1R21CA229919-01 (R21) ApplID: 9585251 | |||
---|---|---|---|
Title | Targeting Nodal/TGF-Beta pathway to inhibit invasion and growth of retinoblastoma | ||
Institution | JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | ||
Principal Investigator | ASNAGHI, LAURA | NCI Program Director | Arya |
Cancer Activity | Biochemistry and Pharmacology | Division | DCTD |
Funded Amount | $213,694 | Project Dates | 07/03/2018 - 06/30/2020 |
Fiscal Year | 2018 | Project Type | Grant |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Childhood Cancers (100.0%) Metastasis (50.0%) |
N/A | ||
Research Type | |||
Systemic Therapies - Discovery and Development | |||
Abstract | |||
Project Summary Retinoblastoma is an aggressive tumor of the retina and the most common intraocular cancer in childhood, causing about 4,000 deaths annually worldwide. While the primary tumor can be successfully treated mostly by systemic and/or local chemotherapy, metastases in the central nervous system (CNS) or in distant organs, such as bone and bone marrow, are more resistant to therapy and still remain the leading cause of death due to retinoblastoma. Since the molecular factors driving metastatic spread are still not understood, there is an urgent and unmet need to elucidate the pathways responsible for retinoblastoma invasion, in order to find new therapeutic targets to block dissemination of this aggressive childhood malignancy. The overall goal of this project is therefore to identify invasion-promoting molecular pathways in retinoblastoma, and to develop targeted therapies which will prevent its spread outside the eye and growth at distant sites. Here we propose to investigate the Nodal/TGF-? signaling as a new strategy to efficiently inhibit retinoblastoma invasion and growth into the CNS, since we found that this pathway was potently upregulated in all cases of invasive retinoblastoma that we analyzed by next generation RNA sequencing, as compared to non-invasive cases. Therefore, our central hypothesis is that targeting Nodal/TGF-? signaling represents a new approach to inhibit retinoblastoma invasion and metastatic growth. To test this hypothesis, we plan to repress this pathway either genetically, by short hairpin RNA (shRNA), at both the ligand and the receptor level, or pharmacologically, using chemical inhibitors of the Nodal/TGF-? signaling. We will investigate in vitro the effects that the pharmacological or genetic inhibition of the Nodal/TGF-? signaling might have on invasion, overall growth, proliferation, clonogenicity, survival, cell death, and differentiation, in multiple patient-derived retinoblastoma cell lines, established from either primary tumors or vitreous seeds. Importantly, we will pursue these aims also in vivo, using an innovative orthotopic model of retinoblastoma invasion in zebrafish, which we have recently established in our lab, for monitoring and quantifying retinoblastoma growth and invasion using longitudinal intravital imaging methods. This model will facilitate our efforts by providing a rapid and economical method to test the effects of various genetic and pharmacological manipulations in an in vivo setting. However, to ensure robust and reproducible data across species, confirmatory testing will be performed using intraocular murine xenografts as well." |