Combination therapy to inhibit neuroblastoma growth Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced state IV neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains at <20%, providing a compelling reasons to better understand the molecular mechanisms that can be targeted to treat this disease. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign tumors. In patients with residual or recurring benign tumors, there is increasing concern about radiation-related side effects that may occur even with highly accurate therapies such as radiosurgery. Despite some therapeutic effect, recent evidence has shown that irradiation may promote malignant behaviors of cancer cells both in vitro and in vivo by activating several pathways involved in tumor invasiveness, angiogenesis and metastasis. Another consequence of radiation is that tumors often become resistant to radiation. An increasing number of long-term survivors with late sequelae highlight the need for novel therapeutic approaches. Tumor growth and angiogenesis occur in the context of the extracellular matrix (ECM), the levels and deposition of which are controlled in part by secreted protein, acidic and rich in cysteine (SPARC), a matricellular glycoprotein. SPARC modulates cellular interaction with the ECM and has diverse roles in normal cells, many of which have been shown to contribute to tumorigenesis. The relative levels of SPARC expression in normal brain decreased with malignant transformation, as indicated by our group and others. Our preliminary studies demonstrated that over-expression of SPARC inhibited neuroblastoma cell proliferation, migration, angiogenesis and tumor growth in vivo compared to parental and EV- transfected cells. We also provided that SPARC may act as a sensitizer to radiotherapy. We hypothesize that modulation of SPARC combined with radiation and the anticancer effects of these treatments will be determined.
The specific aims of this proposal are as follows:
In Specific Aim 1, we will evaluate the effects of the p-SPARC and radiation, alone and in combination, on neuroblastoma cell migration and invasion in both in vitro and in vivo models.
In Specific Aim 2, we will determine the effects of p-SPARC and radiation, alone and in combination, on neuroblastoma cell growth, proliferation, adhesion and apoptosis.
In Specific Aim 3, we will determine the effect of p-SPARC and radiation, alone and in combination, on neuroblastoma cell interactions with the microenvironment of both in vitro and in vivo and the effect of p-SPARC and radiation, alone and in combination, on angiogenesis both in vitro and in vivo. This combination of in vitro basic science experiments and translational in vivo studies will provide the basis for development of a new therapeutic approach to neuroblastoma tumors which are resistant to conventional radiotherapy.
Neuroblastoma accounts for 10% of all juvenile cancers. Advanced stage neuroblastoma in children over one-year old is largely incurable using current treatment protocols. However, an increasing number of long-term survivals with secondary effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a comprehensive analysis to determine the therapeutic benefit of SPARC expression in combination with radiation for the treatment of neuroblastoma.
|Sailaja, G S; Bhoopathi, Praveen; Gorantla, Bharathi et al. (2013) The secreted protein acidic and rich in cysteine (SPARC) induces endoplasmic reticulum stress leading to autophagy-mediated apoptosis in neuroblastoma. Int J Oncol 42:188-96|
|Gorantla, Bharathi; Bhoopathi, Praveen; Chetty, Chandramu et al. (2013) Notch signaling regulates tumor-induced angiogenesis in SPARC-overexpressed neuroblastoma. Angiogenesis 16:85-100|