Clone of Cancer Research Scholars Program 2017-2018 Funded Collaborations

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.

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.

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.