[18F]FDG PET/MRI enables early chemotherapy response prediction in pancreatic ductal adenocarcinoma

Purpose In this prospective exploratory study, we evaluated the feasibility of [18F]fluorodeoxyglucose ([18F]FDG) PET/MRI-based chemotherapy response prediction in pancreatic ductal adenocarcinoma at two weeks upon therapy onset. Material and methods In a mixed cohort, seventeen patients treated with chemotherapy in neoadjuvant or palliative intent were enrolled. All patients were imaged by [18F]FDG PET/MRI before and two weeks after onset of chemotherapy. Response per RECIST1.1 was then assessed at 3 months [18F]FDG PET/MRI-derived parameters (MTV50%, TLG50%, MTV2.5, TLG2.5, SUVmax, SUVpeak, ADCmax, ADCmean and ADCmin) were assessed, using multiple t-test, Man–Whitney-U test and Fisher’s exact test for binary features. Results At 72 ± 43 days, twelve patients were classified as responders and five patients as non-responders. An increase in ∆MTV50% and ∆ADC (≥ 20% and 15%, respectively) and a decrease in ∆TLG50% (≤ 20%) at 2 weeks after chemotherapy onset enabled prediction of responders and non-responders, respectively. Parameter combinations (∆TLG50% and ∆ADCmax or ∆MTV50% and ∆ADCmax) further improved discrimination. Conclusion Multiparametric [18F]FDG PET/MRI-derived parameters, in particular indicators of a change in tumor glycolysis and cellularity, may enable very early chemotherapy response prediction. Further prospective studies in larger patient cohorts are recommended to their clinical impact.

Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma

Background Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. Methods Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC. Results An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT. Conclusions Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.

Pan-Cancer analysis of clinical significance and associated molecular features of glycolysis

Background Tumor glycolysis acts as a major promoter of carcinogenesis and cancer progression. Given its complex mechanisms and interactions, a comprehensive analysis to reveal its clinical significance and molecular features is urgent. Materials and Methods Based on a well-established glycolysis gene expression signature, we quantified 8633 patients across different cancer types from The Cancer Genome Atlas (TCGA) and evaluated their prognostic associations. High tumor glycolytic activity correlated with inferior overall survival in pan-cancer patients (hazard ratio: 1.70, 95% confidence interval: 1.20–2.40, P = 0.003). The prognostic value of glycolysis was stable regardless of clinical parameters and correlated with molecular subtypes. The prognostic significance of glycolysis was validated using another three independent datasets. In addition, genome, transcriptome, and proteome profiles were utilized to characterize distinctive molecular features associated with glycolysis.Results Mechanistically, glycolysis fulfilled the fundamental needs of tumor proliferation in multiple ways. Exploration of the relationships between glycolysis and tumor infiltrating immune cells showed that glycolysis enabled immune evasion of tumor cells. Mammalian target of rapamycin inhibitors and dopamine receptor antagonists represent classes of compounds that can effectively reverse the glycolytic status of cancers.Conclusion Our study provides an in-depth molecular understanding of tumor glycolysis and may have practical implications for clinical cancer therapy.

Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

β-Asarone Increases Chemosensitivity by Inhibiting Tumor Glycolysis in Gastric Cancer

β-asarone is the main active ingredient of the Chinese herb Rhizoma Acori Tatarinowii, which exhibits a wide range of biological activities. It was confirmed to be an efficient cytotoxic agent against gastroenteric cancer cells. However, the exact mechanism of β-asarone in gastric cancer (GC) remains to be elucidated. The present study showed the inhibitory effect of β-asarone on three types of different differentiation stage GC cell lines (MGC803, SGC7901, and MKN74) in a dose-dependent manner. Meanwhile, the synergistic sensitivity of β-asarone and cisplatin was confirmed by using the median-effect principle. Flow cytometry assay revealed that under both normoxia and CoCl2-induced hypoxia conditions, β-asarone can induce apoptosis of GC cells, which can block GC cells in the cell cycle G2/M phase, showing obvious subdiploid peak. Moreover, the activity of lactic dehydrogenase (LDH), an enzyme that plays an important role in the final step of tumor glycolysis, was significantly decreased in GC cells following treatment with β-asarone. Mechanistically, β-asarone can reduce pyruvate dehydrogenase kinase (PDK) 1, phospho(p)-PDK1, PDK4, hypoxia-inducible factor 1-α (HIF1α), c-myc, STAT5, and p-STAT5 expression, which revealed how β-asarone affects tumor glycolysis. In conclusion, the present study provided evidence in support of the hypothesis that the increase of chemotherapy sensitization by β-asarone is associated with the inhibition of tumor glycolysis.