microRNA-21 Blockade of Triple Negative Breast Cancer

Triple negative breast cancerTNBCis an orphan disease that attacksUS women every yearTNBC cells lack human estrogen receptorprogesterone receptorand epidermal growth factor receptorHerthe targets of existing medicinesTNBC recurs after standard of care chemotherapy and radiationkilling its victims withinyearsNew promising therapies such as poly ADP ribosepolymerasePARPinhibitors only benefit a small subset of patients with BRCAmutationsThusTNBC shows a critical need for molecularly targeted therapyMost TNBC cells and associated stroma show high microRNAmiRwhich decreases tumor suppressor proteins that keep cell growth in checkA molecularly targeted therapeutic to block miRin TNBC is our objectivePremiseWe have designed a strong miRblocking agent using aminomethyl bridged nucleic acidBNAwith strong basepairingTm andgtClow toxicityand serum stabilityconjugated to a peptide ligand for endocytosis by the insulin like growth factorreceptorIGF Rof TNBC tumors show constitutive IGF R signalingThe peptide ligand for IGF R provides a unique strategy for delivering miRblocker specifically into the TNBC cellsOur agent basepairs with miRin the RNAinduced silencing complexRISCfreeing target mRNAs from miRattackOur miRBNA elevated tumor suppressor proteinssuppressed immune checkpoint gene expressionincreased apoptosisslowed proliferation and migration in multiple TNBC linesBNA peptide in sterile saline can be administered by infusionOur strategy optimizes cancer cell specific delivery to block proliferation and immune checkpointscovered by a pending PCT patent applicationlicensed by Bound Therapeutics LLCHypothesisOur unique design for short microRNA blockers conjugated to a receptor ligand will direct TNBC cell uptake and slow the growth of TNBC orthotopic xenografts with minimal toxicityAimMeasure the effects of the lead miRblocker on proliferationapoptosisinvasionand cellular expression of miRtarget mRNAs and checkpoint proteins inmolecular subtypes of TNBC cellsMeasure tumor response and immune activation by the lead miRblocker in TNBCTluciferase orthotopic xenografts in immunocompetent syngeneic micePredicted resultsSignificant inhibition of tumor growth and immune checkpointsand elevation of T cell responseAimMeasure toxicity of the lead miRblocker in human hepatocytes by transcriptome analysisMeasure toxicity of the lead miRblocker in mice by liver and kidney serum markers and weightMeasure on target and off target transcriptome effectspharmacokineticsand biodistribution of the lead miRblocker in the mouse modelPredicted resultsMinimal toxicity to human hepatocytes and murine host cellsImpactWe seek proof of concept to derisk the commercialization of a BNA peptide TNBC therapeuticenabling a full preclinical study of potencyT cell responsetoxicologyand pharmacokineticsprior to IND and a Phase I single agent safety trialWe expect that miRNA blockade will significantly increase TNBC patient survival We propose to slow the growth of triple negative breast cancer cells with minimal side effectsWe discovered a new principle in the genetic code of triple negative breast cancer cells that enables us to design novelsafer medicinesWe will identify the version of our triple negative breast cancer medicine that works best in human triple negative breast cancer cells in culturethen test our medicine in living laboratory miceleading to future trials in human triple negative breast cancer patients