Summary Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.

SUMMARY Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intra-operative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.

Purpose To evaluate the accuracy and reproducibility of quantitative chemical shift-encoded MRI (CSE-MRI) to quantify proton-density fat-fraction (PDFF) in a fat-water phantom across sites, vendors, field strengths and protocols. Methods Six sites (three vendors: GE/Philips/Siemens) participated in this study. A phantom containing multiple vials with various oil-water suspensions (PDFF:0–100%) was built, shipped to each site and scanned at 1.5T and 3T using two CSE protocols per field strength. Confounder-corrected PDFF maps were reconstructed using a common algorithm. To assess accuracy, PDFF bias and linear regression with the known PDFF were calculated. To assess reproducibility, measurements were compared across sites, vendors, field strengths and protocols using analysis of covariance (ANCOVA), Bland-Altman analysis and the intra-class correlation coefficient (ICC). Results PDFF measurements showed overall absolute bias (across sites, field strengths and protocols)=0.22% with 95% CI:(0.07%,0.38%), and R2>0.995 relative to the known PDFF at each site, field strength and protocol (slopes: 0.96–1.02, intercepts: −0.56%–1.13%). ANCOVA did not show effects of field strength (p=0.36), or protocol (p=0.19). There was a significant effect of vendor (F=25.13,p=1.07×10−10), with bias= −0.37% (Philips) and −1.22% (Siemens) relative to GE. The overall ICC was 0.999. Conclusion CSE-based fat quantification is accurate and reproducible across sites, vendors, field strengths and protocols.

Childhood epilepsy has a severe impact on parental QOL and psychological health, and recognition of possible correlations between parental QOL and background variables will be helpful to improve parental QOL.

Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the a subunit, which heterodimerizes with HIF1b, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control !4 months was achieved in 42% of patients.Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n ¼ 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNAsequencing studies.Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2a, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance.Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).