Sarcomas are rare malignancies that historically have lacked research funding
BY BOB HECKER
Like orphan malignancies generally, sarcomas are uncommon, and research into their causes and treatment are underfunded. They are a broad and heterogeneous group of cancers that make up less than 1 percent of adult malignancies and about 10 percent of childhood cancers.
Sarcomas arise from cells that resemble those that compose bone and a variety of soft tissues. Skeletal sarcomas include osteosarcoma, chondrosarcoma and Ewing sarcoma. Soft-tissue sarcomas (STS) occur in striated and smooth muscle, fibrous and adipose tissue, blood vessels, nerve tissue, tendons and the lining of joints.
Because sarcomas are rare, grant support to study them is limited, but sarcoma expert Raphael Pollock, MD, PhD, director of Ohio State’s Division of Surgical Oncology and chief of surgical services at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), leads a federally funded multi-institutional research program, including investigators at the OSUCCC – James, that should help scientists better understand and treat these diseases.
Prior to his recruitment to Ohio State in 2013, Pollock worked 31 years at The University of Texas MD Anderson Cancer Center. In October 2012, he became principal investigator for a fve-year, $11.5 million Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI). The grant itself was awarded to the Sarcoma Alliance for Research through Collaboration (SARC), a nonprofit consortium of physicians and scientists dedicated to the development of new treatments for sarcoma.
“Our SPORE is an innovative approach to integrating translational and clinical study of an orphan malignancy that historically has been understudied,” Pollock says.
The NCI expects about 12,000 new cases of STS and 3,000 new cases of primary bone sarcoma in the United States in 2014, as well as 4,740 deaths from STS and 1,460 deaths from bone sarcoma. Incidence rates have risen slightly over the past 35 years.
As many as 100 STS subtypes have been described according to site of origin, genetic alterations, behavior, metastatic mechanisms and response to therapy, Pollock notes. “Since the early 1970s, overall five-year survival rates for sarcoma have remained static at about 50 percent,” he adds. “Our SPORE has the potential to provide major therapeutic advances.”
HDAC Inhibitor Trial
In addition to serving as principal investigator (PI) for the entire SARC SPORE, Pollock is co-PI for one of its four projects (see sidebar), along with Shreyaskumar Patel, MD, of MD Anderson Cancer Center, and Edwin Choy, MD, PhD, of Massachusetts General Hospital. The project is entitled “Histone Deacetylase Inhibitor (HDACi)-Based Therapeutic Strategies for the Treatment of Genetically Complex Soft Tissue Sarcoma” and evaluates a novel systemic therapy possibility for genetically complex STS.
Preclinical studies suggest that a class of drugs called histone deacetylase (HDAC) inhibitors might improve outcomes for these patients. HDACs help regulate gene expression and are also involved in cancer progression. The Pollock/Patel/Choy trial evaluates an HDAC inhibitor called mocetinostat plus the chemotherapy drug gemcitabine in adults with advanced STS.
Mocetinostat is designed to selectively inhibit specific HDACs. Patient accrual is under way. “We hope to enroll 20 to 25 patients per year, or about 100 patients overall, for this multi-institutional trial, which includes Ohio State,” Pollock says.
The researchers want to learn whether the combination of the HDAC inhibitor and gemcitabine is more effective than either agent alone. “HDAC inhibitors have shown activity in a variety of STSs,” Pollock says. “But to date, these agents have typically been administered alone instead of in combination with standard chemotherapy.”
The project also includes laboratory and animal studies to learn whether blocking a particular HDAC (there are 18 isoforms) can produce the same therapeutic efficacy but with less toxicity. “If our novel approach works,” Pollock says, “it may form a new approach for future STS clinical trials involving other sarcoma subtypes and ultimately improve sarcoma patient management.”
The OSUCCC – James, in conjunction with Nationwide Children’s Hospital (NCH) in Columbus, has a history of research in adult and pediatric sarcoma, with a mix of veteran and younger investigators.
Peter Houghton, PhD
Houghton directs the Center for Childhood Cancer and Blood Diseases at The Research Institute at NCH. He is a member of the OSUCCC – James Translational Therapeutics Program, and he develops sarcoma models for the SPORE’s Tissue and Pathology core. “We have grown 20 tumors that are now being molecularly characterized,” Houghton says.
In addition, Houghton is PI for a five-year, $7.8 million NCI Program Project Grant (PPG, CA165995) awarded in 2013 for studying childhood sarcomas. Through three projects, Houghton and his colleagues explore three separate but integrated signaling pathways active in these malignancies.
They are characterizing the interrelationship of these pathways and identifying potential agents to inhibit them.
“Whereas the SPORE focuses on adult sarcoma, our PPG focuses on pediatric sarcoma,” says Houghton. “That said, there is reason to consider Ewing sarcoma in adults and osteosarcoma in adults as similar diseases to those occurring in children at the molecular level. Thus, our research on childhood sarcoma may have direct application to certain adult sarcomas.”
Houghton serves on the SARC Developmental Therapeutics Committee along with Pollock, who notes that Ohio State is the only academic institution in the nation to have principal investigators for both a SPORE grant and a PPG for sarcoma research.
Denis Guttridge, PhD
Guttridge co-leads the OSUCCC – James Translational Therapeutics Program and leads one of the three PPG projects. His sarcoma-related research also includes a recent study published in the journal Science Signaling describing a molecular mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma – the most common pediatric sarcoma – and other STSs.
“Over 70 percent of children with sarcoma are considered cured, but the five-year survival rate is 30 percent or less for those with advanced disease,” Guttridge says. “Because these cancers are rare, few cancer centers research them and translate findings to the clinic.”
At the OSUCCC – James, Guttridge says, basic and clinical scientists’ interactions include weekly sarcoma tumor-board meetings directed by Joel Mayerson, MD, and extend to research laboratories across the university and at NCH.
Joel Mayerson, MD
Mayerson, an orthopaedic surgeon, directs the Division of Musculoskeletal Oncology in the Department of Orthopaedics. He also is medical director of the sarcoma service for The James. His research and clinical specialties include adult and pediatric bone and soft tissue sarcomas, adjuvant chemotherapy for STSs, the use of positron emission tomography in managing bone and soft tissue sarcomas, metastatic carcinoma to bone, and complex limb reconstruction in adults and children.
Mayerson came to Ohio State in 2001 and helped build the sarcoma program from one person “to a program that our institution uses as a model for multidisciplinary care,” he says. He adds that the SPORE and PPG are helping Ohio State become a leader in developmental therapeutics for STS.
“The sarcoma program now encompasses one of the most, if not the most, complete continuums of clinical and research faculty in the United States, involving the OSUCCC – James, NCH and Ohio State’s College of Veterinary Medicine,” Mayerson says. “As the only sarcoma program in the country to have both a SPORE grant and a pediatric Program Project Grant simultaneously, we can use molecular advances in medicine to change the paradigm of sarcoma care throughout the world.”
Cheryl London, DVM, PhD
The College of Veterinary Medicine link to sarcoma research at Ohio State stems primarily from London, a researcher who studies canine cancers and is a member of the OSUCCC – James, and her many colleagues. London is a co-leader for one of the three PPG projects and leads the PPG’s Comparative Animal Core. Comparative oncology integrates research on naturally occurring cancers in animals with the study of cancer biology and treatment in humans, for the benefit of both. Guttridge says that, through London and her canine clinic, “We plan to test one of the drugs we are developing in our PPG in her patients with osteosarcoma.”
“Data from clinical trials in dogs with spontaneous cancer can be used to identify disease-related genes and to explore the safety and bioactivity of new therapeutic approaches to human cancers,” says London, who directs the College of Veterinary Medicine’s Clinical Trials Ofce (CTO). She notes that 60-70 percent of trials performed through the CTO are cancer-related. Guttridge says this collaboration with the College of Veterinary Medicine “is another example of why our sarcoma team is so complete.”
O. Hans Iwenofu, MD
Iwenofu is an assistant professor of Pathology at Ohio State and one of only a few fellowship-trained soft tissue and bone pathologists in the nation. His research focuses on discovery of novel biomarkers and characterization of the molecular underpinnings for these orphan tumors. Iwenofu also presents and discusses the adult sarcoma cases at a weekly sarcoma tumor-board meeting.
He believes that the rare and complex nature of sarcomas needs a comprehensive and multidisciplinary approach “to advance frontiers that will change the entire landscape of treatment and outcome.
“Our integrated sarcoma program is a unique resource that will doubtless get significant traction from Dr. Pollock’s SARC SPORE grant,” Iwenofu says. “This is an exciting time for sarcoma research at Ohio State.”
Young Ohio State Researchers Receive SARC Awards
Each year SARC issues three Career Development Awards to promising young investigators in sarcoma. Two of the 2014 awards went to Ohio State researchers James L. Chen, MD, and David Liebner, MD.
Liebner is an assistant professor of Medicine (Division of Medical Oncology) and of Biomedical Informatics. Chen is an assistant professor of Biomedical Informatics and of Medicine (Division of Medical Oncology).
Liebner combines clinical expertise in sarcoma and melanoma with a research focus in cancer bioinformatics. His vision is to develop and leverage computational tools that integrate with the Electronic Health Record (EHR) to improve prognostic and predictive models in sarcoma and melanoma. Chen specializes in genomics and complex computational modeling. He is interested in identifying molecular biomarkers using automated genomic techniques. These biomarkers may help clinicians personalize treatment for sarcoma and other cancers.
“Our growing sarcoma program benefts from the perspectives of talented junior investigators such as Drs. Liebner and Chen,” Pollock says. “It’s gratifying to know that we have young scientists at Ohio State who are interested in this disease.”
The young investigators are part of the highly collaborative sarcoma program that brings together basic, translational and clinical researchers at the OSUCCC – James and Nationwide Children’s Hospital. Backed by the SARC SPORE and an NCI program project grant, the program holds great potential to improve sarcoma care, Houghton says.
“Having the sarcoma SPORE at Ohio State strengthens our laboratory and clinical research in this disease, potentially cross-feeding therapeutic ideas between the adult and pediatric fields,” he says.
Pollock agrees. “We have a real sense of teamwork, and a strong desire to expand our efforts to help sarcoma patients. Ohio State is super that way.”
Components of the SARC Spore
The sarcoma SPORE (CA168512) is led by principal investigator (PI) Raphael Pollock, MD, PhD, and has four research projects. It also includes administrative, tissue and pathology, clinical trials and biostatistics cores, and a Career Developmental Program and a Developmental Research Program.
Here are the four projects:
“Histone Deacetylase Inhibitor (HDACi)-Based Therapeutic Strategies for the Treatment of Genetically Complex Soft Tissue Sarcoma.” Co-PIs: Raphael Pollock, MD, PhD, the OSUCCC – James; Shreyaskumar Patel, MD, MD Anderson Cancer Center; Edwin Choy, MD, PhD, Massachusetts General Hospital. (Pollock also leads the administrative core.)
“Identification of Therapeutic Windows for NFI-Related Malignant Peripheral Nerve Sheath Tumor.” Co-PIs: Yuan Zhu, PhD, Children’s National Medical Center, Washington, D.C.; Laurence Baker, DO, University of Michigan.
“Investigating G-Protein Coupled Receptors (GPCRS) as Biomarkers of Aggressive Disease and Novel Therapeutic Targets in Ewing Sarcoma.” Co-PIs: Elizabeth Lawlor, MD, PhD; Rashmi Chugh, MD, both of the University of Michigan.
“Development of Quantitative Imaging Biomarkers for Assessing Response to Sarcoma Therapy.” Co-PI’s: Jefrey Yap, PhD, University of Utah; Lawrence Schwartz, MD, Columbia University.
Other collaborators in the SPORE are at Harvard University, Stanford University, the Albert Einstein College of Medicine in New York City, Cancer Research and Biostatistics (CRAB®) in Seattle, Wash., and the NCI.