2017-2018 Funded Collaborations
International Collaborative Grants
Macrophages-Shuttling of miRNA Via Exosomes Reprograms Glucose Metabolism in Pancreatic
The overall goal of this joint research proposal is to characterize the effect of macrophage-derived exosomes (MDEs) on cancer cell progression. We hypothesized that tumor associated macrophages transmit specific miRNAs via exosomes to cancer cells, promoting tumor growth by reprogramming glucose metabolism. Based on our preliminary data that was presented above, we will further explore the role of exosomes as a vehicle to selectively modulate metabolic pathways in PDA tumor. The aims of the current study focus on three elements of the stroma-neoplastic circuit: 1) Exosomal signaling between macrophages and cancer cells, 2) The influence of specific exosomal-derived miRNA on cancer cell physiology and 3) the effect of MDEs and their content on cancer cells’ glucose metabolism.
Modifying the prey: targeting of signal regulators with siRNA for improved viral oncolysis
The development of novel and efficient therapies for metastatic prostate cancer (PCa) is an urgent need. A main challenge in this development is the concomitant targeting of alterations to PCa cells (e.g. neuroendocrine trans-differentiation) and the accumulation of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment. This accumulation inhibits Tcell responses and decreases anti-tumor immunity. This challenge is further enhanced by the chemo-resistance of neuroendocrine prostate cancer cells (NEPC). To confront such challenge, we propose a synergistic collaboration that combines two novel therapeutic modalities (i) Oncolytic virotherapy which employs oncolytic viruses to directly kill cancer cells and elicit anti-tumor immunity; and (ii) therapeutic oligonucleotides, which concomitantly reduce the tumorigenic potential of PCa cells and enhance anti-tumor immunity through specific targeting of the expression of signaling regulators in tumor- and myeloid-derived suppressor cells. We will employ EHDV-TAU, a novel oncolytic orbivirus developed by the Ehrlich and Bacharach labs, which explores cancer-induced defects to the innate-immune antiviral responses to target PCa cells, and CpG-conjugated oligodeoxynucleotides (ODN) or siRNA, developed by the Kortylewski lab, to specifically silence STAT3 and/or STAT1 in TLR9+ myeloid and PCa cells.
Metallocorroles for imaging and therapy in malignant melanoma
We propose to perform metastatic melanoma imaging in the brain, based on injecting human malignant melanoma cells (SK-MEL-28) loaded with metallocorroles that are either fluorescent, or NIR-emitting, or suitable MRI contrast agents. The proposal builds on preliminary results obtained via previous collaborations between the PI’s, which identified the structural requirements of the corroles for efficient, fast and irreversible endocytosis and development of methodologies for following that and related processes. The synthesis and application of an amphiphilc Gd(III) corrole for MRI applications is novel.
Theranostic Metallodrugs for Imaging and Fighting Cancer
We propose to develop metallocorroles as versatile theranostic agents with fluorescence, NIR emission, and MRI contrast enhancement imaging modalities. Spectroscopic properties and biological activities can be tuned by judicious choice of the chelated metal ion and by functional group substitutions around the corrole periphery. Detailed studies of different chemical combinations have led to the design of new metallocorroles that exhibit efficient and irreversible endocytosis across a variety of cell types with wide ranging cytotoxicities. One major conclusion reached from the ongoing collaboration between us (my group at the Technion and John Termini’s group from COH) is that while lipophilic metallocorroles provide the greatest flexibility for the optimization of bioimaging and therapeutic properties, their limited aqueous solubility seriously impedes practical medical applications. The Technion group has now discovered an extremely facile and novel formulation methodology that provides water-soluble nanocages composed of lipophilic corroles and native serum proteins. Preliminary cytotoxicity screens performed at COH revealed IC50 values for gold corrole nanocages in the nanomolar range, an orders of magnitude improvement relative to the same reagent solubilized by DMSO, amphiphilic metallocorroles, or cis-platin. We will perform in depth research on the applicability of bio-nanocages for imaging as well as antitumor therapy, including examination of variables affecting size, solubility, and uptake; comparisons of cytotoxicity and mechanism of action relative to related formulations; as well as targeting effects exhibited by the proteins used for nanocage formulation. The non-toxic bio-nanocages will be used for the aforementioned imaging studies, with focus on evaluating both extra- and intracellular trafficking. During my sabbatical at COH, John Termini and I will co-supervise the experimental work performed by researchers from both groups, analyze the results and design new directions with the explicit intention of and using the newly acquired results as the foundation for writing and submitting research proposals to the NIH and/or similar peer-reviewed funding agencies.
About the Israel Cancer Research Fund
Israel Cancer Research Fund, a 501(c)(3) organization, is the largest nationwide charitable organization in North America solely devoted to supporting cancer research in Israel. Since its establishment in 1975, ICRF has provided more than 2,200 grants to outstanding cancer researchers whose laboratories are located in all of the leading research institutions, universities and hospitals across Israel. For more information, visit www.icrfonline.org.