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Principal Investigator: Robert F Place
Organization: MIRECULE, INC.
Fiscal Year: 2020
Award: $1,000,000
Funding agency: National Cancer Institute
Abstract:
In this phase 2 SBIR application, miRecule proposes to develop a microRNA-based therapeutic mimic of miR-
30-5p (miRecule candidate MC-30) for the treatment of multi-drug resistant (MDR) cancers. Head and Neck
Squamous Cell Carcinoma (HNSCC) is the 6th most common form of cancer. Greater than half of patients
present with late stage III or IV disease, with an average 5-year survival rate of ~40%. HNSCC tumors have high
levels of genetic mutations leading to high tumor heterogeneity and drug resistance. miR-30-5p expression is
widely repressed in tumor tissues and MIR30 gene deletion is observed in ~30% of HNSCCs. Loss of miR-30-
5p expression correlates with poor survival outcome in 100% of Oropharyngeal HNSCC patients (OPSCC),
which represents our initial clinical population. miR-based therapeutics offer a disruptive approach for
treatment of MDR cancer by targeting both primary oncogenic pathways and mechanisms of intrinsic or
acquired resistance. EGFR targeted therapy is often compensated for by overexpression of growth factor
receptors (GFRs) MET and IGF1R. However, we have discovered that miR-30-5p simultaneously targets and
repress all three of these GFRs. The rationale for miR-30-5p replacement therapy is that it will be superior in its
ability to treat heterogeneous late-stage HNSCC due to its ability to regulate not only EGFR, but also MET, IGF-
1R, and over two dozen other mRNAs confirmed to be deregulated in tumor tissue and associated with
proliferation, adhesion, migration, extracellular matrix remodeling, and differentiation. In phase 1 of our SBIR,
we developed a chemically-modified mimic of miR-30-5p with >1000x improved nuclease stability and 5X activity
in HNSCC models compared to the natural microRNA. We also demonstrated simultaneous inhibition of a dozen
critical oncogenes in HNSCC with evidence that our mimic to can overcome cisplatin and EGFR-related drug
resistance. We also demonstrated that of our clinically validated LNP formulation, which targets solid tumors via
an scFv against the transferrin receptor (TfR), overcomes the challenge of delivery to cancer cells by having
activity at a low dose of 1 mg/kg in vivo. This was demonstrated in both biodistribution studies and four
different in vivo models of HNSCC that all showed strong sensitivity to MC-30. In this Phase II SBIR study,
we propose to: 1) Characterized PK/PD and non-GLP Tox studies of MC-30. 2) Create a compelling data
package that demonstrates dose-dependent efficacy of MC-30 in syngeneic and PDX models. 3) Demonstrate
the competitive advantage of MC-30 over approved cisplatin, cetuximab, and anti-PD-1 therapies with potential
for combination use. 4) Validate our proposed clinical population of OPSCC patients in a mini ex vivo clinical
trial. 5) Optimize scale-up, manufacturing, and CMC release tests for MC-30. The sum of these studies will
support filing an orphan drug application, enable our pre-IND meeting, guide our clinical development, and
validate outside investment in MC-30.
Terms: <3-D><3-Dimensional><3D><Adhesions><Animals><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Biodistribution><Biological><Blood><Blood Reticuloendothelial System><Body Tissues><CD71><CDDP><Cancer Genes><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cell Body><Cell-Extracellular Matrix><Cells><Cetuximab><Chemicals><Chemistry><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><Clinical Data><Clinical Trials><Combined Modality Therapy><Common Rat Strains><Cysplatyna><Cytotoxic Chemotherapy><Cytotoxic Therapy><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Development><Dichlorodiammineplatinum><Disease><Disorder><Dose><Drug resistance><Drugs><ECM><EGF Receptor><EGFR><ERBB Protein><Early-Stage Clinical Trials><Effectiveness><Encapsulated><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Extracellular Matrix><Family><Formulation><Gene Deletion><Genes><Genetic mutation><Genomics><Goals><Growth Factor Overexpression><Growth Factor Receptors><HER1><HNSCC><HNSCC of the oropharynx><Half-Life><Head and Neck Carcinoma><Head and Neck Neoplasms><Head and Neck Squamous Cell Carcinoma><Head and neck squamous cell carcinoma of the oropharynx><IGF1R><IGF1R gene><Injections><Insulin-Like Growth Factor 1 Receptor Gene><Intratumoral heterogeneity><Investments><Legal patent><Link><Luciferase Immunologic><Luciferases><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measurement><Measures><Medication><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Oligo><Oligonucleotides><Oncogenes><Oncogenic><Oropharyngeal HNSCC><Oropharyngeal Head and Neck Squamous Cell Carcinoma><Orphan Drugs><Outcome><PD-1 antibody><PD-1 antibody therapy><PD-1 therapy><PD1 antibody><PD1 antibody therapy><PD1 based treatment><PK/PD><Patents><Pathway interactions><Patients><Peyrone's Chloride><Peyrone's Salt><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Platinum Diamminodichloride><Population><Privatization><Production><Rat><Rats Mammals><Rattus><Replacement Therapy><Resistance><Rodent Model><SBIR><SCCHN><Sampling><Sequence Alteration><Signal Pathway><Small Business Innovation Research><Small Business Innovation Research Grant><Solid Neoplasm><Solid Tumor><Sum><Survival Rate><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TGF-alpha Receptor><TRFR><Technology><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Toxicology><Transcript><Transferrin Receptor><Transferrin Receptor 1><Transforming Genes><Transforming Growth Factor alpha Receptor><Tumor Tissue><Up-Regulation><Upregulation><Urogastrone Receptor><aPD-1 therapy><aPD-1 treatment><aPD1 therapy><aPD1 treatment><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-PD1 therapy><anti-PD1 treatment><anti-cancer therapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1 antibodies><anti-programmed cell death protein 1 therapy><anticancer therapy><base><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer progression><cancer therapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical development><combination therapy><combined modality treatment><combined treatment><cytokine><cytotoxic><developmental><drug discovery><drug resistant><drug/agent><effective therapy><effective treatment><efficacy study><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><gene deletion mutation><genomic alteration><head and neck squamous cell cancer><head and neck tumor><heterogeneity in tumors><improved><in vivo><in vivo Model><innovate><innovation><innovative><intra-tumoral heterogeneity><intratumor heterogeneity><lipid nanoparticle><mRNA><malignancy><manufacturing scale-up><meetings><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA replacement therapy><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA replacement therapy><microRNA-based therapy><migration><mouse model><multi-drug resistant cancer><multi-modal therapy><multi-modal treatment><multidrug resistant cancer><murine model><nano medicinal><nano medicine><nano particle delivery><nanomedicinal><nanomedicine><nanoparticle delivered><nanoparticle delivery><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><nuclease><nucleic acid-based therapeutics><oligos><overexpress><overexpression><pathway><pharmacokinetics and pharmacodynamics><phase I protocol><process optimization><programmed cell death protein 1 therapy><proto-oncogene protein c-erbB-1><resistance to Drug><resistant><resistant to Drug><response><scale up><small molecule><standard of care><survival outcome><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic nucleic acids><three dimensional><tumor><tumor heterogeneity><tumor progression>