A Novel Targeted Nanomedicine Delivering MicroRNA-30-5p ReplacementTherapy for Multi-drug Resistant Cancer Treatment

AbstractIn this SBIR application miRecule proposes to develop a microRNA based therapeutic mimic of miRpmiRecule candidate MCfor the treatment of multi drug resistantMDRcancersHead and Neck Squamous Cell CarcinomaHNSCCis theth most common form of cancerGreater than half of patients present with late stage III or IV diseasewith an averageyear survival rate ofHNSCC tumors have high levels of genetic mutations leading to high tumor heterogeneity and drug resistancemiRp expression is widely repressed in tumor tissuesand MIRgene deletion is observed inof HNSCCsmiR based therapeutics offer a disruptive MDR cancer treatment by targeting both the primary oncogenic pathways and potentially suppressing mechanisms of intrinsic or acquired resistanceEGFR targeted therapy is often resisted by overexpression of the compensating growth factor receptorsGFRsMET and IGF RWe have made the novel discovery that miRp can target and repress all three of these GFRsThe rationale for our design is that a miRp mimic will be superior in its ability to treat heterogeneous late stage HNSCC due to its ability to regulate not only EGFRbut also METIGFRand over two dozen other mRNAs confirmed to be deregulated in tumor tissue and associated with over proliferationadhesionmigrationextracellular matrix remodelingand differentiationOur early study shows that a chemically modified mimic of miRpexhibiting significantly improved efficacy over the biological microRNAwas effective at inhibiting tumor growth in vivo in a preclinical model of HNSCCA significant hurdle for nucleic acid therapeutics is a lack of an efficient means of delivering them specifically to target cancer cellsespecially at the metastatic stageTo overcome this obstaclewe employ two unique strategiesFirstour chemically modified mimic of miRp has vastly improved nuclease stability and activitydecreasing the amount of mimic that needs to be present in the cell to produce the desired effectand extending the duration of responseSecondour mimics are encapsulated in a clinically validated tumortargeted liposomal nanodelivery systemscLThe nanocomplex carries an scFv antibody fragment against the transferrin receptorTfRwhich is up regulated on the surface of most cancer cells and triggers uptake via receptor mediated endocytosisIn this Phase I SBIR study we aim to we will characterize the half life of our lead nuclease stabilized mimic in HNSCC cellstargeting of multiple oncogenic mRNAs and signaling pathwaysand test our hypothesis that it can more effectively combat drug resistance in vitroAimWe will test this mimic in a cetuximab and cisplatin resistant orthotopic xenograft mouse model of HNSCC and compare directly with standard of care cisplatin and cetuximabWe will also assess potential toxicity and offtarget effectsAIMSuccessful completion of these studies will demonstrate the feasibility of MCas a drug candidate and dosing regimen to be used in future PKTOXADMEand other animal studies as required for an IND packageOnce FDA approved and commercially available MCwill offer an effective treatment of MDR HNSCC and perhaps other cancers for which there are currently no treatment options Project NarrativeHNSCC is theth most common form of cancerGreater than half of patients present with late stage III or IV diseasewith an averageyear survival rate ofIn this Phase I SBIR study we will first identify a mimic of miRp with the ability to down regulate key oncogenic pathway targets in HNSCCNext we will test the feasibility of using a nanocomplex to treat tumor growthmetastasisand progression in HNSCC mouse modelsOnce developed and regulatory approvedthe novel miRp therapeutic will offer an effective treatment of multi drug resistant cancers for which there are currently no treatment options and survival is measured in months