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Principal Investigator: Andrea L Kasinski
Organization: PURDUE UNIVERSITY
Fiscal Year: 2023
Award: $386,276
Funding agency: National Cancer Institute
PROJECT SUMMARY
Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA
therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical
impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of
two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to
the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years
of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this
space is attributed to inability to deliver RNAi safely and effectively. We previously developed a method that can
safely deliver therapeutic microRNAs (miRNAs) to tumors that overexpress the folate receptor. However, the
anti-tumor response was short-lived due to instability of the miRNA and poor pharmacokinetics, necessitating
frequent dosing. To overcome these insufficiencies requires a stabilized miRNA that retains targeting activity.
Recently we screened a panel of fully modified versions of miR-34a (FM-miR-34a) and identified one with >400-
fold increased stability and outstanding in vivo efficacy when conjugated to folate. Treatment of mice implanted
with breast cancer xenografts with folate-FM-miR-34a resulted in complete cures in two out of six mice and
significant tumor regression in the remaining four. Based on this exciting data, here we propose to advance FM-
miR-34 forward in two ways. In Aim 1 we will evaluate the activity, efficacy, and safety profile of FM-miR-34a in
in vivo models of lung and prostate cancer. FM-miR-34a will be conjugated to: i) folate for delivery to lung cancer,
and ii) PSMA-617, a ligand that targets prostate specific membrane antigen (PSMA) for delivery to prostate
cancer. In Aim 2 we propose to capitalize on the stability afforded by FM-miR-34 to increase the circulation ½
time of folate-FM-miR-34 and PSMA-617-FM-miR-34a though incorporating an albumin binding moiety (ABM)
into the ligands. Using these ligands we will evaluate serum albumin binding and stability of the new ligands. We
will also verify that conjugation to ABM does not alter the activity of miR-34a nor cell binding and internalization
kinetics. Finally, we will assess in vivo distribution of ligand-ABM-miR-34a conjugates.
At the completion of this work we expect to have an all-encompassing miRNA delivery vehicle that can
target a stabilized tumor suppressive RNAs specifically to NSCLC and prostate cancer. We will also have new
ligands with increased circulation ½ life. The data obtained will ultimately have a significant impact in cancer
treatment by providing new opportunities to advance the next phase of miRNA-based therapeutics. While
proposed for NSCLC and prostate cancer, based on the utility of miR-34a for treating other cancers and
overexpression of the folate receptor alone on many epithelial cancers, including ovary, kidney, and colon
cancers, successful completion of this study could have far-reaching positive consequences.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Affinity><Albumins><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antitumor Response><Binding><Biodistribution><Blood Serum><Breast Cancer><COVID-19 virus><COVID19 virus><Cancer Drug><Cancer Treatment><Cancers><Carcinoma><Cell Body><Cells><Circulation><Clinic><Clinical><CoV-2><CoV2><Colon Cancer><Colon Carcinoma><Coupling><Data><Diagnostic><Disease><Disorder><Dose><Drug Kinetics><Drug Targeting><Epithelial cancer><FDA approved><FOLH><FOLH1><FOLH1 gene><Folate><Folate Hydrolase 1><Folic Acid><Funding><GCP2><Gene Targeting><Generations><Glutamate Carboxypeptidase II><Goals><Half-Life><Heterograft><Heterologous Transplantation><Hour><Implant><Kidney Cancer><Kidney Carcinoma><Kinetics><Lead><Life><Ligands><Liver><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><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 Tumor of the Prostate><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Mission><Molecular Interaction><Murine><Mus><N-Acetylated Alpha-Linked Acidic Dipeptidase 1><NAALAD1><NAALADase I><NIH><NSCLC><NSCLC - Non-Small Cell Lung Cancer><National Institutes of Health><Neoplastic Disease Chemotherapeutic Agents><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Oncology><Oncology Cancer><Ovary Cancer><PSM><PSMA><Pb element><Pharmacokinetics><Phase><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Property><Prostate CA><Prostate Cancer><Prostate malignancy><Prostate-Specific Membrane Antigen><Prostatic Cancer><Pteroylglutamic Acid><Public Health><Pulmonary Cancer><Pulmonary malignant Neoplasm><Quelling><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA therapy><RNA vaccine><RNA-based vaccine><RNAi><Renal Cancer><Renal carcinoma><Renal clearance function><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Serum Albumin><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Small RNA><Specificity><Testing><Therapeutic Agents><Therapeutic antibodies><Time><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor-Specific Treatment Agents><United States National Institutes of Health><Vitamin M><Work><Wuhan coronavirus><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer drug><anti-cancer therapy><anti-tumor response><anticancer agent><anticancer drug><anticancer therapy><cancer cell><cancer in the colon><cancer therapy><cancer-directed therapy><coronavirus disease 2019 virus><coronavirus disease-19 virus><delivery vector><delivery vehicle><epithelial carcinoma><folate carrier><folate receptor><folate-binding protein><folate-methotrexate transporter><folic acid binding protein><folic acid receptor><hCoV19><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><improved><in vivo><in vivo Model><lung cancer><mRNA vaccine><mRNA-based vaccine><malignancy><malignant breast neoplasm><malignant breast tumor><methotrexate-binding protein><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA delivery><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA delivery><microRNA-based therapeutic><microRNA-based therapy><nCoV2><neoplasm/cancer><nuclease><ovarian cancer><overexpress><overexpression><prevent><preventing><prostate cancer cell><prostate tumor cell><renal clearance><risk mitigation><safety study><success><therapeutic RNA><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><tumor><uptake><vitamin Bc><xeno-transplant><xeno-transplantation>