Identification of CSPG4 as a promising target for translational combinatorial approaches in osteosarcoma

Abstract

Background: Osteosarcoma (OSA) is a highly metastatic pediatric bone tumor. Adjuvant chemotherapy and surgical resection represent standard treatments; however, the prognosis is still poor. Effective strategies are urgently needed. Chondroitin sulfate proteoglycan (CSPG)4 is a transmembrane proteoglycan with a low expression in normal tissues but high expression in several solid tumors, where it plays a central tumorigenic role. Therefore, it represents a promising therapeutic target. The high homology between human and canine CSPG4 and the recognized translational power of canine tumors as preclinical models for human malignancies prompted us to evaluate CSPG4 expression and the consequences of its immune-targeting for both human and canine OSA treatment. Methods: We analyzed CSPG4 overexpression in human and canine OSA samples and its significance for the survival of OSA patients. We exploited functional in vitro experiments to assess the antitumor potential of CSPG4 immune-targeting. Results: CSPG4 is overexpressed in OSA and has possible clinical implications as suggested by an evident correlation between CSPG4 overexpression and a shorter survival for both OSA-affected humans and dogs. The potential of CSPG4 immune-targeting for OSA treatment came from the ability of anti-CSPG4 monoclonal antibodies and sera, derived from human-CSPG4-DNA vaccinated canine patients, to significantly inhibit human and canine CSPG4-positive OSA cell proliferation, migration, and osteospheres generation. Moreover, CSPG4 immune-targeting has been shown to potentiate the effect of doxorubicin. Conclusions: Overall, these results provide the rationale to investigate the CSPG4 immune-targeting as a promising weapon for the treatment of CSPG4-positive OSA canine patients, to be successfully translated to a human setting.

In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model

“…CSPG4 is a promising target antigen highly expressed in multiple tumor types, including melanoma, glioblastoma, breast carcinomas, osteosarcoma and hematologic cancers. 25,35 Originally believed to have a very limited distribution in normal adult tissues, 36 CSPG4 expression has since been observed Figure 3. Molecular analysis of immediate effects of in vivo α-CSPG4 rIgE administration.…”

Electroporation-Based Treatments in Small Animal Veterinary Oral and Maxillofacial Oncology

“…GET of human CSPG4 (hCSPG4) has also been shown to be safe and effective in the treatment of dogs with spontaneous OMM ( 70 , 71 ); the human sequence of CSPG4 was intentionally used in these studies due to its high homology and similarity to canine CSPG4 and demonstrated ability to induce a specific humoral response against the human and canine protein, which is related to the successful outcome of the treatment ( 68 ). CSPG4 immune targeting also appears to be a promising treatment modality for appendicular OSA in dogs, as documented in an in vitro model ( 69 ).…”

“…As CSPG4 displays low expression levels on healthy adult (human and canine) cells and is expressed on the cell surface (Class 1 oncoantigen), it is an ideal target for effective anti-cancer immunotherapy in dogs and humans. A canine model appears to be very useful in translational studies, as CSPG4 expression was found in canine malignant melanoma and osteosarcoma (OSA) ( 68 , 69 ) and has been related to significantly shorter survival in dogs with appendicular OSA ( 69 ). GET of human CSPG4 (hCSPG4) has also been shown to be safe and effective in the treatment of dogs with spontaneous OMM ( 70 , 71 ); the human sequence of CSPG4 was intentionally used in these studies due to its high homology and similarity to canine CSPG4 and demonstrated ability to induce a specific humoral response against the human and canine protein, which is related to the successful outcome of the treatment ( 68 ).…”

Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast Cancer

“…To measure cell migrative ability [ 54 ], 2 × 10 4 MDA-MB-231 and 4T1 cells were seeded in the top chamber of a 24-transwell plate (8 μm pore size; Corning, Amsterdam, The Netherlands) after 1 h of pre-incubation with 1:50 dilutions of pooled sera from mice vaccinated with AX09 or MS2 wt or left untreated in a serum-free medium. Then, the bottom chambers of the transwell plates were filled with 600 μL of complete growth medium and the cells were incubated at 37 °C in a 5% CO 2 atmosphere.…”