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Principal Investigator: Oleh Taratula
Organization: OREGON STATE UNIVERSITY
Fiscal Year: 2024
Award: $438,608
Funding agency: National Cancer Institute
Project Summary
Cachexia is a debilitating metabolic disorder that affects 50% of all cancer patients. Numerous clinical trials
confirmed that the wasting of skeletal muscle mass is the hallmark of cachexia. During the course of the R37
parent grant, the research team developed the first messenger RNA (mRNA) therapy for metastatic ovarian
cancer and cachexia-induced muscle wasting. It is based on lipid nanoparticles (LNPs) that deliver follistatin
mRNA predominantly to cancer cells following intraperitoneal administration. The secreted follistatin protein,
endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with
aggressive ovarian cancer and ameliorates cachexia in this condition. By altering the cancer cell phenotype,
mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors,
and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally,
the mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and
counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia.
Recent literature demonstrates that activin A increases the metastatic potential and decreases survival in head
and neck cancers. Therefore, the research team will assess the efficacy of the developed mRNA therapy to
reduce metastasis and preserve muscle mass in a new preclinical model of metastatic head-and-neck carcinoma
that readily metastasizes to the lung and exhibits all the hallmark features of human cachexia.
Whilst the loss of lean muscle mass is the hallmark of cancer cachexia, treatment for cachectic patients must
also comprise therapeutic strategies that target systemic inflammation and stimulate appetite to ensure adequate
energy and protein consumption. The research team will also develop the appetite-stimulatory therapy based on
the above-discussed LNPs loaded with mRNA coding for both ghrelin and its specific O-acyltransferase (GOAT,
required for full ghrelin activation). Previous reports suggest that ghrelin, a gut-secreted hormone, is a potential
therapeutic agent for the treatment of appetite and weight loss in patients with cachexia. The proposed study will
evaluate the efficacy of ghrelin mRNA-based therapy to improve food intake, body composition, and survival in
a murine pancreatic cancer model of cachexia. Finally, anti-inflammatory therapy for the treatment of systemic
inflammation in cancer cachexia will be developed using anti-inflammatory drug-loaded nanoparticles that
accumulate efficiently at the site of inflammation following systemic administration. The research team has
already constructed polymeric nanoparticles equipped with peptides as a targeting moiety for vascular cell
adhesion molecule 1 (VCAM1) that is overexpressed in endothelial cells during inflammatory insults, with
particularly high expression in hypothalamic centers regulating appetite. The efficacy of these IRAK4 inhibitor-
loaded nanoparticles to reduce hypothalamic inflammation and increase food intake will be evaluated in the
above-discussed murine pancreatic cancer model.
Terms: <Activin-Binding Protein><Activins><Acyltransferase><Affect><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Appetite><Appetite stimulated><Applications Grants><Attenuated><Behavior><Behavioral><Binding><Blood Serum><Body Composition><Body Weight decreased><CD106><CD106 Antigens><CDDP><Cachectic><Cachexia><Cancer Cachexia><Cancer Model><Cancer Patient><Cancer Treatment><CancerModel><Cancers><Cause of Death><Cell Body><Cells><Circulation><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical Trials><Code><Coding System><Consumption><Cysplatyna><Data><Desire for food><Dichlorodiammineplatinum><Differentiation and Growth><Disease><Disorder><Drugs><EC 2.3><EYDF><Eating><Embryonic Muscle Cells><Endocrine Gland Secretion><Endothelial Cells><Ensure><Exhibits><FSH-Releasing Protein><Fats><Fatty acid glycerol esters><Follistatin><Food Intake><Gene Delivery><Glycoproteins><Goals><Grant Proposals><Head and Neck Cancer><Head and Neck Carcinoma><Health><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hormone secretion><Hormones><Human><Hypothalamic structure><Hypothalamus><INCAM-110><IRAK4><IRAK4 gene><Increased food appetite><Inducible Cell Adhesion Molecule 110><Inflammation><Inflammatory><Interleukin-1 Receptor-Associated Kinase 4><Intravenous><Investigators><Kupffer Cells><Leanness><Literature><Liver><Liver Cells><Lung><Lung Respiratory System><Malignant Cell><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant neoplasm of lung><Malignant neoplasm of ovary><Mediating><Medication><Messenger RNA><Metabolic><Metabolic Diseases><Metabolic Disorder><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Lung><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Muscle Atrophy><Muscular Atrophy><Myoblasts><NY-REN-64><Nanoplatform><Nanotechnological platform><Neoplasm Metastasis><Nutritional Support><Ovary Cancer><PDA model><PDAC Model><Pancreas><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Ductal Adenocarcinoma><Patients><Peptides><Persons><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Preparations><Phenotype><Platinum Diamminodichloride><Play><Pre-Clinical Model><Preclinical Models><Precursor Muscle Cells><Production><Proliferating><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><QOL><Quality of life><REN64><RNA based therapeutics><RNA based therapy><RNA therapy><Receptor Protein><Reporting><Research><Research Personnel><Researchers><Role><Route><Secondary Neoplasm><Secondary Tumor><Serum><Site><Skeletal Muscle><Solid Neoplasm><Solid Tumor><Stellate Sinusoidal Macrophage><Stomach><Subcutaneous Injections><Syndrome><System><Technology><Testing><Therapeutic><Therapeutic Agents><Therapeutic Hormone><Thesaurismosis><Thinness><Toxic effect><Toxicities><Treatment Efficacy><Treatment outcome><VCAM><VCAM-1><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><Voluntary Muscle><Weight Loss><Weight Reduction><Wild Type Mouse><activin A><antagonism><antagonist><anti-cancer therapy><appetite loss><attenuate><attenuates><body weight loss><cancer associated cachexia><cancer cell><cancer induced cachexia><cancer metastasis><cancer progression><cancer therapy><cancer-associated muscle wasting><cancer-directed therapy><cancer-induced muscle atrophy><cancer-induced muscle loss><cancer-induced muscle wasting><cancer-related cachexia><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><determine efficacy><differentiation factors><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><energy balance><erythroid differentiation factor><erythroid differentiation protein><evaluate efficacy><examine efficacy><gastric><ghrelin><head/neck cancer><hepatic body system><hepatic organ system><homo-activin A><hormonal secretion><hypothalamic><improved><increased appetite><increased hunger><inhibitor><intervention efficacy><intraperitoneal><intravenous administration><intravenous injection><lean body mass><lipid based nanoparticle><lipid nanoparticle><liver macrophage><lung cancer><lung metastasis><mRNA><mRNA delivery><malignancy><malignant ascites><malignant head and neck tumor><messenger RNA delivery><metabolism disorder><metastasize to the lung><morphogenic factors><morphogens><mouse model><murine model><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle wasting><nano medicinal><nano medicine><nano particle><nano particle delivery><nano polymer><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanopolymer><nanosized particle><nanotechnology platform><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><nutritional care><nutritional therapy><ovarian cancer><overexpress><overexpression><pancreatic cancer model><pancreatic ductal adenocarcinoma model><pancreatic tumor model><parent grant><pharmacologic><physical impairment><pre-clinical study><preclinical study><preservation><prevent><preventing><pulmonary><pulmonary metastasis><receptor><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><skeletal preservation><social role><subcutaneous><subdermal><subdermal injection><systemic inflammation><systemic inflammatory response><therapeutic RNA><therapeutic efficacy><therapy efficacy><translational opportunities><translational potential><translational therapeutics><translational therapy><tumor><tumor cell metastasis><tumor progression><tumor-induced cachexia><tumor-induced muscle wasting><validation studies><wildtype mouse><wt-loss>