clinical benefit (pain relief) in patients with recurrent or nocytes. In neuroblastoma anti-GD2 antibody, Ch14.18 metastatic GCTB (15). significantly improves event free and overall survival (7). Ewing sarcoma. Ewing sarcoma is a small round blue More than 90% of osteosarcomas express GD2 (8). In the cell tumor that arises from bone or soft tissue and is phase I/Ib trial of the murine anti-GD2 antibody, 14.2G2a, characterized by a translocation involving EWSR1 and one plus IL-2, 1 of 2 patients with osteosarcoma treated had a of several genes in the E twenty-six family of transcription complete response persisting for 8 months (9). factors, most often FLI1. The EWSR1-FLI1 translocation is 5838 Clin Cancer Res; 18(21) November 1, 2012 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst August 28, 2012; DOI: 10.1158/1078-0432.CCR-12-0875 Linking Sarcoma Biology to Novel Therapeutics Table 1. New targets and new agents for pediatric sarcomas Diagnosis Agent(s) of interest Clinical trials open or pending Osteosarcoma Anti GD2 mAb IGF1R mAb þ TOR inhibitor Denosumab Multitargeted TKI Mifamurtide Ewing sarcoma IGF1R mAb þ chemotherapy IGF1R mAb þ TOR inhibitor Phase II PARP inhibitor or phase I in combinations Rhabdomyosarcoma Sonic hedgehog inhibitor IGF1R mAb þ TOR inhibitor Nonrhabdomyosarcoma soft tissue sarcoma IGF1R mAb Crizotinib (IMT) Lisitinib (GIST) Abbreviations: mAb, monoclonal antibody; TKI, tyrosine kinase inhibitor; TOR, (mammalian) target of rapamycin. present in 85% of Ewing sarcoma. The insulin-like growth cations between the DNA-binding domain of either PAX3 or factor (IGF) pathway has been shown to