A large Asian pharmaceutical company, requiring a high-level of oncology and imaging expertise, approached Molecular Imaging to investigate, validate and compare FDG and FLT as PET tracers that could be used to quantify efficacy for a series of targeted anticancer agents.
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Modality Overview
Positron emission tomography (PET), a nuclear medicine imaging technique, generates 3D images of injected PET radiotracers.
18F-fluorodeoxyglucose (18F-FDG), a glucose analog, is the most common PET radiotracer and is used for assessment of tissue metabolism. As a measure of glucose utilization, 18F-FDG enters the cell via glucose transporters and is irreversibly trapped once it is phosphorylated. Since tumors generally have elevated metabolism, 18F-FDG uptake can be used as a functional biomarker for therapeutic response.
The 18F-labelled nucleoside thymidine (18F-FLT) quantifies DNA synthesis. After uptake, 18F-FLT is phosphorylated and trapped in proliferating cells. Though 18F-FLT is not incorporated into DNA during the timeframe of PET imaging, it is a measure of thymidine uptake and phosphorylation. Therefore, 18F-FLT can function as a reliable biomarker for tumor proliferation.
Approach
An initial study, designed by our pharmacology and imaging experts, demonstrated significant FLT uptake decline, acutely, after each dose in an extended-dosing schedule. Follow up studies recommended, and executed by our staff, showed the utility of FLT in providing information about dose dependence of efficacy and helped in optimization of the dosing schedule for the test compound.
FDG PET imaging showed inhibition of FDG uptake through mean standardized uptake values (SUV), but tumor heterogeneity confounded the uptake time course as the control tumor became larger and more heterogeneous. To manage this, our imaging staff designed a custom image-thresholding approach to remove the effect of the tumor uptake heterogeneity. They used MATLAB scripts to automate the thresholding and to generate parameters that were verified to be more sensitive to drug activity.
Due to the time difference (Asia vs. US), we proposed customized client communication. At the end of each day, data collected that day were sent to the client for morning review. The optimized data exchange enabled the client to participate fully in the project. As the client made daily decisions, our lead scientists could respond and implement the changes immediately.
During the course of the repeat studies in this program, our extended team designed and implemented a custom report template that provided clearer communication of results and tailored the final product report to the client’s needs.
Outcome
The results of Molecular Imaging’s study were presented as novel findings at a major international scientific conference. An IND application to the FDA was filed with the imaging data used as primary supporting evidence, and the results are currently being used to justify, and design, PET imaging in a forthcoming clinical trial for the resultant lead candidate.
A large pharmaceutical company, under unusually tight timelines for a clinical development decision, contacted Molecular Imaging for input on study design to enable verification of anti-angiogenesis after anti-cancer treatment using a drug against a novel target. The client’s indication of interest was brain metastasis from primary lung tumors.
We start our process before imaging even begins. With our deep pharmacology and models expertise, your imaging studies are well informed before they begin.
Modality Overview
MRI is based on the phenomenon of nuclear magnetic resonance (NMR). MRI contrast agents can be leveraged to improve diagnostic sensitivity, or provide unique biomarkers for properties including blood flow, blood volume and tissue perfusion. A clinical standard in oncology, Dynamic Contrast-Enhanced (DCE) MRI utilizes gadolinium-based contrast agents and allows the quantification of spatially-resolved parameters that are measures of tumor permeability, blood flow and vascular surface area.
Bioluminescence imaging (BLI) relies on detection of light from luciferase-expressing cells in an animal. This is commonly achieved through implantation of cells engineered to express luciferase constitutively. Emission of light from these cells or tissues occurs following systemic injection of the luciferase substrate, luciferin.
Approach
Our pharmacology and imaging experts developed a study plan using an intracranial implant of a relevant lung tumor line as a model for lung metastasis. The quick, effective collaboration resulted in studies that would verify tumor growth inhibition and also validate DCE MRI-based parameters as clinically-relevant, imaging-based readouts for anti-angiogenesis.
The challenge was that there were no models on hand that expressed the unique new target. Following internally-established processes, our oncology pharmacology staff performed rapid diligence and identified a tumor cell line that expressed the target. However, the tumor cell line existed only at an academic institution. Our business development staff therefore got involved and quickly negotiated and finalized a deal to license the tumor line, enabling studies that met the aggressive clinical development timelines for the drug under study.
Rapidly and effectively-executed preclinical studies highlighted tumor growth response to the test compound and, in parallel, a sustained anti-angiogenic effect as measured through the DCE MRI–based Ktrans and IAUC parameters. Prioritized work by the data analysis and report review teams provided data and report delivery within the unusually short deadlines defined by the client.
Outcome
Based on the successful outcome within the time constraints, the client asked Molecular Imaging to perform similar work for new molecules coming through the pipeline.
Due to the repeat nature of the work, our scientists suggested greater efficiencies could be achieved by transfection of the cell line with a luciferase transporter. Assuming verification of target consistency with the parent line, a luciferase-transfected cell line would provide an efficient optical-imaging means for selecting and matching tumors for studies, and tracking tumor growth and response over time.
The client agreed with the recommendation and requested Molecular Imaging to transfect the cell line for future collaborative studies. After successful transfection and verification of target expression in the new cell line, Molecular Imaging proposed a screening program for the pipeline molecules based on BLI, with efficacy thresholds being used to send more promising candidates through full DCE MRI-based testing for anti-angiogenesis verification and validation of DCE MRI-based endpoints for potential clinical trial use.
A company, with a large portfolio of highly-performing anti-inflammatory agents, approached Molecular Imaging to design multi-faceted studies that could enable accurate triage and identification of a lead molecule for clinical development. The initial challenge was to separate three potential lead candidate molecules in terms of anti-inflammatory, disease-modifying activity. Molecular Imaging leadership quickly recognized the potential for a highly-beneficial, long-term partnership that would involve imaging biomarker testing and validation, with the goals of providing short-term and long-term decision making benefits for the client company.
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Modality Overview
Positron emission tomography (PET), a nuclear medicine imaging technique, generates 3D images of injected PET radiotracers.
18F-fluorodeoxyglucose (18F-FDG), a glucose analog, is the most common PET radiotracer and is used for assessment of tissue metabolism. As a measure of glucose utilization, 18F-FDG enters the cell via glucose transporters and is irreversibly trapped once it is phosphorylated. Since tumors generally have elevated metabolism, 18F-FDG uptake can be used as a functional biomarker for therapeutic response.
Fluorescence molecular tomography (FMT) technology enables quantitative imaging of fluorescent probe concentration to the picomolar level with no tissue depth limitation. It can be used to assess disease progression and drug response at the molecular and target levels. FMT imaging of activatable fluorescent probes can be used both for quantifying the early and mechanistic aspects of rheumatoid arthritis and other inflammatory diseases.
Micro-computed tomography (micro-CT) is an X-ray-based modality that enables high-resolution, three-dimensional (3D) image generation. Different tissue types attenuate X-rays to varying degrees, largely based on differing density, leading to CT-image contrast. The large density differences between bone, soft tissue and air make them readily distinguished by CT.
Approach
In collaboration with the client, our pharmacology experts determined that the requested collagen-induced arthritis (CIA) model may not reciprocate the target biology and that the collagen antibody-induced arthritis (CAIA) model did incorporate the target biology, making this model the best choice.
In order to extract the best dataset possible to optimize the chances of delineating performance of multiple active agents, our scientists suggested a multi-modality study, in which both FDG PET imaging (provides a biomarker for synovial metabolic activity) and FMT imaging (using exogenous probes activated by cathepsins and MMPs) be incorporated.
Both cathepsin and MMP-activated probes have been shown to provide biomarkers that correlate better with histopathologic readouts, compared with traditional paw swelling and clinical-score-based end points. Additionally, FDG PET has been shown to provide an early readout for inflammation that is more specific than traditional measures, and complementary to the cathepsin and MMP-modulated biomarkers.
Our scientists also recommended the use of micro-CT imaging, when indicated by ongoing study data, as readouts for the bone aspect of the arthritic disease.
Teaming up, our pharmacology and imaging experts designed complex, logistically-challenging studies that were executed by the combined multi-disciplinary teams over a programmatic partnership with the client company. The studies generated large, rich, multi-parametric datasets that were mined, yielding imaging biomarker validation within the context of the client company's pipeline. The imaging biomarkers generated information complementary to the measured traditional end points.
In one case, a molecule showed a promising effect in inhibiting bone damage, as shown through micro-CT imaging; however, the mechanism for this puzzled the client. To resolve the question, our scientists suggested a FMT-based imaging strategy using a cathepsin K-activated fluorescent probe, based on literature that suggested the dominant pathway for bone degradation in the model being used was through osteoclasts.
Since cathepsin K is activated in this pathway, it was hypothesized that the cathepsin K-activated probe would provide a biomarker for the test agent’s bone protective effects. Imaging data clearly showed this effect and demonstrated that the drug acted through this pathway in protecting bone. The information was used to leverage new funding for a novel bone protective agent development program at the client’s company.
Outcome
The client went on to successfully use this multi-modality imaging approach as a screening tool for a large number of molecules that were in the company R&D pipeline. In less than 12 months, the data for this programmatic series pointed toward a lead candidate molecule that consistently performed more favorably in inhibition of inflammation than a comparator standard of care used under optimal dosing conditions.
A drug discovery company requested Molecular Imaging to develop an efficacy-testing methodology for a number of promising drug candidates which focused on a relatively new, oncologic target.
We set the bar for industry related protocols. With our broad set of efficient, validated, industry protocols, we are the benchmark in the preclinical imaging field.
Modality Overview
Positron emission tomography (PET), a nuclear medicine imaging technique, generates 3D images of injected PET radiotracers.
18F-fluorodeoxyglucose (18F-FDG), a glucose analog, is the most common PET radiotracer and is used for assessment of tissue metabolism. As a measure of glucose utilization, 18F-FDG enters the cell via glucose transporters and is irreversibly trapped once it is phosphorylated. Since tumors generally have elevated metabolism, 18F-FDG uptake can be used as a functional biomarker for therapeutic response.
Approach
Our pharmacology and imaging experts partnered to design a series of comprehensive studies using xenografts known to express the oncologic target. The xenograft studies demonstrated significant efficacy, and subsequently led to a decision identifying a lead molecule for clinical development.
During the preclinical-study design phase, our team hypothesized that FDG PET would potentially provide an efficacy biomarker that could be used acutely following successful target modulation. They designed the FDG PET studies to comprehensively validate, or invalidate, the use of FDG uptake as a biomarker for the drug candidate’s efficacy. A series of studies, measuring efficacy, target modulation via a PD biomarker and FDG uptake through PET imaging, demonstrated that FDG PET was able to provide an early readout for efficacy and target modulation in target-expressing preclinical models.
Outcome
As a result of the partnership with Molecular Imaging, the client was able to leverage the preclinical dataset to close a major licensing deal with a large pharmaceutical company. A key advantage that emerged from the study was that the identified imaging biomarker could also potentially be used in clinical trials as a surrogate for target modulation.
The lead candidate molecule went into clinical development, and through the application of PET scans in the patient population, demonstrated significant FDG uptake suppression. PET imaging showed that the treatment resulted in almost complete acute suppression of tumor metabolism in advanced-stage cancer patients.