Research Idea: For the last 20 years, cellular biologists have been focusing on the role of Ras signaling pathway in neurofibromatosis 1(NF1) and its lethal derivation, malignant peripheral nerve sheath tumor (MPNST). Ras-like (Ral) proteins are crucial members of the Ras family, shown to play a pivotal role in human tumors. Because Ral guanine nucleotide exchange factors (Ral-GEFs) are direct effectors of Ras, the Ral signaling pathway has been traditionally considered a Ras-effector pathway. We introduced RalA, for the first time, as an important regulator of the biological features of MPNST with potentials for being targeted for treatment of this malignancy. Subsequently, in 2012, our team was first to report that RalA is overactivated in the cancer stem cell (CSC) fraction of MPNST tumors. Now we intend to further evaluate the in-vivo potentials of inhibition of this pathway as a therapeutic strategy against MPNST.
Concept: We are proposing RalA activation as a central signaling abnormality with important biological ramifications in etiology and pathogenesis of MPNST. Overactivation of this pathway is not only a dominant theme in MPNST population of differentiated cells but is also a major characteristic of CD133+ CSCs. Therefore, RalA signaling pathway is not only important in terms of understanding the biology of MPNST but might also have play a crucial role in developing novel therapies against this deadly disease.
Hypothesis: Inhibition of RalA signaling pathway reduces the in-vivo tumor growth of MPNST.
Objectives: Answering following questions are main objectives of this proposal:
1-Does inhibition of RalA in differentiated or cancer stem cells from MPNST origin result in the inhibition of in-vivo tumorigenesis and/or regression of established tumors? This is an important step in assessing the potentials of gene-specific silencing of RalA as a therapeutic strategy for MPNST. Subcutaneous (SC) mouse model will be used for such purpose.
2-Does interruption of RalA binding to RalBP1 result in the regression of MPNST in-vivo? We have provided primary evidence that interruption of RalA to RalBP1 by a cell-penetrable peptide (CPP) can result in a significant loss of viability of MPNST cells in-vitro. With consideration to the lack of any specific inhibitors of RalA, such CPP can be fundamental in further development of a novel drug therapy strategy for targeting RalA signaling in MPNST.
Innovation: We are living in an era which many novel therapies are designed on the basis of our knowledge about signaling machinery of cancer cells. This proposal opens a new horizon for advancing our knowledge about the biology of MPNST which has the potential to lead to future therapeutic and early detection strategies.