title: Toward a drug development path that targets metastatic progression in osteosarcoma.
abstract: Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting.
authors.affiliation: Molecular Oncology Section, Metastasis Biology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois; t-fan@illinois.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.affiliation: Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine of Yeshiva University; Division of Hematology/Oncology, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx;
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
authors.affiliation: Cancer Biology and.
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
authors.affiliation: Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.affiliation: Center for Childhood Cancer, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Sarcoma Oncology, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York; Departments of.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Kansas University Medical Center, Kansas City, Kansas;
authors.forename: Danny R
authors.initials: DR
authors.lastname: Welch
authors.affiliation: Laboratory of Molecular Pharmacology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.affiliation: Laboratory of Cancer Biology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Department of Pathology, University of British Columbia; BC Cancer Research Centre, Vancouver, British Columbia; and.
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina;
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Pediatrics, Harvard Medical School; Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.affiliation: Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota;
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.affiliation: Huntsman Cancer Institute & Primary Children's Medical Center, University of Utah, Salt Lake City, Utah;
authors.forename: Lor
authors.initials: L
authors.lastname: Randall
authors.affiliation: Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado; Departments of.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Withrow
authors.affiliation: Comparative Oncology Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Melissa
authors.initials: M
authors.lastname: Paoloni
authors.affiliation: Tumor Microenvironment Section, Pediatric Oncology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Rosandra
authors.initials: R
authors.lastname: Kaplan
authors.affiliation: Molecular Pharmacology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.affiliation: Cancer Therapy Evaluations Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.affiliation: National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.affiliation: Oncology and Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia;
authors.forename: Aykut
authors.initials: A
authors.lastname: Uren
authors.affiliation: Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas;
authors.forename: Shreyaskumar R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, Arizona;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trent
authors.affiliation: Clinical Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan;
authors.forename: Denise
authors.initials: D
authors.lastname: Reinke
authors.affiliation: Children's Oncology Group, QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Monrovia;
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkaukas
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California;
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.affiliation: Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary
chemical_list: D000970:Antineoplastic Agents