Systems Radiopharmacotherapy: A Paradigm in Drug Repurposing with Immune Modulatory Potential

Abstract

We earlier showed through Systems Biology approaches that genotoxic stress response evoked by cancer, infection, and radiation injury have similarities, particularly at the gastrointestinal tract. The aim of this work is to identify by systems biology approaches how two similar pathologies can act as surrogate model in drug screening. Molecular Imaging methodologies were used earlier to show binding of osteoporosis drug bisphosphonate to prostate (Papineni et. al. http://cancerres.aacrjournals.org/content/71/8_Supplement/5327) and ovarian cancer tumors and its potential drug repurposing candidature. More recently, we presented similar drug re-tasking potential of 2-Deoxyglucose (2-DG) in anti-infection (Ahmed et. al. http://cancerres.aacrjournals.org/content/76/14_Supplement/LB-317). Mitigation of citrobacter rodentium infection by dietary treatment by 2-DG (0.4%) observed by us were analyzed and compared with the anti-infection response of alendronate to these enteric bacteria reported elsewhere. A systems approach analysis is developed and will be discussed to show the cross-talk and communication between different cells, and the integrated responses to pathogens and disease by 2-DG and bisphosphonate particularly the anticancer and anti-infection actions. A role in EGFR signaling along with modulation in the infiltrating immune response cells by these two dissimilar compounds seem to play a profound bridging event in anticancer and anti-infection activity. The glucose mimic by restoring the Notch and Wnt pathway presents the stemness in the colon with a distinct role in DCLK1 and LGR 5 positive stem cells dynamics. These candidate drugs more recently are shown to modulate immune suppression through inhibition of CD11b+ Ly6C high monocytic myeloid-derived suppressor cells MDSCs (M-MDSCs) differentiation and in the osteoclast based activation of Natural killer (NK) cells. These system biology strategies thus provides opportunities for drug repurposing in personalized cancer therapy and in anti-microbial management during cancer treatment. Also pave way for safer drugs in prevention and therapy of HER family-driven cancers.