Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression
In United States, each year 650 children are diagnosed with neuroblastoma (NB) [1], an embryonal malignancy of sympathetic nervous system that is remarkable for its clinical heterogeneity [2]. Patients with the invasive/metastatic high-risk stage-IV NB showed refraction with all conventional therapeutic modalities and is associated with dismal prognosis [3]. High recurrence rate (20.2%) entailing substantial fractions of both local (17%-74% of patients) [4–8] and distant metastasis (46.8%) present considerable challenges for the clinical management of NB. With only 13 months since first diagnosis to recurrence, the survival ratio was 43% for local and 10% for systemic recurrences. Clinical and laboratory evidence suggests that several human cancers contain populations of rapidly proliferating clonogens that can have substantial impact on local control following chemoradiotherapy [9]. Tumor cell repopulation may arise from remnant cells of the original neoplasm that have escaped therapeutic intervention and later become visible at the original site. Radiotherapy (RT), now widely used for high-risk NB patients after chemotherapy, significantly improved the survival rate [10]. Patients, however, have been confronted with relapse and developed drug/radiation resistance, possibly through favoring alternative pathways. Therapeutic doses of radiation (IR) has been shown to activate various transcription factors including NFκB [11] and studies have suggested their influential role in tumorigenesis and progression [12]. Recently, we demonstrated the radiation triggered NFκB initiates TNFα cross signaling dependent maintenance of NFκB that in turn promotes survival advantage in both in vitro and in vivo NB models [13]. To that end, identifying ‘drug-deliverables’ that selectively disrupt IR-induced NFκB-TNFα feedback signaling and impedes NFκB maintenance could deter NFκB-dependent survival advantage and potentiate RT in NB cure.