Neuroblastoma (NB) the most frequent extra cranial solid tumor, with only 10% survival after systemic recurrence accounts for 15% of all childhood cancer fatalities. Recurring tumor may arise from remnant cells of neoplasm that have escaped therapeutic intervention and later become visible at original site. We have shown that inhibition of NFkB enhanced radiotherapy (RT)-induced cell-death in NB cells. To that note, identifying and delivering compounds that selectively targets NFkB would prove beneficial in mitigating NB relapse/metastasis. We hypothesize that: (1) NB cells that survive RT may result in the development of survival advantage mediated by persistent NFkB activation through NFkB-TNFalpha positive feed back cycle (PFC). This response could lead to clonal expansion'and tumor recurrence. (2) RT-induced inhibition of eNOS regulated NO activates MMP9 dependent transactivation of NFkB, which in turn modulates MMP/TIMP balance that leads to NB progression/metastasis and (3) Selective, two dimensional targeting of RT-induced NFkB with EF24-loaded immunoliposomes targeting GD2 (EF24-IL=>GD2) may result in complete prevention of NB relapse/metastasis. Using NB xenograft model, we will determine:
(Aim 1) whether RT could initiate PFC leading to a persistent activation of NFkB and subsequent survival advantage and initiation of clonal expansion.
(Aim 2) whether IR regulated eNOS dependent NO activates MMP9 and to study its role in NFkB dependent MMP/TIMP imbalance, NB progression and metastasis.
(Aim 3) the efficacy of EF24-IL=>GD2 in inhibiting IR-induced NFkB-TNFa cross signaling dependent persistent activation of NFkB mediated survival advantage and clonal expansion and (Aim 4) the potential effect of EF24-1L=>GD2 in IR-inhibited eNOS-NO dependent MMP9 induced NFkB mediated NB progression and metastasis. On completion, this study will provide insight into the orchestration of NFkB after RT and its downstream response. Most importantly, this study could lead to the development of a "deliverable" to test in clinical settings to mitigate local failure and metastasis, that could lead to a positive impact on NB patients.
This study will not only throw light on the molecular blue print that underlies the neuroblastoma relapse, progression and metastasis;this study will also delineate the clinical efficacy of EF24, the analogue of known anti-oxidant curcumin and more importantly the targeted delivery of this compound precisely to NB sites. Achieving this in pre-clinical model would lead to test the approach in clinical settings, and this would shift a huge archetype in current practice that could positively impact innumerable NB patients.
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