Therapeutic vulnerability of an in vivo model of alveolar soft part sarcoma (ASPS) to antiangiogenic therapy.
In vivo growth of alveolar soft part sarcoma (ASPS) was achieved using subcutaneous xenografts in sex-matched nonobese diabetic severe combined immunodeficiency mice. One tumor, currently at passage 6, has been maintained in vivo for 32 months and has maintained characteristics consistent with those of the original ASPS tumor including (1) tumor histology and staining with periodic acid Schiff/diastase, (2) the presence of the ASPL-TFE3 type 1 fusion transcript, (3) nuclear staining with antibodies to the ASPL-TFE3 type 1 fusion protein, (4) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS, (5) stable expression of signature ASPS gene transcripts and finally, the development and maintenance of a functional vascular network, a hallmark of ASPS. The ASPS xenograft tumor vasculature encompassing nests of ASPS cells is highly reactive to antibodies against the endothelial antigen CD34 and is readily accessible to intravenously administered fluorescein isothiocyanate-dextran. The therapeutic vulnerability of this tumor model to antiangiogenic therapy, targeting vascular endothelial growth factor and hypoxia-inducible factor-1 alpha, was examined using bevacizumab and topotecan alone and in combination. Together, the 2 drugs produced a 70% growth delay accompanied by a 0.7 net log cell kill that was superior to the antitumor effect produced by either drug alone. In summary, this study describes a preclinical in vivo model for ASPS which will facilitate investigation into the biology of this slow growing soft tissue sarcoma and demonstrates the feasibility of using an antiangiogenic approach in the treatment of ASPS.
Vistica
David T
DT
Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA. visticad@mail.nih.gov
Hollingshead
Melinda
M
Borgel
Suzanne D
SD
Kenney
Susan
S
Stockwin
Luke H
LH
Raffeld
Mark
M
Schrump
David S
DS
Burkett
Sandra
S
Stone
Gary
G
Butcher
Donna O
DO
Shoemaker
Robert H
RH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D000068258:Bevacizumab; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019772:Topotecan / Q000494:pharmacology*; D014178:Translocation, Genetic / Q000235:genetics; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C422743:ASPSCR1 protein, human; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C069203:TFE3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D019772:Topotecan