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Principal Investigator: WADIH ARAP
Organization: RBHS -CANCER INSTITUTE OF NEW JERSEY
Fiscal Year: 2021
Award: $642,358
Funding agency: National Cancer Institute
ABSTRACT
Eight percent of patients diagnosed with prostate cancer progress to lethal metastatic disease. Development of
resistance to androgen-deprivation therapy and eventually, to last line chemotherapeutics such as
enzalutamide (ENZ), contribute to lethal, metastatic prostate cancer. While interest to identify tumor-specific
molecular signatures, termed precision medicine, is gaining popular favor, it requires identification of
physiologically accessible targets. By diverting the function of a molecular tumor target by conventional anti-
cancer drugs, rates of tumor growth are expected to decrease; however, this does not take into account
acquired drug resistance mechanisms which are dependent on systemic drug stability, solubility or toxicity.
One method to stabilize poorly soluble and/or highly toxic drugs, and potentially overcome resistance, is to
encapsulate drugs in nanoparticles (NPs) to prevent their degradation and enhance their circulation time.
Moreover, accumulation of loaded NPs at the tumor site can be improved by adding tumor-specific targeting
moieties that induce NP endocytosis, thereby improving the therapeutic index while minimizing collateral
damage to healthy cells. A prostate tumor-specific biomarker, the 78 kDa glucose-regulated protein (GRP78),
was identified by the Pasqualini and Arap team by screening antibodies from prostate cancer patient sera.
GRP78 is a biomarker of disease progression and, crucial to our proposed research, we recently identified
human recombinant anti-GRP78 antibodies with optimal in vivo tumor targeting. In this proposal, our objective
is to generate GRP78-targeted NPs against ENZ-resistant prostate cancer. We will employ the novel, modular
“protocell” platform developed by the Brinker team. Protocells consist of a porous silica core, which can be
engineered to accommodate varied and combination cargos, encapsulated within a supported lipid bilayer that
protects and retains the cargo, and provides a biocompatible surface for conjugation to targeting and/or
trafficking ligands. The Brinker team demonstrated exceptional stability of targeted, first-generation protocells
in vivo with specific binding and cargo delivery to individual circulating leukemia cells. Instead of delivering
chemotherapeutic drugs that work at the protein level, we propose to deliver small interfering RNAs (siRNAs)
directed against the long non-coding RNA, PCA3. We showed that interfering with PCA3 inhibits growth of
human prostate xenografts. Guided by predictive modeling conducted by the Cristini team, our modular
GRP78-targeted protocells will be designed to package PCA3 siRNAs to selectively bind to GRP78-expressing
prostate cancer cells, and deliver PCA3 siRNAs intracellularly to inhibit tumor growth. Our project is a first-in-
field study that galvanizes our current combined expertise and technology. The dual prostate tumor “centric”
feature of these next generation NP prototype platforms increases their specificity and efficacy, and overcomes
the limitation of conventional standard-of-care drugs, particularly in the case of acquired drug resistance.
Terms: <14-Hydroxydaunomycin><3-D><3-Dimensional><3D><Adriamycine><Affect><Anti-Cancer Agents><Antibodies><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Area><Binding><Biodistribution><Biological Markers><Blood Circulation><Bloodstream><Body Tissues><Breast Neoplasms><Breast Tumors><Cancer Drug><Cancer Patient><Cancer Treatment><Cell Body><Cells><Chelating Agents><Chelators><Chemistry><Circulation><Clinical Trials><Complex><Complexons><Confocal Microscopy><Cristobalite><Data Analyses><Data Analysis><Development><Diagnosis><Diffusion><Disease><Disease Progression><Disorder><Dose><Doxorubicin><Doxorubicina><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Stability><Drug resistance><Drugs><Encapsulated><Endocytosis><Engineering><Environment><Equation><Fluorescence Agents><Fluorescent Agents><Fluorescent Dyes><Formulation><Functional RNA><Generalized Growth><Generations><Growth><Heterograft><Heterologous Transplantation><Histology><Human><Hybrids><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Individual><LNCaP><Label><Ligands><Lipid Bilayers><Liposomal><Liposomes><Macrogols><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mammary Cancer><Mammary Neoplasms><Math><Math Models><Mathematics><Medication><Metastatic Prostate Cancer><Methods><Modeling><Modern Man><Modification><Molecular><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><Neoplastic Disease Chemotherapeutic Agents><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acids><Paper><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Physiologic><Physiological><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Property><Prostate><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Carcinoma Metastatic><Prostate Gland><Prostate Neoplasms><Prostate Tumor><Prostatic Cancer><Prostatic Gland><Prostatic Neoplasia><Prostatic Neoplasms><Proteins><Publishing><Radio><Reaction><Recombinants><Research><Resistance><Resistance development><Resistant development><Resolution><SPECT><SPECT imaging><Safety><Sand><Shapes><Short interfering RNA><Silica><Silicon Dioxide><Single-Photon Emission-Computed Radionuclide Tomography><Site><Small Interfering RNA><Solid Neoplasm><Solid Tumor><Solubility><Specificity><Structure><Structure-Activity Relationship><Surface><TM-MKR><Technology><Testing><Therapeutic><Therapeutic Index><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Translations><Transmission Electron Microscopy><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treatment outcome><Treatment-related toxicity><Tridymite><Tumor Cell><Tumor Markers><Tumor Suppressor Proteins><Tumor-Specific Treatment Agents><Untranslated RNA><Validation><Variant><Variation><Work><Xenograft><Xenograft procedure><Xenotransplantation><acquired drug resistance><androgen ablation therapy><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><anti-cancer drug><anti-cancer therapy><anticancer agent><anticancer drug><anticancer therapy><base><bio-markers><biocompatibility><biologic marker><biomarker><biomaterial compatibility><cancer therapy><cancer-directed therapy><chemical structure function><circulating leukemia cell><clinical applicability><clinical application><computer based prediction><cytotoxic><data interpretation><design><designing><developing resistance><developmental><drug resistant><drug/agent><field based data><field learning><field study><field test><fluorescent dye/probe><glucose-regulated proteins><imaging><improved><in vivo><insight><interest><intervention efficacy><lead candidate><light scattering><lipid bilayer membrane><mammary tumor><mathematic model><mathematical model><mathematical modeling><molecular profile><molecular signature><multi-scale modeling><multiscale modeling><nano><nano carrier><nano medicinal><nano medicine><nano particle><nano particle delivery><nano particle drug><nano-sized particle><nanocarrier><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanoparticle drug><nanosized particle><nanotechnology platform><neoplastic cell><next generation><noncoding><novel><ontogeny><overexpress><overexpression><particle><precision medicine><precision-based medicine><prediction model><predictive modeling><prevent><preventing><prostate cancer cell><prostate cancer treatment><prostate tumor cell><prototype><real-time images><realtime image><resistance mechanism><resistance to Drug><resistant><resistant mechanism><resistant to Drug><screening><siRNA><single photon emission computed tomography><site targeted delivery><standard of care><structure function relationship><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic nanoparticles><therapeutic outcome><therapeutic toxicity><therapy efficacy><therapy outcome><therapy toxicity><three dimensional><trafficking><treatment toxicity><tumor><tumor biomarker><tumor growth><tumor specific biomarker><tumor suppressor><tumor xenograft><xeno-transplant><xeno-transplantation>