Combination therapy with a novel humanized antibody to secreted frizzled related protein 2 for sarcoma
Sarcomas are a heterogeneous group of malignancies with a 50% mortality at 5 years across all subtypes and stages. The 5 year survival for patients with metastatic disease is only 15%.The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long-term benefit. Single-agent doxorubicin is currently the standard of care and has produced response rates of 20% to 25%. Anti-VEGF therapy has activity in sarcoma but with response rate of only 12%. New targeted agents are greatly needed to improve response and survival. Recent reports provide evidence that SFRP2 can enhance tumor aggressiveness and progression in several cancer types, including angiosarcoma, osteosarcoma, melanoma, renal cell carcinoma, breast cancer, lung cancer, malignant glioma, and prostate cancer. We previously generated a murine (m)SFRP2 monoclonal antibody (mAb) and evaluated its efficacy for therapeutic and diagnostic applications. Treatment with the mSFRP2 mAb inhibits angiosarcoma and breast cancer growth in mice. To move towards clinical translation we generated a humanized (h)SFRP2 mAb which inhibits angiosarcoma, breast carcinosarcoma, and osteosarcoma growth in vivo and has no immunogenicity (preliminary data). We have observed that the hSFRP2 mAb has direct effects at inducing tumor cell apoptosis, inhibiting tumor cell migration, and inhibiting angiogenesis. Several mechanisms through which SFRP2 stimulates tumor growth in vitro have been described: SFRP2 activates the non-canonical Wnt calcineurin/ nuclear factor of activated T-cells c3 (NFATc3) pathway in both tumor cells and endothelial cells in vitro, which is antagonized by the mSFRP2 mAb. NFAT is a transcription factor that has multiple functions in tumorigenesis including cell growth, survival, invasion, and angiogenesis. The receptor that SFRP2 binds to to activate the calcineurin/ NFAT pathway in endothelial and tumor cells is FZD5 (ref).. Based on these mechanisms of anti-SFRP2 therapy, we plan to design mechanistically based combination therapy to evaluate for additivity with other anti-cancer agents. We hypothesize that the hSFRP2 mAb will synergize with chemotherapy and anti-angiogenic therapy, and be efficacious in drug resistant cells.