Molecular MR Imaging of the Desmoplastic Response in Pancreatic Cancer

DESCRIPTIONprovided by applicantWe propose to establish a new method for non invasive characterization of the pancreatic ductal adenocarcinomaPDACmicroenvironment by using the collagen specific magnetic resonance imagingMRIprobe CMto interrogate the desmoplastic stroma of these lesionsPancreatic ductal adenocarcinomaPDACis the fourth leading cause of cancer related death in the United States with overdeaths each yearPDAC is often not detected until metastases are present and is insensitive to many traditional chemotherapeutic drugswhich has led to a dismal five year survival rate ofPDAC is especially notable for an intense fibrotic stromal response known as the andquot desmoplastic reactionandquotwhich influences tumor survival and progression in a complex mannerDesmoplastic stroma is characterized by up to afold increase in collagen compared with the normal pancreasCurrentlythere are no effective ways to non invasively image or monitor the desmoplastic status of PDAC tumorsWe intend to address this need by developing a high resolution MRI method for characterizing desmoplasia based on specific contrast enhancement of Type I collagenOur preliminary data has established that the prototype Type I collagen targeted imaging probe EPcan specifically detect desmoplasia in an orthotopic syngeneic PDAC mouse modelThe probe is small enoughDathat it readily extravasates from the blood vessels into the tumor interstitiumIt hasGd chelates for potent MRI signal enhancementOur development compound CMshares the same mechanism of action as EPbut has been refined to incorporate the exceedingly stable macrocyclic GdDOTAGA chelateswhich are necessary to prevent gadolinium dissociation during human useCMhas been synthesized on a multi gram scale using standard solid phase peptide and conjugation coupling chemistriesis readily formulated for IV injectionThe pharmacokinetics and collagen targeting efficacy of CMhave been established in rodent and large animal preclinical models of organ fibrosisand demonstrate rapid distribution to the fibrotic targetfast renal excretionand whole body eliminationIn Phase I of this studywe will synthesize CMand a mutated control probe CMand will demonstrate similar MR relaxivity and pharmacokinetic properties but an absence of collagen affinity for CMNextwe will evaluate the ability of CMto specifically detect desmoplasia associated with PDACcompared to the non targeted probe CMand the standard GdDTPAIn Phasewe will use CMenhanced MRI to quantify tumor permeability and desmoplasiacollagen contentover time in a transgenic mouse model of PDACWe will also use CMenhanced MRI to monitor the reduction in fibrotic stroma in response to a desmoplasia inhibitorlosartanWe will then image mice undergoing monotherapy or combination therapy with losartan and traditional chemotherapygemcitabineand determine if we can use imaging to predict responseFinallyto enable clinical translation of this technologywe will synthesize CMunder cGMP conditions and perform GLP toxicity studies in rodents PUBLIC HEALTH RELEVANCEPancreatic ductal adenocarcinomaPDACis the fourth leading cause of cancer related death in the United States with overdeaths each yearPDAC is characterized by an intense fibrotic reaction and stromal cell infiltration known as the andquot desmoplastic reactionandquotThe resulting stiffscar like tumor microenvironment may hold the key to understanding the nature of PDAC chemoresistanceHoweverthere are currently no noninvasive tools to enable monitoring of the desmoplastic response in PDAC patientsThe goal of this proposal is to develop a noninvasive magnetic resonance imagingMRImethod to quantify and monitor desmoplasia using a probe targeted to the fibrotic stromal tumor microenvironment