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-101 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 40,000 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 6.7%. PDAC is especially notable for an intense fibrotic stromal response known as the desmoplastic reaction which influences tumor survival and progression in a complex manner. Desmoplastic stroma is characterized by up to a 3-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- 3533 can specifically detect desmoplasia in an orthotopic syngeneic PDAC mouse model. The probe is small enough (~4000 Da) that it readily extravasates from the blood vessels into the tumor interstitium. It has 3 Gd chelates for potent MRI signal enhancement. Our development compound CM-101 shares the same mechanism of action as EP-3533 but has been refined to incorporate the exceedingly stable macrocyclic GdDOTAGA chelates, which are necessary to prevent gadolinium dissociation during human use. CM-101 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- 101 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-101 and a mutated control probe CM-125 and will demonstrate similar MR relaxivity and pharmacokinetic properties but an absence of collagen affinity for CM-125. Next, we will evaluate the ability of CM-101 to specifically detect desmoplasia associated with PDAC, compared to the non-targeted probe CM-125 and the standard GdDTPA. In Phase 2, we will use CM-101 enhanced MRI to quantify tumor permeability and desmoplasia (collagen content) over time in a transgenic mouse model of PDAC. We will also use CM-101 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-101 under cGMP conditions and perform GLP toxicity studies in rodents.
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States with over 40,000 deaths each year. PDAC is characterized by an intense fibrotic reaction and stromal cell infiltration known as the 'desmoplastic reaction'. 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.
|Erstad, Derek J; Sojoodi, Mozhdeh; Taylor, Martin S et al. (2018) Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. Dis Model Mech 11:|