Mark Dunphy

Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo

Glutamine-based PET imaging takes advantage of gliomas’ glutamine addiction and can be used to assess metabolic nutrient uptake in gliomas. A PET approach to brain tumors Positron emission tomography, or PET, is a common method of imaging tumors by detecting their uptake of a radioactively labeled tracer. Radiolabeled glucose, in particular, is often used for this type of imaging, because tumor cells are often highly dependent on glycolysis and require large amounts of glucose to maintain their metabolism. Unfortunately, this method cannot be used to image brain tumors, because regular brain cells are also highly dependent on glucose. Now, Venneti et al. have used mouse models and human patients to show that radiolabeled glutamine, which is also taken up by tumor cells, can be used to image brain tumors and distinguish them from normal brain and even from tumors that are no longer growing. Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-18F-(2S,4R)-fluoroglutamine (18F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced 18F-FGln tumor avidity, corresponding with decreased tumor burden. 18F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where 18F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that 18F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.

Radiopharmaceuticals in Preclinical and Clinical Development for Monitoring of Therapy with PET

This review article discusses PET agents, other than 18F-FDG, with the potential to monitor the response to therapy before, during, or after therapeutic intervention. This review deals primarily with non–18F-FDG PET tracers that are in the final stages of preclinical development or in the early stages of clinical application for monitoring the therapeutic response. Four sections related to the nature of the tracers are included: radiotracers of DNA synthesis, such as the 2 most promising agents, the thymidine analogs 3′-18F-fluoro-3′-deoxythymidine and 18F-1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)thymine; agents for PET imaging of hypoxia within tumors, such as 60/62/64Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) and 18F-fluoromisonidazole; amino acids for PET imaging, including the most popular such agent, l-[methyl-11C]methionine; and agents for the imaging of tumor expression of androgen and estrogen receptors, such as 16β-18F-fluoro-5α-dihydrotestosterone and 16α-18F-fluoro-17β-estradiol, respectively.

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions.

Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer

The integral role of positron-emission tomography (PET) using the glucose analog tracer fluorine-18 fluorodeoxyglucose (FDG) in the staging of non-small cell lung cancer (NSCLC) is well established. Evidence is emerging for the role of PET in response assessment to neoadjuvant therapy, combined-modality therapy, and early detection of recurrence. Here, we review the current literature on these aspects of PET in the management of NSCLC. FDG-PET, particularly integrated 18F-FDG-PET/CT, scans have become a standard test in the staging of local tumor extent, mediastinal lymph node involvement, and distant metastatic disease in NSCLC. 18F-FDG-PET sensitivity is generally superior to computed tomography (CT) scans alone. Local tumor extent and T stage can be more accurately determined with FDG-PET in certain cases, especially in areas of post-obstructive atelectasis or low CT density variation. FDG-PET sensitivity is decreased in tumors <1 cm, at least in part due to respiratory motion. False-negative results can occur in areas of low tumor burden, e.g., small lymph nodes or ground-glass opacities. 18F-FDG-PET-CT nodal staging is more accurate than CT alone, as hilar and mediastinal involvement is often detected first on 18F-FDG-PET scan when CT criteria for malignant involvement are not met. 18F-FDG-PET scans have widely replaced bone scintography for assessing distant metastases, except for the brain, which still warrants dedicated brain imaging. 18F-FDG uptake has also been shown to vary between histologies, with adenocarcinomas generally being less FDG avid than squamous cell carcinomas. 18F-FDG-PET scans are useful to detect recurrences, but are currently not recommended for routine follow-up. Typically, patients are followed with chest CT scans every 3–6 months, using 18F-FDG-PET to evaluate equivocal CT findings. As high 18F-FDG uptake can occur in infectious, inflammatory, and other non-neoplastic conditions, 18F-FDG-PET-positive findings require pathological confirmation in most cases. There is increased interest in the prognostic and predictive role of FDG-PET scans. Studies show that absence of metabolic response to neoadjuvant therapy correlates with poor pathologic response, and a favorable 18F-FDG-PET response appears to be associated with improved survival. Further work is underway to identify subsets of patients that might benefit individualized management based on FDG-PET.

The epichaperome is an integrated chaperome network that facilitates tumour survival

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes—dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically ‘rewired’ to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

High SUVmax on FDG-PET Indicates Pleomorphic Subtype in Epithelioid Malignant Pleural Mesothelioma: Supportive Evidence to Reclassify Pleomorphic as Nonepithelioid Histology

Background: We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as nonepithelioid (biphasic/sarcomatoid) histology because of its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM. Methods: Clinical data were collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0). Results: The median overall survival of epithelioid tumors with high SUVmax (n = 12) was significantly shorter (7.1 months) than that of epithelioid tumors with low SUVmax (n = 54, 18.9 months, p < 0.001) and comparable to nonepithelioid tumors (n = 12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n = 9) had marginally higher SUVmax (mean ± SD: 10.6 ± 5.9) than epithelioid nonpleomorphic subtype (n = 57, 6.5 ± 3.2, p = 0.050), and were comparable to that of nonepithelioid tumors (n = 12, 9.1 ± 4.8). Among the epithelioid tumors with high SUVmax (n = 12), 50% (n = 6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low SUVmax (n = 54), 6% (n = 3) showed epithelioid pleomorphic subtypes (p = 0.001). A positive correlation between mitotic count and SUVmax was observed (r = 0.30, p = 0.010). Conclusions: Pleomorphic subtype of epithelioid MPM showed higher SUVmax than the epithelioid nonpleomorphic subtype and was similar to nonepithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as nonepithelioid.

In vivo microcartography and subcellular imaging of tumor angiogenesis: A novel platform for translational angiogenesis research

PURPOSE To eliminate the variable of tumor heterogeneity from a novel in vivo model of tumor angiogenesis. EXPERIMENTAL DESIGN We developed a method to navigate tumor neovasculature in a living tissue microenvironment, enabling relocation of a cell- or microregion-of-interest, for serial in vivo imaging. Orthotopic melanoma was grown, in immunocompetent Tie2GFP mice. Intravital multiphoton fluorescence and confocal reflectance imaging was performed, on a custom microscope with motorized stage and coordinate navigation software. A point within a Tie2GFP+ microvessel was selected for relocation. Custom software predicted target coordinates based upon reference points (tissue-embedded polystyrene beads) and baseline target coordinates. Mice were removed from the stage to make previously-obtained target coordinates invalid in subsequent imaging. RESULTS Coordinate predictions always relocated target points, in vivo, to within 10-200 microm (within a single 40x field-of-view). The model system provided a virtual living histology of tumor neovascularization and microenvironment, with subcellular spatial resolution and hemodynamic information. CONCLUSIONS The navigation procedure, termed in vivo microcartography, permits control of tissue heterogeneity, as a variable. Tie2 may be the best reporter gene identified, to-date, for intravital microscopy of tumor angiogenesis. This novel model system should strengthen intravital microscopy in its historical role as a vital tool in oncology, angiogenesis research, and angiotherapeutic drug development.

Adaptive Neoadjuvant Chemotherapy Guided by 18 F-FDG PET in Resectable Non-Small Cell Lung Cancers: The NEOSCAN Trial

Introduction: Although perioperative chemotherapy improves survival in patients with resectable lung cancers, systemic recurrence remains common. Neoadjuvant chemotherapy permits response assessment and an opportunity to switch treatment regimens. Response measured by fludeoxyglucose (18F‐FDG) positron emission tomography (PET) correlates with clinical outcomes better than computed tomography (CT) does. This trial assessed PET‐measured response rate to alternative chemotherapy in patients with a suboptimal PET response after two cycles of neoadjuvant chemotherapy. Methods: This phase II study enrolled patients with resectable stage IB–IIIA lung cancers (primary tumor ≥ 2 cm and peak standard uptake value [SUVpeak] ≥ 4.5). Patients had a pretreatment 18F‐FDG PET/CT scan before two cycles of cisplatin (or carboplatin) plus gemcitabine (squamous cell carcinoma) or pemetrexed (adenocarcinoma) and then a repeat PET/CT scan. If SUVpeak in the primary tumor decreased by at least 35%, patients continued the initial chemotherapy. Individuals with less than a 35% PET response were switched to vinorelbine plus docetaxel. Postoperative radiotherapy was recommended to all patients with positive N2 nodes. A Simons optimal two‐stage design was used to evaluate the primary end point of a PET Response in Solid Tumors–defined response rate to vinorelbine plus docetaxel in previously nonresponding patients. Results: Forty patients were enrolled. Fifteen patients (38% [95% confidence interval: 38–53]) had less than a 35% decrease in SUVpeak, and 13 received vinorelbine plus docetaxel. The study met its primary end point with 10 of 15 PET metabolic responses to alternate therapy (67%). Chemotherapy toxicities never precluded surgical exploration. Conclusions: Utilizing 18F‐FDG PET/CT to assess response and change preoperative chemotherapy in nonresponding patients can improve radiographic measures of response. This adaptive approach can also be used to test new drugs, attempting to optimize perioperative chemotherapy to achieve better long‐term outcomes.

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

The revolution in cancer genomics has uncovered a variety of clinically relevant mutations in primary brain tumours, creating an urgent need to develop non-invasive imaging biomarkers to assess and integrate this genetic information into the clinical management of patients. Metabolic reprogramming is a central hallmark of cancer, including brain tumours; indeed, many of the molecular pathways implicated in the pathogenesis of brain tumours result in reprogramming of metabolism. This relationship provides the opportunity to devise in vivo metabolic imaging modalities to improve diagnosis, patient stratification, and monitoring of treatment response. Metabolic phenomena, such as the Warburg effect and altered mitochondrial metabolism, can be leveraged to image brain tumours using techniques including PET and MRI. Moreover, genetic alterations, such as mutations affecting isocitrate dehydrogenase, are associated with unique metabolic signatures that can be detected using magnetic resonance spectroscopy. The need to translate our understanding of the molecular features of brain tumours into imaging modalities with clinical utility is growing; metabolic imaging provides a unique platform to achieve this objective. In this Review, we examine the molecular basis for metabolic reprogramming in brain tumours, and examine current non-invasive metabolic imaging strategies that can be used to interrogate these molecular characteristics with the ultimate goal of guiding and improving patient care.

Coincidental presentations of ganglioneuroma and atypical perforated appendicitis detected by fluorodeoxyglucose positron emission tomography/computed tomography.

An 11-year-old boy presented with acute nausea and right lower quadrant pain. A contrast-enhanced CT demonstrated a 10-cm left retroperitoneal mass and no other suspicious findings. An fluorodeoxyglucose positron emission tomography/computed tomography performed 2 days later demonstrated inflammatory findings in the region of the appendix, hypermetabolic right psoas adenopathy, and the known retroperitoneal mass, which was less hypermetabolic. At laparoscopic surgery, an acute perforated appendicitis, walled-off by omentum, was discovered. Biopsy of the retroperitoneal mass was compatible with ganglioneuroma. This case exemplifies the utility of fluorodeoxyglucose positron emission tomography/computed tomography for detecting an inflammatory or infectious process coincident with a neighboring neoplastic process.