Tumor Glucose Utilization Research Articles

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma.

In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood. We retrospectively included 19 EwS samples (17 patients). Affymetrix gene expression was correlated with maximal standardized uptake value (SUVmax) using machine learning, linear regression modelling, and gene set enrichment analyses for functional annotation. Expression of five genes correlated (MYBL2, ELOVL2, NETO2) or anticorrelated (FAXDC2, PLSCR4) significantly with SUVmax (adjusted p-value ≤ 0.05). Additionally, we identified 23 genes with large SUVmax effect size, which were significantly enriched for "neuropeptide Y receptor activity (GO:0004983)" (adjusted p-value = 0.0007). The expression of the members of this signaling pathway (NPY, NPY1R, NPY5R) anticorrelated with SUVmax. In contrast, three transcription factors associated with maintaining stemness displayed enrichment of their target genes with higher SUVmax: RNF2, E2F family, and TCF3. Our large-scale analysis examined comprehensively the correlations between transcriptomics and tumor glucose utilization. Based on our findings, we hypothesize that stemness may be associated with increased glucose uptake, whereas neuroectodermal differentiation may anticorrelate with glucose uptake.

Higher SUVmax on FDG-PET is associated with shorter survival in adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is an aggressive, rare malignancy. 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) assesses tumor metabolism and glucose utilization. We hypothesized that higher maximum standard uptake value (SUVmax) is associated with decreased survival. MethodsWe performed a retrospective analysis of patients with ACC. Included patients (n = 26) had an FDG-PET scan available with a documentable SUVmax. Patients were dichotomized into “High” (≥8.4, n = 12) and “Low” (<8.4, n = 14) SUVmax. Univariate analysis and survival analysis were performed to compare groups. ResultsDemographics between groups were equivalent. The high SUVmax cohort demonstrated lower survival (median 479 days or 15.7 months) compared to the low group (median 1490 days or 48.6 months, p = .01). Log-Rank curve confirmed differences in survival (p = .007). ConclusionsHigher SUVmax was associated with significantly worse survival in ACC and may reflect a more aggressive phenotype. FDG-PET may provide clinically useful information to determine prognosis and treatment. Further studies should prospectively evaluate using FDG-PET/CT in ACC.

CTNI-14. EVALUATING METABOLIC ALTERATIONS IN PATIENTS WITH EGFR ACTIVATED RECURRENT GLIOBLASTOMA (RGBM) BY INHIBITING EGFR WITH OSIMERTINIB

Abstract BACKGROUND EGFR activated GBM is highly metabolically active and effective targeting with EGFR TKis in human-tumor models rapidly attenuates glucose metabolism engaging apoptotic machinery. Rapid changes in glucose uptake using 18F-FDG-PET is an effective predictive biomarker of therapeutic response in these models. Clinical 18F-FDG-PET may allow investigators to obtain early readout on EGFR TKi in this patient population. We explore this approach using osimertinib in EGFRamp/p53wt rGBM. METHODS EGFRamp/p53wt rGBM patients were treated with oral osimertinib 240mg for three days followed by 160mg/day until progression. F18-FDG-PET scan was obtained as a double baseline, 24 hours apart, prior to dosing with osimertinib. Third scan was obtained after 3 doses of 240mg. Primary objective defines test-retest variance of tumor FDG uptake before osimertinib and to evaluate if osimertinib significantly decreases glucose utilization after three doses. Study-drug and funding provided by AstraZeneca. RESULTS 12 pts were evaluated, 10 female, median age 57.5 years (44-61). Volumetric mRANO showed no responses, 6 SD, 5 PD, and one NE. Median PFS was 31 days, no patient achieved 6-month-PFS and median OS was 5.5 months. No new adverse event signal appeared. Double baseline PET SUV mean was 0.97 (normalized to whole cerebellum) with upward trend from first to second scan with mean percent change of 2.8 and 95% CI(0.7,5.1). Change in PET from 2nd to 3rd showed mean percent change -3.2 with 95% CI (-11.1,4.8). Preclinical models suggest 15-20% attenuation is needed to predict improved outcomes in patients treated with EGFR-TKi. CONCLUSION F18-FDG-PET has little variance with test-retest showing upward trend with second scan. Post osimertinib F18-FDG-PET shows limited attenuation of tumor FDG uptake. No clinical signal was seen in study. Deeper attenuation of FDG uptake may be needed to show clinical effect from EGFR inhibitors. F18-FDG-PET can be used to evaluate change in tumor glucose utilization.

A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers.

Since Warburg's observation that most cancers exhibit elevated glycolysis, decades of research have attempted to reduce tumor glucose utilization as a therapeutic approach. Hexokinase (HK) activity is the first glycolytic enzymatic step; despite many attempts to inhibit HK activity, none has reached clinical application. Identification of HK isoforms, and recognition that most tissues express only HK1 while most tumors express HK1 and HK2, stimulated reducing HK2 activity as a therapeutic option. However, studies using HK2 shRNA and isogenic HK1+HK2- and HK1+HK2+ tumor cell pairs demonstrated that tumors expressing only HK1, while exhibiting reduced glucose consumption, progressed in vivo as well as tumors expressing both HK1 and HK2. However, HK1-HK2+ tumor subpopulations exist among many cancers. shRNA HK2 suppression in HK1-HK2+ liver cancer cells reduced xenograft tumor progression, in contrast to HK1+HK2+ cells. HK2 inhibition, and partial inhibition of both oxidative phosphorylation and fatty acid oxidation using HK2 shRNA and small-molecule drugs, prevented human liver HK1-HK2+ cancer xenograft progression. Using human multiple myeloma xenografts and mouse allogeneic models to identify potential clinical translational agents, triple therapies that include antisense HK2 oligonucleotides, metformin, and perhexiline prevent progression. These results suggest an agnostic approach for HK1-HK2+ cancers, regardless of tissue origin.

Utilization of18F-Fluorodeoxyglucose–Positron Emission Tomography To Understand the Mechanism of Nicotinamide Phosphoribosyltransferase Inhibitors In Vivo

Cancer cells are highly dependent on NAD+/NADH produced via the nicotinamide salvage pathway. The rate-limiting enzyme in this pathway is the nicotinamide phosphoribosyltransferase (NAMPT), which we have targeted with novel NAMPT inhibitors. NAMPT inhibition elicits depletion of total cellular NAD+ levels and ultimately cytotoxicity via depletion of cellular ATP levels. 18F-fluorodeoxyglucose- positron emission tomography (FDG-PET) is a translational imaging tool to assess glucose utilization in tumors and normal tissue. We used FDG-PET to understand the timing of ATP depletion in vivo and better understand the pharmacology of NAMPT inhibitors. Because of the intimate relationship between cellular ATP levels and cell viability, we developed an in-depth understanding of our NAMPT inhibitor pharmacology and the relationship with changes in tumor FDG uptake. Taken together, we show that FDG-PET could be used as a biomarker in clinical studies to understand dose and provide proof of mechanism for NAMPT inhibitors. SIGNIFICANCE STATEMENT: Our imaging data suggest that tumor 18F-fluorodeoxyglucose uptake can provide insight into the ATP status inside the tumor after nicotinamide phosphoribosyltransferase (NAMPT) therapy, with a novel NAMPT inhibitor. Such an approach could be used clinically as a pharmacodynamic biomarker to help understand the implications of dose, schedule, rescue strategy, or other clinical biomarkers.

Abstract 3045: Pilot study of kernel-based dynamic (KBD) FDG-PET in patients with borderline resectable pancreatic cancer

Abstract Introduction: Patients (pts) with borderline resectable (BR) pancreatic cancer (PC) derive a clear survival benefit when margin-negative resection can be achieved after neoadjuvant treatment (tx). As such, reliable imaging is desperately needed to identify those patients with the best chance of surgical benefit. Current imaging with CT/MRI and standard 18F-fludeoxyglucose (FDG) PET lacks sensitivity and specificity to resolve residual tumor contact with the large blood vessels of the vascular groove. Dynamic PET with kernel-based image reconstruction developed by our group has potential to overcome limits of standard static PET by robust parametric imaging of radiotracer kinetics. KBD FDG-PET provides the FDG kinetic parameter K1 for tumor perfusion and Ki for tumor glucose utilization. A lower Ki/K1 ratio indicates a better perfused, less metabolically active tumor and is derived by our method without need for separate perfusion CT/MRI. Methods: Pts with PC staged as BR as defined by consensus guidelines were eligible. Pts were assessed by CA 19-9 and CT/MRI along with KBD FDG-PET both pre-tx and post-tx. KBD FDG PET was performed by IV bolus of 10 mCi of FDG followed by 60-min PET data acquisition. A 3-compartment model with 5 micro kinetic parameters K1, k2, k3, k4, and fv was used where K1 (mL/min/mL) denotes the rate constant of FDG transport from plasma to tissue, k2 (1/min) the transport rate from tissue to plasma, k3 (1/min) the rate of FDG conversion to FDG 6-phosphate, k4 (1/min) the rate of dephosphorylation, and fv the fractional blood volume. Ki was calculated from micro parameters by the formula K1*k3/(k2+k3). Parametric images of these kinetic parameters were obtained by voxel-wise implementation of kinetic modeling. Results: 4 pts were enrolled, 3 pts had pre- and post-tx KBD FDG-PET, and 2 pts were resected. In the 3 evaluable pts, an overall 62% decrease in tumor glucose utilization was observed (mean pre-tx Ki=.03, [range .013-.045]; mean post-tx Ki=.011 [range .004-.016]. Mean pre-tx K1=.37 (range .26-.50) and mean post-tx K1=.38 (range .31-.46). Delta Ki was -17%, -47%, and -91% and delta Ki/K1 was -9%, -28%, and -95% in pts 1, 2, 3 respectively. Pt 3 had the highest pre-tx Ki and the lowest pre-tx K1, but had a &amp;gt;90% decrease in Ki and Ki/K1 post-tx, indicating a significant decrease in metabolic activity and concomitant increase in perfusion. Despite persistent superior mesenteric vein (SMV) abutment on standard post-tx imaging, margin-negative resection was achieved. In contrast, pt 1 had the lowest pre-tx Ki and highest pre-tx K1, but had a &amp;lt;20% decrease in Ki and Ki/K1 post-tx. Like Pt 3, Pt 1 also had SMV contact on standard post-tx imaging, but in contrast, experienced margin-positive resection. Conclusions: KBD FDG-PET is a promising modification of standard static PET that provides useful kinetic parameters for evaluation of PC resectability. Citation Format: John P. Schwerkoske, Guobao Wang, Kit W. Tam, Jasmine C. Huynh, Heather H. Hunt, Michael L. Rusnak, Cameron C. Foster, Michael T. Corwin, Karen E. Matsukuma, Dorina Gui, May T. Cho, Richard J. Bold, Ramsey D. Badawi, Edward J. Kim. Pilot study of kernel-based dynamic (KBD) FDG-PET in patients with borderline resectable pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3045.

Heterogeneity in Cancer Metabolism: New Concepts in an Old Field.

Significance: In the last years, metabolic reprogramming, fluctuations in bioenergetic fuels, and modulation of oxidative stress became new key hallmarks of tumor development. In cancer, elevated glucose uptake and high glycolytic rate, as a source of adenosine triphosphate, constitute a growth advantage for tumors. This represents the universally known Warburg effect, which gave rise to one major clinical application for detecting cancer cells using glucose analogs: the positron emission tomography scan imaging.Recent Advances: Glucose utilization and carbon sources in tumors are much more heterogeneous than initially thought. Indeed, new studies emerged and revealed a dual capacity of tumor cells for glycolytic and oxidative phosphorylation (OXPHOS) metabolism. OXPHOS metabolism, which relies predominantly on mitochondrial respiration, exhibits fine-tuned regulation of respiratory chain complexes and enhanced antioxidant response or detoxification capacity.Critical Issues: OXPHOS-dependent cancer cells use alternative oxidizable substrates, such as glutamine and fatty acids. The diversity of carbon substrates fueling neoplastic cells is indicative of metabolic heterogeneity, even within tumors sharing the same clinical diagnosis. Metabolic switch supports cancer cell stemness and their bioenergy-consuming functions, such as proliferation, survival, migration, and invasion. Moreover, reactive oxygen species-induced mitochondrial metabolism and nutrient availability are important for interaction with tumor microenvironment components. Carcinoma-associated fibroblasts and immune cells participate in the metabolic interplay with neoplastic cells. They collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus participating in tumorigenesis and resistance to treatments.Future Directions: Characterizing the reciprocal metabolic interplay between stromal, immune, and neoplastic cells will provide a better understanding of treatment resistance. Antioxid. Redox Signal. 26, 462–485.

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.

Clinical application of 18F-fluorodeoxyglucose positron emission tomography for assessment and evaluation after therapy for malignant hepatic tumor.

Positron emission tomography (PET) is widely available and its application with 2-[18F] fluoro-2-deoxy-d-glucose (18F-FDG) in oncology has become one of the standard imaging modalities in diagnosing and staging of tumors, and monitoring the therapeutic efficacy in hepatic malignancies. Recently, investigators have measured glucose utilization in liver tumors using 18F-FDG and positron emission tomography/computer tomography (PET/CT) in order to establish a diagnosis of tumors, assess their biologic characteristics and predict therapeutic effects on hepatic malignancies. The PET/CT with 18F-FDG may further enhance the hepatic malignancy diagnostic algorithm by accurate diagnosis, staging, restaging and evaluating its biological characteristics, which can benefit the patients suffering from primary and metastatic hepatic tumors such as hepatocellular carcinoma (HCC), cholangiocarcinoma (CCC), and metastatic liver tumor.

Abstract 1003: A link between lactate dehydrogenase A, lactate and tumor phenotype identified by imaging

Abstract Metabolic changes in primary tumors have a significant impact on tumor progression and on the development of the metastatic phenotype. In cancer patients, serum total lactate dehydrogenase (LDH) levels are often increased, and the gene for LDH-A protein, is frequently upregulated in tumors (Koukourakis, Giatromanolaki et al. 2003). These features have been linked to poor prognosis, and a greater metastatic potential has been reported in patients with high LDH serum levels. Since LDH-A protein is required for the maintenance and progression of many tumors (Fantin, St-Pierre et al. 2006), it is also becoming a potential target for cancer therapy (Le, Cooper et al. 2010; Seth, Grant et al. 2011). We investigated the relationship between LDH-A expression and lactate production in two isogenic breast cancer lines (67NR and 4T1) (Serganova, Rizwan et al. 2011). These two cell lines were derived from a single mammary tumor that developed spontaneously in a BALB/c mouse. Each subclone was shown to have different phenotypic properties (Aslakson and Miller 1992). LDH-A expression, lactate concentration, glucose utilization and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels (measured by magnetic resonance spectroscopic imaging (MRSI)) and tumor glucose utilization (measured by [18F] 2-deoxy-2-fluoro-D-glucose positron emission tomography ([18F]FDG-PET)) was assessed in orthotopic breast tumors derived from these cell lines. We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate ten-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less intense hypoxia staining was observed in the larger 67NR tumors, and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. We show that lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure to evaluate the aggressive and metastatic potential of primary breast tumors. We hypothesized that tumor lactate levels monitored by MRSI will reflect LDH-A enzymatic activity and tumor phenotype. We also suggest that lactate-MRSI is a more sensitive measure than [18F]FDG-PET, and could be used in the clinic to evaluate the aggressive potential of primary breast tumors. Aslakson, C. J. and F. R. Miller (1992). Cancer Res 52(6): 1399-1405. Fantin, V. R., J. St-Pierre, et al. (2006). Cancer Cell 9(6): 425-434. Koukourakis, M. I., A. Giatromanolaki, et al. (2003). Br J Cancer 89(5): 877-885.Le, A., C. R. Cooper, et al. (2010). Proc Natl Acad Sci U S A 107(5): 2037-2042. Serganova, I., A. Rizwan, et al. (2011). Clin Cancer Res 17(19): 6250-6261. Seth, P., A. Grant, et al. (2011). Neoplasia 13(1): 60-71. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1003. doi:1538-7445.AM2012-1003

Metabolic Imaging: A Link between Lactate Dehydrogenase A, Lactate, and Tumor Phenotype

We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. LDH-A expression, lactate concentration, glucose utilization, and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels [measured by magnetic resonance spectroscopic imaging (MRSI)] and tumor glucose utilization [measured by [(18)F]2-deoxy-2-fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET)] was assessed in orthotopic breast tumors derived from these cell lines. We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate 10-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less-intense hypoxia staining was observed in the larger 67NR tumors and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Lactate-MRSI has a greater dynamic range than [(18)F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors.

Emetine Promotes von Hippel-Lindau-Independent Degradation of Hypoxia-Inducible Factor-2α in Clear Cell Renal Carcinoma

Inactivating mutations of the von Hippel-Lindau (VHL) tumor suppressor gene are associated with inherited VHL syndrome, which is characterized by susceptibility to a variety of neoplasms, including central nervous system hemangioblastoma and clear cell renal cell carcinoma (CCRCC). Mutations in the VHL gene are also found in the majority of sporadic clear cell renal carcinoma, the most common malignant neoplasm of the human kidney. Inactivation of VHL ubiquitin ligase is associated with normoxic stabilization of hypoxia-inducible factor-1α and 2-α (HIF-1α and HIF-2α), transcriptional regulators of tumor angiogenesis, invasion, survival, and glucose utilization. HIF-2α has been particularly implicated in the development of CCRCC. Although several inhibitors of HIF-1α have been described, these drugs typically have a minimal affect on HIF-2α. 786-O is a VHL-deficient CCRCC cell line that constitutively expresses only HIF-2α and is therefore suitable for the screening of novel HIF-2α inhibitors. Using this cell line, we have identified emetine as a specific inhibitor of HIF-2α protein stability and transcriptional activity. Without altering HIF-2α mRNA level, emetine rapidly and dramatically down-regulated HIF-2α protein expression in 786-O cells. HIF-2α down-regulation was accompanied by HIF-2α ubiquitination and was reversed by proteasome inhibition. Emetine-induced HIF-2α down-regulation was confirmed in three additional VHL-renal cancer cell lines, was insensitive to the prolyl hydroxylase inhibitor dimethyloxaloyl glycine, and did not require neural precursor cell expressed developmentally down-regulated-8, suggesting that emetine accesses a previously undescribed cullin-independent proteasome degradation pathway for HIF-2α. These data support the use of emetine or structurally related compounds as useful leads for the identification of novel HIF-2α inhibitors.

Correlation between FLT-PET and Ki-67 change in breast cancer during neoadjuvant chemotherapy.

TPS182 Background: [18F]-fluorothymidine (FLT) PET is an emerging imaging modality that measures change in cellular uptake of a radiolabeled thymidine analogue and may provide a more direct assessment of alterations in cell proliferation than changes in tumor size or glucose utilization. FLT-PET may be a useful tool in early clinical development for new oncology therapeutics. A high correlation between pre-treatment FLT uptake and Ki-67 expression in breast and lung cancer has been shown in small studies, but there have been no studies examining the correlation between change in FLT uptake and change in tissue-based measures of proliferation. The goal of this study is to determine whether a change in breast tumor FLT-PET standardized uptake value (SUV), pre- and post-treatment, correlates with the change in tumor Ki-67 labeling index (LI) during the same period. In addition, the correlation between change in tumor volume and the change in FLT uptake, Ki-67 LI, or a gene signature of cell proliferation wil...

Acetylsalicylic acid and salicylic acid decrease tumor cell viability and glucose metabolism modulating 6-phosphofructo-1-kinase structure and activity

The common observation that cancer cells present higher glycolytic rates when compared to control cells leads to the proposal of glycolysis as a potential target for the development of anti-tumoral agents. Anti-inflammatory drugs, such as acetylsalicylic acid (ASA) and salicylic acid (SA), present anti-tumoral properties, inducing apoptosis and altering tumor glucose utilization. The present work aims at evaluating whether ASA could directly decrease cell glycolysis through inhibition of the major regulatory enzyme within this pathway, 6-phosphofructo-1-kinase (PFK). We show that ASA and SA inhibit purified PFK in a dose-dependent manner, and that this inhibition occurs due to the modulation of the enzyme quaternary structure. ASA and SA promote the dissociation of the enzyme active tetramers into quite inactive dimers, a common regulatory mechanism of this enzyme. The inhibitory effects of ASA and SA on PFK are fully reversible and can be prevented or reverted by the binding of the enzyme to the actin filaments. Both drugs are also able to decrease glucose consumption by human breast cancer cell line MCF-7, as well as its viability, which decrease parallelly to the inhibition of PFK on these cells. In the end, we demonstrate the ability of ASA and SA to directly modulate an important regulatory intracellular enzyme, and propose that this is one of their mechanisms promoting anti-tumoral effects.

Imaging of tumor glucose utilization with positron emission tomography

In recent years, imaging of tumor glucose metabolism with positron emission tomography and fluorodeoxyglucose (FDG-PET) has become a routine test for detection, staging and restaging of malignant lymphomas and many solid tumors. FDG-PET is also increasingly used to monitor the effects of chemotherapy. The success of FDG-PET in oncologic imaging has generated considerable interest in understanding the molecular mechanisms underlying the markedly accelerated glucose use of almost all human cancers. Recent studies have indicated that there may be a close relation between the activation of oncogenic signaling pathways and cellular glucose utilization. For example deregulation of Akt, ras and MYC as well as loss of p53 function have been reported to confer increased glucose metabolic rates in cancer cells. These findings suggest that imaging of tumor glucose utilization may represent a marker for the activity of oncogenic pathways and metabolic changes during therapy may be used as a readout for the effectiveness of drugs targeting these pathways. However, the mechanisms for increased glucose metabolic activity of cancers cells are multifactorial and clinical studies will be necessary to determine in which context imaging of tumor glucose metabolism may be used for treatment monitoring.

Utility of decreased FDG SUV as a response and prognostic indicator in multiple myeloma therapy with BiRD

8607 Background: To assess the utility of post-treatment [Rx] FDG SUV decrease from pre-Rx SUV as an indicator of response and prognosis [RPI] in Multiple Myeloma [MM] patients [pts] receiving BiRD therapy. Methods: 11 pts [6 M; 5 F] with active clinical and serologic MM [Salmon-Dury Class IIa (4), IIIa (6), III (1)] had FDG PET/CT pre and post BiRD Rx. Iliac crest [IC] and Index Lesion [IL] SUV obtained from images 60 min post 12–15 mCi FDG pre & post BiRD [Biaxin, lenalidomide (R) & Dexamethasone [D], 40 mg on day 1, 2,3,8,15 and 22]. BiRD is an innovative 23 day immunomodulator regimen in clinical trials for MM treatment. Pre and post Rx interval varied from 3–12 months depending upon pts ability to tolerate protocol. Results: 4 pts had CR; 4 PR; 3 minimal Respnse [mR]. Mean pre Rx SUV for CR: Rt IC/Lt IC/IL =3.9, 3.9, 6.7; PR = 5.1, 3.9, 9.3; mR = 3.5, 3.7, 3.6. Mean Post-Rx SUV: CR = 2.1, 2.2, 2.5; PR = 2.2, 2.1, 5.2; mR = 2.9, 2.4, 1.7. % Change SUV for CR = 46, 41, 44; PR = 50, 46, 54; mR = 0, 37, 49. Zero value due to 1 outlier; otherwise average 36%. Conclusions: Whereas post Rx SUV change is a promising RPI in many tumors, it was not useful in MM pts Rx with BiRD. 41–54% SUV decrease was seen regardless of clinical response. BiRD involves high doses of D which inhibits tumor glucose utilization. Effect of D dose and interval to FDG PET is undetermined in MM. Steroid administration may be another variable affecting FDG SUV. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene Celgene

Imaging Update: New Windows, New Views

The recent progress in our understanding of the molecular-genetic mechanisms active in many diseases and the application of new biologically based approaches in therapy are exciting new developments that have emerged following mapping of the human genome. Novel “molecular therapies” have been

Positron emission tomography/computer tomography: Challenge to conventional imaging modalities in evaluating primary and metastatic liver malignancies

Computer tomography (CT) and magnetic resonance imaging (MRI), as conventional imaging modalities, are the preferred methodology for tumor, nodal and systemic metastasis (TNM) staging. However, all the noninvasive techniques in current use are not sufficiently able to identify primary tumors and even unable to define the extent of metastatic spread. In addition, relying exclusively on macromorphological characteristics to make a conclusion runs the risk of misdiagnosis due mainly to the intrinsic limitations of the imaging modalities themselves. Solely based on the macromorphological characteristics of cancer, one cannot give an appropriate assessment of the biological characteristics of tumors. Currently, positron emission tomography/computer tomography (PET/CT) are more and more widely available and their application with (18)F-fluorodeoxyglucose ((18)F-FDG) in oncology has become one of the standard imaging modalities in diagnosing and staging of tumors, and monitoring the therapeutic efficacy in hepatic malignancies. Recently, investigators have measured glucose utilization in liver tumors using (18)F-FDG, PET and PET/CT in order to establish diagnosis of tumors, assess their biologic characteristics and predict therapeutic effects on hepatic malignancies. PET/CT with (18)F-FDG as a radiotracer may further enhance the hepatic malignancy diagnostic algorithm by accurate diagnosis, staging, restaging and evaluating its biological characteristics, which can benefit the patients suffering from hepatic metastases, hepatocellular carcinoma and cholangiocarcinoma.

Monitoring Tumor Glucose Utilization by Positron Emission Tomography for the Prediction of Treatment Response to Epidermal Growth Factor Receptor Kinase Inhibitors

The mechanisms underlying the sensitivity of non-small cell lung cancer to epidermal growth factor receptor (EGFR) kinase inhibitors are complex, and there are no established markers to accurately predict treatment outcome in individual patients. We investigated whether tumors responding to EGFR inhibitors can be identified by measuring treatment-induced changes in glucose utilization by positron emission tomography with the glucose analogue fluorodeoxyglucose (FDG-PET). We studied a panel of cell lines with a spectrum of sensitivity to EGFR kinase inhibitors. After incubation with the EGFR kinase inhibitor gefitinib for various time points, FDG uptake, glucose transport rates, and hexokinase activity were determined. FDG uptake in vivo was assessed by microPET imaging of tumor xenografts in mice. In gefitinib-sensitive cell lines, there was a dramatic decrease in FDG uptake as early as 2 hours after treatment. Immunoblots showed the translocation of glucose transporters (GLUT3) from the plasma membrane to the cytosol; glucose transport rates were reduced 2.6-fold at this time. There was also a modest reduction of hexokinase activity. These metabolic alterations preceded changes in cell cycle distribution, thymidine uptake, and apoptosis. MicroPET studies showed an up to 55% decrease of tumor FDG uptake in sensitive xenografts within 48 hours. In contrast, gefitinib-resistant cells exhibited no measurable changes in FDG uptake, either in cell culture or in vivo. Glucose metabolic activity closely reflects response to gefitinib therapy. FDG-PET may be a valuable clinical predictor, early in the course of treatment, for therapeutic responses to EGFR kinase inhibitors.

Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction

A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response. Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET. Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients. This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.