COLLAGEN MEDICAL LLC — Department of Health and Human Services SBIR Phase I: 102

Description

DESCRIPTION provided by applicant We propose to establish a new method for non invasive characterization of the pancreatic ductal adenocarcinoma PDAC microenvironment by using the collagen specific magnetic resonance imaging MRI probe CM to interrogate the desmoplastic stroma of these lesions Pancreatic ductal adenocarcinoma PDAC is the fourth leading cause of cancer related death in the United States with over deaths each year PDAC is often not detected until metastases are present and is insensitive to many traditional chemotherapeutic drugs which has led to a dismal five year survival rate of PDAC is especially notable for an intense fibrotic stromal response known as the andquot desmoplastic reactionandquot which influences tumor survival and progression in a complex manner Desmoplastic stroma is characterized by up to a fold increase in collagen compared with the normal pancreas Currently there are no effective ways to non invasively image or monitor the desmoplastic status of PDAC tumors We intend to address this need by developing a high resolution MRI method for characterizing desmoplasia based on specific contrast enhancement of Type I collagen Our preliminary data has established that the prototype Type I collagen targeted imaging probe EP can specifically detect desmoplasia in an orthotopic syngeneic PDAC mouse model The probe is small enough Da that it readily extravasates from the blood vessels into the tumor interstitium It has Gd chelates for potent MRI signal enhancement Our development compound CM shares the same mechanism of action as EP but has been refined to incorporate the exceedingly stable macrocyclic GdDOTAGA chelates which are necessary to prevent gadolinium dissociation during human use CM has been synthesized on a multi gram scale using standard solid phase peptide and conjugation coupling chemistries is readily formulated for IV injection The pharmacokinetics and collagen targeting efficacy of CM have been established in rodent and large animal preclinical models of organ fibrosis and demonstrate rapid distribution to the fibrotic target fast renal excretion and whole body elimination In Phase I of this study we will synthesize CM and a mutated control probe CM and will demonstrate similar MR relaxivity and pharmacokinetic properties but an absence of collagen affinity for CM Next we will evaluate the ability of CM to specifically detect desmoplasia associated with PDAC compared to the non targeted probe CM and the standard GdDTPA In Phase we will use CM enhanced MRI to quantify tumor permeability and desmoplasia collagen content over time in a transgenic mouse model of PDAC We will also use CM enhanced MRI to monitor the reduction in fibrotic stroma in response to a desmoplasia inhibitor losartan We will then image mice undergoing monotherapy or combination therapy with losartan and traditional chemotherapy gemcitabine and determine if we can use imaging to predict response Finally to enable clinical translation of this technology we will synthesize CM under cGMP conditions and perform GLP toxicity studies in rodents PUBLIC HEALTH RELEVANCE Pancreatic ductal adenocarcinoma PDAC is the fourth leading cause of cancer related death in the United States with over deaths each year PDAC is characterized by an intense fibrotic reaction and stromal cell infiltration known as the andquot desmoplastic reactionandquot The resulting stiff scar like tumor microenvironment may hold the key to understanding the nature of PDAC chemoresistance However there are currently no noninvasive tools to enable monitoring of the desmoplastic response in PDAC patients The goal of this proposal is to develop a noninvasive magnetic resonance imaging MRI method to quantify and monitor desmoplasia using a probe targeted to the fibrotic stromal tumor microenvironment