Person: Shah, Khalid
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Khalid
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Shah, Khalid
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Publication Encapsulated stem cells for cancer therapy(Landes Bioscience, 2013) Shah, KhalidStem cells have inherent tumor‑trophic migratory properties and can serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease, making them promising anti‑cancer agents. Encapsulation of therapeutically engineered stem cells in hydrogels has been utilized to provide a physical barrier to protect the cells from hostile extrinsic factors and significantly improve the therapeutic efficacy of transplanted stem cells in different models of cancer. This review aims to discuss the potential of different stem cell types for cancer therapy, various engineered stem cell based therapies for cancer, stem cell encapsulation process and provide an in depth overview of current applications of therapeutic stem cell encapsulation in the highly malignant brain tumor, glioblastoma multiforme (GBM), as well as the prospects for their clinical translation.Publication Targeting c-Met Receptor Overcomes TRAIL-Resistance in Brain Tumors(Public Library of Science, 2014) Du, Wanlu; Uslar, Liubov; Sevala, Sindhura; Shah, KhalidTumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced apoptosis specifically in tumor cells. However, with approximately half of all known tumor lines being resistant to TRAIL, the identification of TRAIL sensitizers and their mechanism of action become critical to broadly use TRAIL as a therapeutic agent. In this study, we explored whether c-Met protein contributes to TRAIL sensitivity. We found a direct correlation between the c-Met expression level and TRAIL resistance. We show that the knock down c-Met protein, but not inhibition, sensitized brain tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptor (DR) 5. This interruption greatly induces the formation of death-inducing signaling complex (DISC) and subsequent downstream apoptosis signaling. Using intracranially implanted brain tumor cells and stem cell (SC) lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that SC expressing a potent and secretable TRAIL (S-TRAIL) have a significant anti-tumor effect in mice bearing c-Met knock down of TRAIL-resistant brain tumors. To our best knowledge, this is the first study that demonstrates c-Met contributes to TRAIL sensitivity of brain tumor cells and has implications for developing effective therapies for brain tumor patients.Publication Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors(Nature Publishing Group UK, 2017) Zhu, Yanni; Bassoff, Nicole; Reinshagen, Clemens; Bhere, Deepak; Nowicki, Michal; Lawler, Sean; Roux, Jérémie; Shah, KhalidDeveloping therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.Publication Brain Tumor Cells in Circulation Are Enriched for Mesenchymal Gene Expression(American Association for Cancer Research (AACR), 2014) Sullivan, James; Nahed, Brian; Madden, M. W.; Oliveira, S. M.; Springer, S.; Bhere, Deepak; Chi, A. S.; Wakimoto, Hiroaki; Rothenberg, S. M.; Sequist, Lecia; Kapur, R.; Shah, Khalid; Iafrate, Anthony; Curry, William; Loeffler, Jay; Batchelor, Tracy; Louis, David; Toner, Mehmet; Maheswaran, Shyamala; Haber, DanielGlioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating brain tumor cells (CTCs). Staining and scoring criteria for GBM CTCs were first established using orthotopic patient-derived xenografts (PDX), and then applied clinically: CTCs were identified in at least one blood specimen from 13/33 patients (39%; 26/87 samples). Single GBM CTCs isolated from both patients and mouse PDX models demonstrated enrichment for mesenchymal over neural differentiation markers, compared with primary GBMs. Within primary GBMs, RNA-in-situ hybridization identifies a subpopulation of highly migratory mesenchymal tumor cells, and in a rare patient with disseminated GBM, systemic lesions were exclusively mesenchymal. Thus, a mesenchymal subset of GBM cells invades into the vasculature, and may proliferate outside the brain.Publication Evaluating the Effect of Therapeutic Stem Cells on TRAIL Resistant and Sensitive Medulloblastomas(Public Library of Science, 2012) Nesterenko, Irina; Wanningen, Simone; Bagci-Onder, Tugba; Anderegg, Maarten; Shah, KhalidMesenchymal stem cells (MSC) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential in medulloblastomas (MB) has not been explored to date. In this study, we engineered human MSC to express a potent and secretable variant of a tumor specific agent, tumor necrosis factor-apoptosis-inducing ligand (S-TRAIL) and assessed the ability of MSC-S-TRAIL mediated MB killing alone or in combination with a small molecule inhibitor of histone-deacetylase, MS-275, in TRAIL-sensitive and -resistant MB in vitro and in vivo. We show that TRAIL sensitivity/resistance correlates with the expression of its cognate death receptor (DR)5 and MSC-S-TRAIL induces caspase-3 mediated apoptosis in TRAIL-sensitive MB lines. In TRAIL-resistant MB, we show upregulation of DR4/5 levels when pre-treated with MS-275 and a subsequent sensitization to MSC-S-TRAIL mediated apoptosis. Using intracranially implanted MB and MSC lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that MSC-S-TRAIL has significant anti-tumor effects in mice bearing TRAIL-sensitive and MS-275 pre-treated TRAIL-resistant MBs. To our knowledge, this is the first study that explores the use of human MSC as MB-targeting therapeutic-vehicles in vivo in TRAIL-sensitive and resistant tumors, and has implications for developing effective therapies for patients with medulloblastomas.Publication A First-Generation Multi-Functional Cytokine for Simultaneous Optical Tracking and Tumor Therapy(Public Library of Science, 2012) Hingtgen, Shawn; Kasmieh, Randa; Elbayly, Elizabeth; Nesterenko, Irina; Figueiredo, Jose-Luiz; Dash, Rupesh; Sarkar, Devanand; Hall, David; Kozakov, Dima; Vajda, Sandor; Fisher, Paul B.; Shah, KhalidCreating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L.