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Brookfield, CT, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.83K | Year: 2015

DESCRIPTION provided by applicant The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to tumor associated macrophages TAMs TAMs are the major component of tumor microenvironment that generally supports tumor growth and interferes with anti tumor therapy These effects are significantly mediated by about of TAMs that are located in tumor perivascular areas and are the major source of pro tumorigenic and pro angiogenic mediators specifically implicated in promotion of tumor angiogenesis and metastatic dissemination There is evidence that various re programming cues can be used to reduce the pro tumorigenic potential of TAMs creating an opportunity for more efficient anti cancer therapy To target perivascular TAMs we selected liposomal formulations of a TLR ligand poly I C that we named Lip PIC The TLR activation stimulates re polarization in TAMs which appears to be relatively safe as it is being developed for various vaccination protocols and at the same time rather efficient in tumor growth inhibition at least in animal tumor models We reasoned that Lip PIC would extravasate through the leaky tumor vasculature to perivascular space the very area of the location of perivascular TAMs To further increase the probability of targeted drug delivery to TAMs we propose to test Lip PIC decorated with annexin V that targets tumor cells undergoing apoptosis Pro tumorigenic TAMs are the known andquot eatersandquot of tumor apoptotic cells presenting an opportunity to use tumor apoptotic cells as andquot Trojan Horseandquot to feed Lip PIC to TAMs Given the complexity of tumor microenvironment that is impossible to reconstruct in tissue culture we reasoned that only in vivo system would be adequate for the proposed proof of principle experiments Therefore we will test our approach in orthotopic T luc mouse breast tumor xenografts in immunocompetent Balb c mice Our Specific Aims are Specific Aim Evaluate the effects of delivery of liposomal poly I C formulation to perivascular TAMs in a breast cancer tumor model Specific Aim Establish if delivery of liposomal poly I C to TAMs could be enhanced by recruitment of apoptotic cells indoxorubicin treated breast cancer model Accomplishing these Specific Aims will provide a proof of principle for using liposomal formulations for delivery of re programming drugs to perivascular TAMs in vivo We envision that the eventual commercial product will be a proprietary optimized liposomal formulation for targeting perivascular TAMs in primary tumor as a part of combination anti cancer therapy PUBLIC HEALTH RELEVANCE The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to specific cells in tumor microenvironment in order decrease their tumor supporting potential and increase their tumor fighting capabilities Two strategies will be tested one based on delivering liposomal drugs to the same andquot neighborhoodandquot where tumor supporting cells reside and the other based on targeting liposomal drugs to dying tumor cells that are expected to serve as andquot Trojan Horseandquot in feeding pro tumorigenic cells in tumor microenvironment


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 222.92K | Year: 2014

The overall goal of this collaborative Fast-Track project is clinical development of a novel 18F PET tracer for molecular imaging of receptors for vascular endothelial growth factor (VEGFR). This receptor is the major anti-angiogenic drug target in oncology patients. Critically, VEGFR prevalence decreases when VEGF/VEGFR anti-angiogenic inhibitors work , and increases when these drugs stop working . These findings provide a rationale for VEGFR imaging for image-guided anti-angiogenic therapy. To provide for high selectivity, specificity, and VEGFR-mediated intracellular accumulation, the 18F PET tracer will be targeted by VEGFR ligand, scVEGF. The protein will be site-specifically derivatized with a strained alkyne for copper-free click- chemistry radiolabeling with 18F-PEG(4)-azide. In Phase I of this project we will select the lead scVEGF/Alkyne conjugate, optimize conditions for 18F radiolabeling, and validate the use of lead tracer for monitoring anti- angiogenic therapy in a murine model of triple neg


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.47M | Year: 2015

DESCRIPTION provided by applicant The overall goal of this collaborative Fast Track project is clinical development of a novel F PET tracer for molecular imaging of receptors for vascular endothelial growth factor VEGFR This receptor is the major anti angiogenic drug target in oncology patients Critically VEGFR prevalence decreases when VEGF VEGFR anti angiogenic inhibitors andquot workandquot and increases when these drugs stop andquot workingandquot These findings provide a rationale for VEGFR imaging for image guided anti angiogenic therapy To provide for high selectivity specificity and VEGFR mediated intracellular accumulation the F PET tracer will be targeted by VEGFR ligand scVEGF The protein will be site specifically derivatized with a strained alkyne for copper free click chemistry radiolabeling with F PEG aside In Phase I of this project we will select the lead scVEGF Alkyne conjugate optimize conditions for F radiolabeling and validate the use of lead tracer for monitoring anti angiogenic therapy in a murine model of triple negative breast cancer In Phase II we will produce cGMP grade conjugate undertake FDA required toxicology and dosimetry studies and proceed to Phase I clinical trials in healthy volunteers PUBLIC HEALTH RELEVANCE We propose to develop a novel first in class F PET tracer for molecular imaging of receptors for vascular endothelial growth factor which are the major drug targets in tumor neovasculature The Fast Track project involves preclinical development of click chemistry F radiolabeling of a novel protein based conjugate cGMP production pre clinical toxicology dosimetry and Phase I clinical trials in healthy volunteers


Backer M.V.,Sibtech, Inc. | Backer J.M.,Sibtech, Inc. | Chinnaiyan P.,H. Lee Moffitt Cancer Center and Research Institute
Methods in Enzymology | Year: 2011

Rapid growth of tumor cells coupled with inadequate vascularization leads to shortage of oxygen and nutrients. The unfolded protein response (UPR), a defense cellular mechanism activated during such stress conditions, is a complex process that includes upregulation of the endoplasmic reticulum chaperones, such as glucose-regulated protein 78 (GRP78). Due to its central role in UPR, GRP78 is overexpressed in many cancers; it is implicated in cancer cell survival through supporting of drug-and radioresistance as well as metastatic dissemination, and is generally associated with poor outcome. This is the reason why selective destruction of GRP78 could become a novel anticancer strategy. GRP78 is the only known substrate of the proteolytic A subunit (SubA) of a bacterial AB 5 toxin, and the selective SubA-induced cleavage of GRP78 leads to massive cell death. Targeted delivery of SubA into cancer cells via specific receptor-mediated endocytosis could be a suitable strategy for assaulting tumor cells. We fused SubA to epidermal growth factor (EGF), whose receptor (EGFR) is frequently overexpressed in tumor cells, and demonstrated that the resulting EGFSubA immunotoxin is an effective killer of EGFR-positive tumor cells. Furthermore, because of its unique mechanism of action, EGFSubA synergizes with UPR-inducing drugs, which opens a possibility for the development of mechanism-based combination regimens for effective anticancer therapy. In this chapter, we provide experimental protocols for the assessment of the effects of EGFSubA on EGFR-positive cancer cells, either alone or in combination with UPR-inducing drugs. © 2011 Elsevier Inc. Source

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