Brookfield, CT, United States
Brookfield, CT, United States

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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.


Backer M.V.,Sibtech, Inc. | Backer J.M.,Sibtech, Inc.
Theranostics | Year: 2012

Angiogenesis is a fundamental requirement for tumor growth and therefore it is a primary target for anti-cancer therapy. Molecular imaging of angiogenesis may provide novel oppor-tunities for early diagnostic and for image-guided optimization and management of therapeutic regimens. Here we reviewed the advances in targeted imaging of key biomarkers of tumor angiogenesis, integrins and receptors for vascular endothelial growth factor (VEGF). Tracers for targeted imaging of these biomarkers in different imaging modalities are now reasonably well-developed and PET tracers for integrin imaging are currently in clinical trials. Molecular imaging of longitudinal responses to anti-angiogenic therapy in model tumor systems revealed a complex pattern of changes in targeted tracer accumulation in tumor, which reflects drug-induced tumor regression followed by vascular rebound. Further work will define the competitiveness of targeted imaging of key angiogenesis markers for early diagnostic and image-guided therapy. © Ivyspring International Publisher.


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


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: | Program: SBIR | Phase: Phase I | Award Amount: 224.94K | Year: 2014

Not Available


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: 385.46K | Year: 2010

DESCRIPTION (provided by applicant): Myocardial infarction is a disabling disease, with infarct size being a major determinant of mortality. To limit infarct size and improve functional recovery, the ischemic myocardium has to be reperfused. However, reperfusion itself causes irreversible damage to the previously ischemic myocardium. A significant part of cardiac injury is caused by apoptosis that starts immediately at the beginning of reperfusion. Therefore, reperfusion injury is considered an important new pharmacologic target for the treatment of patients with ongoing acute myocardial infarction. We propose to develop a targeted liposomal formulation of two drugs proven to protect myocardium through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocytes at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with myocardial infarction. The advantages of the proposed strategy are: 1) delivery of pharmacologically significant amounts of drugs in cardiomyocytes from the first moments of reperfusion, when apoptosis is still reversible, 2) avoiding adverse effects of high-dose regimens that are necessary for free drugs, and 3) intracellular delivery of two drugs working via independent mechanisms increases the probability of successful treatment. Targeted drug-loaded liposomes will be evaluated in primary cultures of cardiomyocytes. We will establish mechanism(s) of internalization in early apoptotic cells and evaluate the therapeutic potential of annexin-targeted drug-loaded liposomes. Biodistribution, targeted drug delivery and the protective effects of the liposomes in vivo will be studied in a mouse model of myocardial ischemia/reperfusion. If successful, the proposed strategy will establish the feasibility of using annexin- targeted therapeutic liposomes as an adjunct therapy for myocardial infarction. It will also advance new technologies in developing therapeutic liposomes for targeted delivery to early-stage apoptotic cells. PUBLIC HEALTH RELEVANCE: We propose to test feasibility of developing a targeted liposomal formulation for two drugs proven to protect ischemic myocardium from lethal reperfusion injury through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocites at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with acute myocardial infarction.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 286.92K | Year: 2011

DESCRIPTION (provided by applicant): We propose to develop a contrast agent for photoacoustic imaging targeted to the receptors of vascular endothelial growth factor (VEGFR), so it can be accumulated and retained in tumor endothelial cells by VEGFR-mediated endocytosis. VEGFR are over expressed in angiogenic tumor vasculature from the very early stages of tumor development and therefore VEGFR imaging can be used for early diagnosis as well as for image-guided optimization and management of anti-angiogenic therapy. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection of abnormal levels of VEGFR in vivo by photoacoustic imaging, we will multiplex near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then conjugate the derivatized dendrimer to VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. For this project we combine the expertise and achievements of three groups, the experts in developing of targeted tracers for imaging of VEGFR in angiogenic vasculature, innovative imaging hardware and software for photoacoustic imaging of tumor lesions, and novel derivatives of ICG for imaging.This study will provide the first-in-class targeted PAI tracer and establish the feasibility of targeted photoacoustic imaging of VEGF receptors in tumor vasculature. If successful, might provide a safe and cost-effective alternative to nuclear imaging for cancerous lesions located at the depths less than 2-3 cm. In Phase II we will establish feasibility of this tracer for early diagnostic of relatively deep tumor lesions, discrimination of malignant and benign lesions, and perform late pre-clinical development of the tracer. PUBLIC HEALTH RELEVANCE: Receptors of vascular endothelial growth factor (VEGFR) are over expressed in angiogenic tumor vasculature from the very early stages of tumor development, therefore VEGFR imaging can be used for early diagnosis and image-guided optimization of anti-angiogenic therapy. We propose to develop a contrast agent for photoacoustic imaging that will be targeted to these receptors, so it can be accumulated and retained in tumor endothelial cells by specific receptor-mediated endocytosis. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection, we will multiplex a near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then site-specifically conjugate the derivatized dendrimer to targeting protein, VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. Thus study will provide the first-in-class targeted tracer for photoacoustic imaging of VEGFR, and might enable a safe, cost-effective alternative to nuclear imaging for detection of cancerous lesions located at the depths less than 2-3 cm.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.79M | Year: 2011

DESCRIPTION (provided by applicant): Currently available anti-angiogenic drugs inhibit VEGF/VEGFR signaling, which leads to transient vascular regression followed by rebound of drug-resistant vasculature, which significantly decrease the therapeutic efficacy of very expensive anti-angiogenic treatment. To overcome this problem, we are developing a cytotoxic 177Lu radiopharmaceutical, scVEGF/Lu. This radiopharmaceutical is based on engineered single-chain VEGF (scVEGF) and it accumulates in tumor endothelialcells via endocytosis mediated by overexpressed VEGFR-2. In Phase I we optimized the composition of scVEGF/Lu, assessed its radiotoxicity and dosimetry and performed initial therapeutic efficacy and mechanistic studies in orthotopic breast tumor models. Our results demonstrate that a single injection of a safe dose of scVEGF/Lu induces destruction of tumor vasculature sustainable for at least 30-35 days and a widespread apoptosis in tumor without significant overall radiotoxicity. In contrast, FDA-approvedsunitinib and bevacizumab failed to induce sustainable destruction of tumor vasculature, suggesting potential advantages of scVEGF/Lu. In Phase II we will focus on late pre-clinical development of scVEGF/Lu as a novel component of anti- angiogenic therapy, using orthotopic mouse models of recurrent breast cancer, including a model of human triple negative breast cancer. First, we will establish the dose- and time-dependences for scVEGF/Lu-induced destruction of tumor vasculature and potential roles of overexpressed endogenous VEGF and immunocompetent environment in therapeutic efficacy of scVEGF/Lu. Next, we will establish optimal sequence for scVEGF/Lu-doxorubicin combination as adjuvant therapy for recurrent breast cancer. Considering that scVEGF is a physiologically active protein, we will also establish the safety profile for scVEGF-PEG-DOTA conjugate. We expect that by the end of Phase II of the project we will have evidence-based indications for safe use of scVEGF/Lu in adjuvant anti-angiogenic therapy for breast cancer. We will also have a GLP-grade for dosimetry studies. This data will be used for filing IND or eIND with FDA for Phase I clinical trials with scVEGF/Lu in breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer, and eventually will be explored for treatment of other cancers. PUBLIC HEALTH RELEVANCE: To increase the efficacy anti-angiogenic therapy, it is necessary to sustain tumor vascular regression and to inhibit vascular rebound. For this, we develop a novel 177Lu radiopharmaceutical, scVEGF/Lu, which delivers lethal doses of 177Lu in tumor endothelial cells. In orthotopic models of breast cancer, scVEGF/Lu induces destruction of tumor vasculature and widespread apoptosis in tumor, without significant overall radiotoxicity. In this project we will evaluate the potential of scVEGF/Lu as a novel component of anti-angiogenic therapy that could make a significant impact on outcome of triple negative breast cancer. We expect that this study will provide evidence-based indications for safe use of scVEGF/Lu as a mono- or combination therapy as adjuvant therapy for breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer and eventually will be explored for treatment of other cancers.

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