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Principal Investigator: MARSHA A MOSES
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $248,243
Funding agency: National Cancer Institute
Project Summary/Abstract
Pancreatic cancer (PC) is one of the most lethal forms of cancer in the United States (5-year survival rate
below 10%). PC patients are usually diagnosed with a non-resectable disease (80-85%) and have a dismal
prognosis with a survival period of only 3-6 months after the diagnosis. Nucleoside analogs (e.g., gemcitabine
and fluorouracil) and platinum-based antineoplastics (e.g., oxaliplatin) are commonly used as chemotherapy
for PC. When administered as free drugs, gemcitabine (Gem), fluorouracil (5-FU) and oxaliplatin (Oxa) display
significant off-target toxicity causing life-threatening adverse effects in many patients. There is an urgent need
to develop new therapeutic strategies consisting of delivery vehicles able to target PC cells, limit Gem, 5-FU
and Oxa off-target toxicity and improve the overall anticancer response.
We have recently patented a platform that uses an unbiased and quantitative screening algorithm for the
discovery and validation of cancer-specific surface antigens. Our recently published results show that
Intercellular Adhesion Molecule 1 (ICAM1), a transmembrane glycoprotein of the immunoglobulin superfamily,
is aberrantly overexpressed in PC and can serve as a PC-specific target. Our results suggest that developing
a novel ICAM1-based precision nanomedicine can be successfully utilized to treat PC patients.
We have recently developed a magnetic extrusion technique to synthesize endosome-derived vesicles
called exosome mimetics (EMs) in a highly efficient and reproducible manner. Our EMs share the same
biological origin, morphology, nanosize and composition with exosomes, a class of natural cell-secreted
extracellular vesicles. Our EM synthesis outperforms conventionally used exosome isolation and loading
protocols in terms of particle yield, batch-to-batch consistency, reproducibility and loading efficiency.
In this proposal,we leverage our expertise in cancer-specific antigen discovery and validation, bio-
nanomaterial engineering, and exosome biology to test the novel hypothesis that EMs expressing ICAM1
nanobody and loaded with Gem, 5-FU and Oxa can be used as a novel delivery vehicle for PC therapy. We
will synthesize EMs engineered with ICAM1 nanobodies that recognize and kill ICAM1-expressing PC cells
and load them with Gem, 5-FU and Oxa. ICAM1-EM will exhibit increased tumor specificity and reduce Gem,
5FU and Oxa off-target delivery and toxicity. These innovative studies have the potential to lead to the
development of novel EM-based therapies that can improve the efficacy of current cancer drug delivery.
With key experimental tools, in vivo models and extensive experience in place, we will address the
following Specific Aims:
1. To engineer ICAM1-targeted exosome mimetics (ICAM1-EMs) using magnetic extrusion method
2. To determine the efficacy of loaded ICAM1-Chemo-EMs in inhibiting PC growth and progression
3. To determine the pharmacokinetics (PK) and biodistribution of loaded ICAM1-Chemo-EMs
Terms: <1-OHP><5-FU><5-Fluracil><5FU><Ablation><Abscission><Address><Adjuvant><Adjuvant Chemotherapy><Adjuvant Drug Therapy><Adjuvant Therapy><Adverse effects><Algorithms><Animal Cancer Model><Anti-Cancer Agents><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Area><Biodistribution><Biological><Biology><CD54 Antigens><Cancer Cause><Cancer Drug><Cancer Etiology><Cancer Treatment><Cancers><Cell Body><Cell Communication><Cell Interaction><Cell Surface Antigens><Cell Surface Glycoproteins><Cell secretion><Cell surface><Cell-to-Cell Interaction><Cells><Cellular Secretion><Cessation of life><Clinical><Death><Development><Diagnosis><Difluorodeoxycytidine><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><EGF Receptor><EGFR><ERBB Protein><Electroporation><Endosomes><Engineering><Environment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Excision><Exhibits><Extirpation><Failure><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Generalized Growth><Goals><Growth><HER1><Heterogeneity><Human><Human Resources><Hypotension><ICAM><ICAM-1><Immune Globulins><Immune mediated therapy><Immunoglobulins><Immunologic Surface Markers><Immunological Surface Markers><Immunologically Directed Therapy><Immunotherapy><Induction Therapy><Intercellular adhesion molecule 1><Legal patent><Life><Lipid Bilayers><Liposomal><Liposomes><Low Blood Pressure><Magnetism><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Manpower><Measures><Medical><Medication><Membrane><Membrane Glycoproteins><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methods><Modern Man><Morphology><Myelosuppression><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplastic Disease Chemotherapeutic Agents><Normal Tissue><Normal tissue morphology><Operative Procedures><Operative Surgical Procedures><Organ><Pancreas Cancer><Pancreatic Cancer><Patents><Patients><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Platinum><Platinum Black><Preparation><Prognosis><Protocol><Protocols documentation><Pt element><Publishing><Receptosomes><Removal><Reproducibility><Scientist><Structure><Surface Antigens><Surface Glycoproteins><Surface Proteins><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survival Rate><TGF-alpha Receptor><Techniques><Testing><Therapeutic><Time><Tissue Growth><Toxic effect><Toxicities><Training><Transforming Growth Factor alpha Receptor><Tropism><Tumor Cell><Tumor-Specific Treatment Agents><Ultracentrifugation><United States><Urogastrone Receptor><Validation><Vascular Hypotensive Disorder><Vesicle><adjuvant treatment><anti-cancer><anti-cancer drug><anti-cancer therapy><aqueous><biologic><c-erbB-1><c-erbB-1 Protein><cancer diagnosis><cancer therapy><cancer type><cancer-directed therapy><chemotherapy><clinical translation><clinically translatable><dFdC><dFdCyd><delivery vector><delivery vehicle><density><determine efficacy><developmental><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><electroporative delivery><engineered exosomes><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><evaluate efficacy><examine efficacy><exosome><experience><extracellular vesicles><gemcitabine><gene electrotransfer><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><improved><in vivo><in vivo Model><induction therapies><innovate><innovation><innovative><instrument><intercellular cell adhesion molecule><lipid bilayer membrane><magnetic><malignancy><manufacture><membrane structure><mimetics><multidisciplinary><nano medicinal><nano medicine><nano particle><nano polymer><nano sized><nano vesicle><nano-sized particle><nanobodies><nanobody><nanomedicinal><nanomedicine><nanoparticle><nanopolymer><nanosized><nanosized particle><nanovesicle><neoplasm/cancer><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleoside analog><ontogeny><overexpress><overexpression><oxaliplatin><oxaliplatine><pancreas development><pancreatic cancer cells><pancreatic cancer patients><pancreatic malignancy><pancreatic tumor cells><particle><patient prognosis><patients with pancreatic cancer><personalized drugs><personnel><precision drugs><preparations><proto-oncogene protein c-erbB-1><resection><response><screening><screenings><sdAb><single domain antibodies><site targeted delivery><success><surgery><systemic toxicity><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutically effective><tool><tumor><tumor specificity><validations>