Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation.

GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual's risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.

Post-therapeutic microRNA-146a in liquid biopsies may determine prognosis in metastatic gastrointestinal cancer patients receiving 90Y-radioembolization.

PURPOSE: The role of microRNA-146a (miR-146a) in defining the tumor immune microenvironment (TIME) is well established. The aim of this study was to evaluate circulating miR-146a as an early prognostic marker of 90Y-radioembolization (90Y-RE) in metastatic liver cancer and to assess the correlation between circulating miR-146a and TIME cellular composition in distant, yet untreated metastases. METHODS: Twenty-one patients with bilobar liver lesions from gastro-intestinal cancer underwent lobar 90Y-RE. Biopsy of contralateral lobe abscopal tumors was acquired at the onset of a second treatment session at a median of 21 days after initial RE, immediately prior to ablation therapy of the contralateral lobe tumor. miR-146a was measured by RT-qPCR in plasma collected 24 h before (T1) and 48 h after (T2) initial unilobar 90Y-RE. The level of miR-146a was correlated with the infiltration of CD4 + , CD8 + , FoxP3 T cells, CD163 + M2 macrophages and immune-exhausted T cells in the abscopal tumor tissue acquired before the second treatment session. RESULTS: Plasma samples collected at T2 showed a higher concentration of miR-146a with respect to T1 in 43% of the patients (p = 0.002). In these patients, tumors revealed a pro-tumorigenic immune composition with enrichment of Tim3 + immune exhausted cells (p = 0.021), in combination with a higher infiltration of CD163 + M2 macrophages and a lower infiltration of CD8 + T cells. Patients with a higher level of miR-146a after 90Y-RE showed a trend to shorter OS (p = 0.055). CONCLUSION: miR-146a may represent a novel prognostic biomarker for 90Y-radioembolization in metastatic liver cancer.

Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19.

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.

MEK1/2 regulates APOBEC3B and polymerase iota-induced mutagenesis in head and neck cancer cells.

Resistance to chemotherapy provides a major challenge in treatment of metastatic cancer. Prolonged exposure to almost any drug regimen leads to the formation of resistant subclones in almost all advanced solid tumors. Tumor heterogeneity because of intrinsic genetic instability is seen as one of the major contributing factors. In this work, we present evidence that genetic instability measured by mutation frequency is induced by treatment with the EGFR inhibitor afatinib or cisplatin in head and neck squamous cancer cells. We find that APOBEC3B and polymerase iota are upregulated, and inhibition of MEK1/2 by U0126 leads to downregulation on the protein level. Costimulation of afatnib and cisplatin with U0126 leads to a significantly lower mutation frequency. These findings may represent a molecular mechanism for dynamically controlling genetic instability during chemotherapy in head and neck squamous cell carcinoma (HNSCC) cancer cells.

Prognostic value of indoleamine 2,3 dioxygenase in patients with higher-risk myelodysplastic syndromes treated with azacytidine.

Hypomethylating agents (HMAs) are widely used in patients with higher-risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine-2,3-dioxygenase (IDO-1) has not yet been evaluated. We observed moderate to strong IDO-1 expression in 37% of patients with high-risk MDS. IDO-1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO-1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO-1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO-1+ MDS, suggesting that IDO-1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO-1 is expressed in more than one-third of patients with higher-risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO-1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors.

c-Rel gain in B cells drives germinal center reactions and autoantibody production.

Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.

Bradykinin Receptor B1 and C-Reactive Protein as Prognostic Factors for Pharyngocutaneous Fistula Development After Laryngectomy.

Pharyngocutaneous fistulae (PCF) are one of the most common complications after laryngectomy. Predisposing risk factors have been studied, yet knowledge to determine which patients are prone to developing a fistula remains scarce. This study aims to establish prognostic parameters to identify individual patients at risk for PCF development. As PCF and inflammation seem to be interwoven, this work focuses on markers able to detect an inflammatory response. We retrospectively analyzed all patients who had undergone a laryngectomy at our clinic in the years 2007 to 2017 (n = 182). Immunohistochemical expression of bradykinin type 1 and 2 receptor and vascular endothelial growth factor receptor 2 was studied in all available tumor samples. Additionally, the clinical inflammation parameters 'body temperature', 'pain', 'c-reactive protein (CRP)', and 'leucocytes' were postoperatively tracked in all patients. The times between fistula diagnosis, therapeutic approach, and hospital discharge were recorded. We found a strong correlation between inflammation and the formation of a fistula. High bradykinin 1 receptor expression in the tumor samples correlated with postoperative PCF development. Persistently elevated CRP and leukocyte levels beyond the 6th postoperative day were also risk factors. A decreased time lapse between PCF diagnosis and surgical revision clearly correlated with a shorter hospital stay. In this study, we identified a bradykinin 1 receptor positive patient group at high risk for development of PCF. We recommend close monitoring for fistula formation in these patients to ensure timely intervention.

Membrane Hsp70-A Novel Target for the Isolation of Circulating Tumor Cells After Epithelial-to-Mesenchymal Transition.

The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre-requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)-an essential element of the metastatic process-is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the "capture" of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)-cmHsp70.1-can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression.

High NOTCH1 mRNA Expression Is Associated with Better Survival in HNSCC.

The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer (HNSCC) patient tissue and cell lines. We analyzed tissue from 195 HNSCCs and tissue from 30 normal patients for mRNA expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 using quantitative real-time PCR. Association of expression results and clinical orpathological factors was examined with multivariate Cox regression. NOTCH1 expression was determined in three Human Papilloma Virus (HPV)-positive and nine HPV-negative HNSCC cell lines. High expression of NOTCH1 was associated with better overall survival (p = 0.013) and disease-free survival (p = 0.040). Multivariate Cox regression confirmed the significant influence of NOTCH1 expression on overall survival (p = 0.033) and disease-free survival (p = 0.029). A significant correlation was found between p16 staining and NOTCH1 mRNA expression (correlation coefficient 0.28; p = 0.01). NOTCH1 was expressed at higher levels in HPV-positive HNSCC cell lines compared with HPV-negative cell lines, which was not statistically significant (p = 0.068). We conclude that NOTCH1 expression is associated with overall survival, and that inhibition of NOTCH1 therefore seems less promising.

Improved overall survival in head and neck cancer patients after specific therapy of distant metastases.

PURPOSE: While metastases directed therapy for oligometastatic disease is recommended in different cancer entities, the treatment of solitary metastases in head and neck squamous cell carcinoma (HNSCC) patients is not clearly defined. METHODS: A retrospective analysis was performed on data from 143 HNSCC patients treated between 2001 and 2016 in a tertiary university hospital. Clinical factors and outcome were measured using the median survival of patients receiving metastases specific therapy in comparison with matched control patients. RESULTS: In 37 patients, distant metastases were treated specifically with either surgery and/or stereotactic ablative radiotherapy and had with 23.97 months a more than three times higher median survival than 10 untreated matched controls with potentially treatable distant metastases (7.07 months). CONCLUSIONS: Our retrospective analysis demonstrates a significant survival benefit for HNSCC patients who received a specific therapy regarding distant metastasis irrespective of localization as compared to a matched control cohort.

The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma.

Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680. In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression. High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line. These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.

Epidermal growth factor receptor variant III in head and neck squamous cell carcinoma is not relevant for targeted therapy and irradiation.

BACKGROUND: The epidermal growth factor receptor (EGFR) is an important regulator of cell growth and survival, and is highly variable in tumor cells. The most prevalent variation of the EGFR extracellular domain is the EGFR variant III (EGFRvIII). Some studies imply that EGFRvIII may be responsible for the poor response to the monoclonal EGFR-antibody Cetuximab, used therapeutically in head and neck squamous cell carcinoma (HNSCC). Due to inconsistent data in the literature regarding EGFRvIII prevalence and clinical relevance in HNSCC, especially its predictive value, we examined EGFRvIII-transfected cell lines and patient tissue samples. RESULTS: In contrast to other recent publications, we were able to demonstrate EGFRvIII expression in HNSCC. However, we noted that the different detection methods yielded inconsistent results. Furthermore, our EGFRvIII transfected and EGFR wild type cell lines exhibited similar characteristics and response rates in the performed in vitro experiments. MATERIALS AND METHODS: We conducted various inhibition and combined irradiation experiments using three EGFRvIII-transfected cell lines. Moreover, a patient cohort of 149 cases consisting of formalin fixed and paraffin embedded (FFPE) and fresh-frozen specimens was assayed via reverse transcriptase PCR (rtPCR) with gel electrophoresis and sequencing for EGFRvIII prevalence. In the rtPCR assays, we used five previously published EGFRvIII primers and EGFRvIII-positive glioblastoma tissue as a positive control. In addition, immunohistochemical staining was conducted. CONCLUSIONS: EGFRvIII can be detected in HNSCC patient samples. Nevertheless, the low prevalence and similar response rates to targeted drugs and irradiation in vitro cast doubt regarding the clinical relevance of EGFRvIII in HNSCC.

Anti-inflammatory effects of the petasin phyto drug Ze339 are mediated by inhibition of the STAT pathway.

Ze339, an herbal extract from Petasites hybridus leaves is effective in treatment of allergic rhinitis by inhibition of a local production of IL-8 and eicosanoid LTB4 in allergen-challenged patients. However, the mechanism of action and anti-inflammatory potential in virally induced exacerbation of the upper airways is unknown. This study investigates the anti-inflammatory mechanisms of Ze339 on primary human nasal epithelial cells (HNECs) upon viral, bacterial and pro-inflammatory triggers. To investigate the influence of viral and bacterial infections on the airways, HNECs were stimulated with viral mimics, bacterial toll-like-receptor (TLR)-ligands or cytokines, in presence or absence of Ze339. The study uncovers Ze339 modulated changes in pro-inflammatory mediators and decreased neutrophil chemotaxis as well as a reduction of the nuclear translocation and phosphorylation of STAT molecules. Taken together, this study suggests that phyto drug Ze339 specifically targets STAT-signalling pathways in HNECs and has high potential as a broad anti-inflammatory drug that exceeds current indication. © 2016 BioFactors, 43(3):388-399, 2017.

Primary tumor-associated expression of CXCR4 predicts formation of local and systemic recurrency in head and neck squamous cell carcinoma.

OBJECTIVES: Despite modern treatment regimens, overall survival in head and neck squamous cell carcinomas (HNSCC) is less than 50% due to local and systemic disease recurrency. The current study aims to identify molecular markers in primary tumor specimens that predict the risk for local and systemic recurrency at the time of initial diagnosis. METHODS: The study included clinic-pathological data of 1,057 HNSCC. MMP2/9, TIMP1/2, CXCR4, and CXCL12 immunohistochemistry was done in 150 randomly selected specimens. For statistics, we employed Chi square, Fisher exact, and Student's t-test. Overall survival (OS) was calculated by Kaplan-Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression for forward selection. RESULTS: CXCR4 positive specimens demonstrated a significant increased risk for tumor recurrency associated death (rT: HR 10.07; p=0.001 / rN: HR 5.04; p=0.013 / rM: HR 2.49; p=0.029) when compared with their unaltered counterparts. Expression of MMP9, TIMP2, CXCR4, and CXCL12 was significantly increased in distant metastasized patients (p<0.0001) and showed significant cross-correlation. In addition, CXCR4 positivity was associated with an increased risk to die due to enhanced T or N status (T1/2 vs. T3/4: HR 5.78; p=0.017; N0 vs. N+: HR 5.18; p=0.033). CONCLUSION: CXCR4 positivity in tumor samples at initial diagnosis were associated with reduced overall survival, in particular with respect to increasing T/N status, local and systemic recurrency.

HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances.

Despite remarkable successes with targeted therapies in the treatment of cancer, resistance can occur which limits the clinical outcome. In this study, we generated and characterized resistant cell clones derived from two different head and neck squamous cell carcinoma (HNSCC) cell lines (Cal27, UD-SCC-5) by long-term exposure to five targeted- and chemotherapeutics (afatinib, MK2206, BEZ235, olaparib and cisplatin). The resistant tumor cell clones showed an increased ERK1/2 expression and an altered expression of the stem-cell markers CD44, ALDH1, Oct4, Sox2, Nanog and Bmi1. None of the single markers alone was predictive for resistance to all five targeted- and chemotherapeutics. Furthermore, long-term exposure of tumor cells to these five drugs resulted in an eightfold increase in the mutational rate compared to untreated cells. Interestingly, targeted- and chemotherapy resistant cell clones remained sensitive to irradiation. Lastly, clones that were resistant to afatinib, MK2206 or BEZ235 showed cross-resistance to further treatment with therapeutics that affect the same signaling pathway, but remained sensitive to those affecting different pathways such as cisplatin and olaparib. In contrast, cell clones which were once resistant to cisplatin or olaparib were found to be multidrug-resistant. These data might indicate that patients with HNSCC benefit more by a first line targeted therapy followed by cisplatin as a second line therapy.

HES1 mRNA expression is associated with survival in sinonasal squamous cell carcinoma.

OBJECTIVE: In squamous cell carcinoma of the pharynx and larynx, NOTCH1 downstream signaling has been shown to be activated. The NOTCH1 signaling pathway has not been examined in detail for sinonasal squamous cell carcinomas (SNSCCs). The aim of this study was to evaluate NOTCH1 signaling by mRNA expression analysis and to examine the occurrence of NOTCH1 mutations in SNSCC. STUDY DESIGN: In a retrospective study, we analyzed tissues from 44 SNSCCs and 56 head and neck squamous cell carcinomas (HNSCCs) at other locations. Expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 mRNA were measured by using quantitative real-time polymerase chain reaction (q-rtPCR). In SNSCC, NOTCH1 mutations were evaluated with sequencing of seven selected exons. RESULTS: Expression of NOTCH1, HEY1, and JAG1 at the mRNA level were significantly higher in tumor tissue compared with normal tissue. In SNSCC, the subgroup of patients with high expression (5th quintile) of HES1 mRNA was associated with better survival (P = .04); however these patients with high expression of HES1 mRNA had also a more favorable tumor stage and grade and more unfavorable resections representing potential confounders. CONCLUSIONS: Key components of NOTCH1 are upregulated at the mRNA level in HNSCCs. The mechanism, clinical significance, and potential therapeutic options should therefore be further evaluated.

Selective inhibition of EGFR downstream signaling reverses the irradiation-enhanced migration of HNSCC cells.

Irradiation, which is one of the standard therapies used to treat squamous cell carcinoma of the head and neck (HNSCC), has been linked to enhanced tumor migration in carcinomas. In this study, we demonstrated that irradiation induced the phosphorylation of AKT, p38 MAPK and ERK. The combined activation of these pathways caused inactivation of GSK3ß kinase, resulting in enhanced tumor cell migration. Here, we describe that the exclusive and specific inhibition of just one of the aforementioned key signaling molecules is sufficient to restore GSK3ß activity and to reduce radiation-induced migration in HNSCC. These data indicate that pharmacological inhibition of pathways targeting GSK3ß could decrease radiation-induced cell migration in HNSCC and thus potentially reduce metastasis and locoregional recurrence in patients.

Epstein-Barr virus infection is strictly associated with the metastatic spread of sinonasal squamous-cell carcinomas.

BACKGROUND: Sinonasal squamous-cell carcinomas (SNSCC) are relatively rare. Thus, data regarding the rate of lymph node metastases are inconsistent in contrast with well-known high metastasis rates in squamous-cell carcinomas of the head and neck (HNSCC) (oral cavity, pharynx and larynx). Hence, the indication for elective neck dissection is difficult in SNSCC. The aim of this study was to assess common genetic alterations and EBV and HPV status as a function of metastasis in SNSCC and HNSCC. METHODS: We retrospectively analyzed 44 SNSCC and 65 HNSCC for TP53, EGFR, KRAS, PIK3CA and BRAF mutations using a high-resolution melting analysis followed by Sanger sequencing. EBV and HPV detection was performed using in situ hybridization for virus encoded RNA. Tumor-associated p16(INK4a) expression was visualized by immunohistochemistry and correlated with HPV infection. The mutation data, EBV and HPV status were statistically compared with the clinical data in SNSCC and HNSCC. RESULTS: TP53 mutations were exclusively associated with shorter survival in SNSCC (p=0.048). All the other markers had no effect on the metastasis rate and survival. In total, 20 of 44 SNSCC were EBV-positive. Only these EBV positive tumors developed lymph node or distant metastases (p=0.008). LMP1 was positive in 14/44 patients. When combining both methods significance for a correlation between EBV/LMP1 positive patients and metastases was even higher (p=0.001). CONCLUSION: In SNSCC, the presence of EBV is strictly associated with metastasis. We recommend an elective neck dissection in patients with EBV-positive SNSCC.

Effects of topoisomerase inhibitors that induce DNA damage response on glucose metabolism and PI3K/Akt/mTOR signaling in multiple myeloma cells.

Hallmarks of cancer cells comprise altered glucose metabolism (aerobic glycolysis) and differences in DNA damage response (DDR). Glucose transporters (GLUT), glycolytic enzymes such as hexokinase (HK) and metabolic pathways (e.g. PI3K/Akt/mTor) have been shown to be upregulated in multiple myeloma and other cancer cell lines. Here we have investigated the effects of clinically used inhibitors of topoisomerases, of DDR and of the PI3K/Akt/mTor pathway on glucose metabolism and on cell survival in multiple myeloma cells. The effects of DNA damaging topoisomerase inhibitors (doxorubicin, etoposide, topotecan), non-DNA damaging agents (bortezomib, vincristine) as well as of molecular inhibitors of DNA damage related kinases PIKKs (KU55933 [ATM], NU7026 [DNA-PKCs]) and PI3K/Akt/mTor signaling (BEZ235 [PI3K/mTor], MK-2206 [Akt]) were analyzed 24 hours after treatment of OPM-2 multiple myeloma cells. For this purpose we monitored [18F]-FDG uptake, cell viability using an ATP assay and expression of GLUT-1, hexokinase II (HKII), cleaved caspase-3 and cleaved PARP via Western-blotting. All topoisomerase inhibitors used could upregulate expression of GLUT-1 and HKII in OPM-2 cells, resulting in elevated [18F]-FDG uptake and promotion of cell survival. In contrast, bortezomib and vincristine induced a decline in [18F]-FDG uptake combined with early induction of apoptosis. Combination treatment with topoisomerase inhibitors and molecular inhibitors of PIKK and PI3K could reverse elevated [18F]-FDG uptake, as observed after application of topoisomerase inhibitors only, and aggravate induction of apoptosis. Thus, elevated glucose consumption in OPM-2 cells can be reversed by targeting both DDR and PI3K/Akt/mTOR signaling, thus providing a promising strategy in the treatment of cancer.