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Clin Cancer Res. 2014 Aug 15;20(16):4200-9. doi: 10.1158/1078-0432.CCR-13-2574. Epub 2014 May 6.

Toward a drug development path that targets metastatic progression in osteosarcoma.

Author information

1
Molecular Oncology Section, Metastasis Biology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
2
Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois; t-fan@illinois.edu.
3
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;
4
Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
5
Cancer Biology and.
6
Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
7
Center for Childhood Cancer, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio;
8
Sarcoma Oncology, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York; Departments of.
9
Kansas University Medical Center, Kansas City, Kansas;
10
Laboratory of Molecular Pharmacology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
11
Laboratory of Cancer Biology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
12
Department of Pathology, University of British Columbia; BC Cancer Research Centre, Vancouver, British Columbia; and.
13
Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
14
Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina;
15
Department of Pediatrics, Harvard Medical School; Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts;
16
Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota;
17
Huntsman Cancer Institute & Primary Children's Medical Center, University of Utah, Salt Lake City, Utah;
18
Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado; Departments of.
19
Comparative Oncology Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
20
Tumor Microenvironment Section, Pediatric Oncology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
21
Molecular Pharmacology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
22
Cancer Therapy Evaluations Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
23
National Cancer Institute, NIH, Bethesda, Maryland;
24
Oncology and Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia;
25
Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas;
26
Translational Genomics Research Institute (TGen), Phoenix, Arizona;
27
Clinical Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
28
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland;
29
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan;
30
Children's Oncology Group, QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Monrovia;
31
Department of Preventive Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California;
32
Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.

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.

PMID:
24803583
PMCID:
PMC4134738
DOI:
10.1158/1078-0432.CCR-13-2574
[Indexed for MEDLINE]
Free PMC Article

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