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Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

Key Points Drug development is a costly, time-intensive and high-risk endeavour, with only two to three approvals for novel therapeutics in new drug classes per year eventually making it to market. New strategies are required to identify promising new drug candidates early on and, likewise, to terminate those candidates that are unlikely to be successful, thus allowing a more rapid and efficient move to pivotal trials. Molecular imaging attempts to characterize and quantify biological processes at the cellular and subcellular level in intact living subjects. It exploits specific molecular probes and intrinsic tissue characteristics as the source of image contrast, providing the potential for understanding of integrative biology, earlier detection and characterization of disease, and evaluation of treatment. As most molecular imaging techniques are routine in clinical radiology departments and have counterparts in the experimental research setting, it is possible to design preclinical experiments that not only predict clinical imaging observations but also provide a mechanistic understanding of the observed biological response. Molecular imaging has the potential to have a significant impact on different phases of drug development, including target expression, compound screening and optimization, as well as Phases I to III clinical studies. Examples are detailed in the text of the article. The option of an exploratory IND (eIND) initiated by the US Food and Drug Administration enables first-in-human molecular imaging studies to be performed with reduced preclinical support as compared to that required for a full IND. Consortia such as the Alzheimer's Disease Neuroimaging Initiative, the American College of Radiology Imaging Network and the High-Risk Plaque Initiative seek to correlate a number of imaging biomarkers with the clinical manifestations of diseases and, if successful, will greatly increase the inclusion of these imaging techniques in exploratory clinical development of novel therapeutics. Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility. Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.

Objective To compare the multidetector CT (MDCT) patterns of local invasion and clinical findings at presentation in patients with adenocarcinoma of the uncinate process of the pancreas to patients with adenocarcinomas in the non-uncinate head of the pancreas. Methods We evaluated the two cohorts for common duct and pancreatic duct dilatation, mesenteric vascular encasement, root of mesentery invasion, perineural invasion and duodenal invasion. In addition, we compared the clinical findings at presentation in both groups. Results Common duct ( P  < 0.001) and pancreatic duct dilatation ( P  = 0.001) were significantly less common in uncinate process adenocarcinomas than in the non-uncinate head of the pancreas. Clinical findings of jaundice ( P =  0.01) and pruritis ( P  = 0.004) were significantly more common in patients with lesions in the non-uncinate head of the pancreas. Superior mesenteric artery encasement ( P  = 0.02) and perineural invasion ( P  = 0.001) were significantly more common with uncinate process adenocarcinomas. Conclusion Owing to its unique anatomic location, adenocarcinomas within the uncinate process of the pancreas have significantly different patterns of both local invasion and clinical presentation compared to patients with carcinomas in the non-uncinate head of the pancreas. Key Points • SMA encasement and perineural invasion were more common with uncinate process adenocarcinomas. • Common bile duct and pancreatic duct dilatation were less common in uncinate process adenocarcinomas • Jaundice and pruritis were more common with lesions elsewhere in the pancreatic head

Contrast-enhanced ultrasound (CEUS) is a safe, relatively inexpensive, and widely available imaging technique using dedicated imaging ultrasound sequences and FDA-approved contrast microbubbles that allow detection and characterization of malignant focal liver lesions with high diagnostic accuracy. CEUS provides dynamic real-time imaging with high spatial and temporal capability, allowing for unique contributions to the already established protocols for diagnosing focal liver lesions using CT and MR imaging. In patients with lesions indeterminate on CT and MRI, CEUS is a helpful problem-solving complementary tool that improves patient management. Furthermore, CEUS assists guidance of liver biopsies and local treatment. Variations of CEUS such as DCE-US and ultrasound molecular imaging are emerging for quantitative monitoring of treatment effects and possible earlier detection of cancer. In this review, basic principles of CEUS techniques and ultrasound contrast agents along with a description of the enhancement patterns of malignant liver lesions are summarized. Also, a discussion of the role of CEUS for treatment guidance and monitoring, intraoperative CEUS, and an outlook on emerging applications is provided.

Purpose In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively. Procedures Rats ( n  = 31) underwent an intramyocardial injection of cardiomyoblasts (2 × 10 6 ) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 μg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis. Results BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (≥16 days) and persistent MR signal (≥42 days). Conclusions Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.

Targeted contrast-enhanced ultrasound imaging is increasingly being recognized as a powerful imaging tool for the detection and quantification of tumor angiogenesis at the molecular level. The purpose of this study was to develop and test a new class of targeting ligands for targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with small, conformationally constrained peptides that can be coupled to the surface of ultrasound contrast agents. Directed evolution was used to engineer a small, disulfide-constrained cystine knot (knottin) peptide that bound to alpha(v)beta(3) integrins with a low nanomolar affinity (Knottin(Integrin)). A targeted contrast-enhanced ultrasound imaging contrast agent was created by attaching Knottin(Integrin) to the shell of perfluorocarbon-filled microbubbles (MB-Knottin(Integrin)). A knottin peptide with a scrambled sequence was used to create control microbubbles (MB-Knottin(Scrambled)). The binding of MB-Knottin(Integrin) and MB-Knottin(Scrambled) to alpha(v)beta(3) integrin-positive cells and control cells was assessed in cell culture binding experiments and compared with that of microbubbles coupled to an anti-alpha(v)beta(3) integrin monoclonal antibody (MB(alphavbeta3)) and microbubbles coupled to the peptidomimetic agent c(RGDfK) (MB(cRGD)). The in vivo imaging signals of contrast-enhanced ultrasound with the different types of microbubbles were quantified in 42 mice bearing human ovarian adenocarcinoma xenograft tumors by use of a high-resolution 40-MHz ultrasound system. MB-Knottin(Integrin) attached significantly more to alpha(v)beta(3) integrin-positive cells (1.76 +/- 0.49 [mean +/- SD] microbubbles per cell) than to control cells (0.07 +/- 0.006). Control MB-Knottin(Scrambled) adhered less to alpha(v)beta(3) integrin-positive cells (0.15 +/- 0.12) than MB-Knottin(Integrin). After blocking of integrins, the attachment of MB-Knottin(Integrin) to alpha(v)beta(3) integrin-positive cells decreased significantly. The in vivo ultrasound imaging signal was significantly higher after the administration of MB-Knottin(Integrin) than after the administration of MB(alphavbeta3) or control MB-Knottin(Scrambled). After in vivo blocking of integrin receptors, the imaging signal after the administration of MB-Knottin(Integrin) decreased significantly (by 64%). The imaging signals after the administration of MB-Knottin(Integrin) were not significantly different in the groups of tumor-bearing mice imaged with MB-Knottin(Integrin) and with MB(cRGD). Ex vivo immunofluorescence confirmed integrin expression on endothelial cells of human ovarian adenocarcinoma xenograft tumors. Integrin-binding knottin peptides can be conjugated to the surface of microbubbles and used for in vivo targeted contrast-enhanced ultrasound imaging of tumor angiogenesis. Our results demonstrate that microbubbles conjugated to small peptide-targeting ligands provide imaging signals higher than those provided by a large antibody molecule.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. Since no targeted therapy is available, gene-directed enzyme prodrug therapy (GDEPT) could be an attractive strategy for treating TNBC. Polyethylene glycol (PEG)ylated-poly(lactic-co-glycolic acid)/polyethyleneimine nanoparticles (PLGA/PEI NPs) were synthesized and complexed with fusion gene. Ultrasound (US) and microbubble (MB) mediated sonoporation was used for efficient delivery of the -DNA-NP complex to TNBC tumor for cancer therapy. Therapeutic effect was evaluated by treating TNBC cells and tumor xenograft by using prodrugs ganciclovir (GCV) and CB1954. TNBC cells treated with GCV/CB1954 prodrugs after transfection of -DNA by PEGylated-PLGA/PEI NP resulted in high apoptotic-index. US-MB image-guided delivery of -DNA-NP complex displayed significant expression level of TK-NTR protein and showed tumor reduction when treated with GCV/CB1954 prodrugs in TNBC xenograft . US-MB image-guided delivery of gene by PEGylated-PLGA/PEI NPs could be a potential prodrug therapy for TNBC in the clinic.

Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment ( P  = 0.005), but not in CT26 tumors ( P  > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors ( P  < 0.001), but not in treated versus control CT26 tumors (P  = 0.796). Early decrease in both PE and AUC by 45–50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.

Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications.

There is a need for noninvasive repeatable biomarkers to detect early cancer treatment response and spare non-responders unnecessary morbidities and costs. Here, we introduce three-dimensional (3D) dynamic contrast enhanced ultrasound (DCE-US) perfusion map characterization as inexpensive, bedside and longitudinal indicator of tumor perfusion for prediction of vascular changes and therapy response. More specifically, we developed computational tools to generate perfusion maps in 3D of tumor blood flow, and identified repeatable quantitative features to use in machine-learning models to capture subtle multi-parametric perfusion properties, including heterogeneity. Models were developed and trained in mice data and tested in a separate mouse cohort, as well as early validation clinical data consisting of patients receiving therapy for liver metastases. Models had excellent (ROC-AUC > 0.9) prediction of response in pre-clinical data, as well as proof-of-concept clinical data. Significant correlations with histological assessments of tumor vasculature were noted (Spearman R > 0.70) in pre-clinical data. Our approach can identify responders based on early perfusion changes, using perfusion properties correlated to gold-standard vascular properties.