Research

Research in the Manning Laboratory focuses on the development, validation, implementation and clinical translation of imaging and chemical probes to non-invasively quantify molecular events in vivo. Our research spans basic science, preclinical models and clinical trials. Our current research projects focus on:

• PET tracers of cancer metabolism as precision imaging diagnostics
  
• PET tracers to predict response to therapy
• Targeted inhibitors of cancer cell metabolism
• PET imaging resource to enhance delivery of individualized cancer therapeutics (PREDICT)

A wealth of proteogenomic information has provided a deep understanding of the molecular pathogenesis of human cancer and has led to improved classification systems of this disease. However, with notable exceptions, accurately diagnosing cancer and subsequently matching patients with optimum therapeutic regimens remain challenging. Complementary to precision medicine approaches (e.g., liquid biopsy), PET leverages labeled, biologically active compounds, or ‘tracers’, to provide quantitative measures of tumor phenotype. Uniquely, PET quantifies functional biological processes, such as the activity of biological targets, as opposed to simply target expression, on a lesion-by-lesion basis.

Clinical decisions regarding the treatment of patients with cancer remain largely guided by anatomical imaging modalities. These methods, namely magnetic resonance imaging (MRI) and x-ray computed tomography (CT), provide little information about the cellular and molecular underpinnings of individual tumors. Improved tools to detect cancers at early, potentially curable stages, to stage patients, and to predict future tumor behavior are needed. Molecular imaging with positron emission tomography (PET) is uniquely poised to improve the clinical management of patients, yet novel PET tracers are required. PET imaging using 18F-FDG, the most commonly utilized molecular imaging tracer in clinical oncology, has limitations for detection of many cancer types. Targeting tumor-specific pathways with 11C-labeled and 18F-labeled tracers represents a promising approach for improved PET imaging of tumors.

Tumor cells adopt distinct metabolic pathways that ensure sufficient supplies of nutrients for growth, proliferation and redox maintenance. We have explored innovative PET tracers related to cancer cell metabolism of glutamine to improve diagnosis in multiple clinical settings, including hepatocellular carcinoma (HCC) and lung cancer. One tracer of interest is (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid (18F-FSPG). 18F-FSPG is a novel glutamic acid derivative identified to target tumor-specific adaptations of intermediary metabolism that functions as a cystine mimetic and is specifically taken up via the system xC- transporter, a glutamate-cystine exchanger.

A major goal in the lab is to evaluate 18F-FSPG, as well as other tracers of cancer metabolism, for detection of tumors in multiple cancer settings. We are currently conducting a Phase I trial to determine the diagnostic potential of 18F-FSPG PET in HCC (NCT02379377). We have also launched pilot studies in pancreatic cancer, cholangiocarcinoma and head and neck squamous cell carcinoma (HNSCC).

Currently there are few effective, standardized and objective approaches to inform early in the course of treatment whether a patient is responding to a particular therapy. CT and MRI are routinely used in the diagnosis, staging and monitoring of tumor response. However, the sensitivity of these methods is limited by image contrast that depends on overt anatomic and morphologic features of the tumor. Use of these methods may also be inadequate for determining efficacy of an intervention, since conventional tumor response is defined on the basis of gross changes in tumor size that are known to be delayed relative to underlying functional and metabolic changes that occur much earlier in the disease course. Thus, there is a great need for objective, quantitative tools that enable early prediction of tumor response that can be used to guide therapy. Complimentary molecular imaging approaches, particularly PET, can improve functional characterization of patients with cancer. There is great potential for an expanded role of PET imaging in the quantitative assessment of molecular responses to intervention.

Our group has been utilizing dual-tracer PET studies featuring multiple complementary isotopes to interrogate multiple targets within oncogenic pathways during a single visit to the PET center. Procedurally, the short half-life of 11C-labeled tracers enables the feasibility to clinically deploy a same-day dual-tracer paradigm with an 18F-labeled tracer. Leading PET tracers under active investigation are 11C-glutamine (11C-Gln) and (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG), biologically orthogonal tracers whose uptake reflect two different aspects of glutamine metabolism. We are evaluating these imaging agents as predictive and prognostic biomarkers of response. It is hoped that through combination of these tracers, unique and complementary insights might be gleaned.

We are currently conducting a clinical trial evaluating glutamine PET imaging with 11C-Gln and 18F-FSPG in patients with metastatic WT RAS colorectal cancer (CRC) undergoing treatment with EGFR-targeted antibody therapy (NCT03275974). We are also conducting a pilot study evaluating 18F-FSPG PET as a measure of treatment response to Y90 radioembolization in HCC.

A well-known hallmark of cancer is the emergence of altered metabolism. Cancer cells utilize glutamine as a carbon source for ATP production, biosynthesis, and as a defense against reactive oxygen species. Given the significance of glutamine to cancer cells, targeting glutaminolysis represents a promising therapeutic approach. One strategy currently being evaluated in clinical trials is targeting glutaminase (GLS1), the enzyme that converts glutamine to glutamate. Another approach is to target glutamine metabolism upstream of glutaminase at the level of glutamine transport. The neutral amino acid transporter, ASCT2 (SLC1A5), is the primary transporter of glutamine in cancer cells and elevated ASCT2 levels have been linked to poor survival in many human cancers. Prior studies have reported that genetic silencing of ASCT2 in cancer cells have resulted in antitumor effects.

Our group has developed the first potent and selective small molecule inhibitor of ASCT2, designated V-9302. V-9302 was shown to have antitumor properties against a number of cancers in vitro and in vivo. We are performing additional preclinical studies evaluating this lead compound to further elucidate molecular determinants of response and identify potential biomarkers.

Another goal is to identify new inhibitors with improved potency and pharmacologic properties. Using medicinal chemistry approaches, we design and synthesize novel compounds. These compounds are then screened using several in vitro assays.