Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with TMZ was able to reduce the expression of glioma stem cells (GSC) marker CD90 particularly in T98G cells but not that of CD133. In vivo experiments showed that combined treatment with TMZ and MET significantly slowed down growth of TMZ-resistant tumors but did not affect overall survival of TMZ-sensitive tumor bearing mice. In conclusion, our results showed that metformin is able to enhance TMZ effect in TMZ-resistant cell line suggesting its potential use in TMZ refractory GBM patients. However, the lack of effect on a GBM malignancy marker like CD133 requires further evaluation since it might influence response duration

[¹⁸F]FDG and [¹⁸F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer

<div><p>Rationale</p><p>Pathological response to neo-adjuvant chemotherapy (NAC) represents a commonly used predictor of survival in triple negative breast cancer (TNBC) and the need to identify markers that predict response to NAC is constantly increasing. Aim of this study was to evaluate the potential usefulness of PET imaging with [¹⁸F]FDG and [¹⁸F]FLT for the discrimination of TNBC responders to Paclitaxel (PTX) therapy compared to the response assessed by an adapted Response Evaluation Criteria In Solid Tumors (RECIST) criteria based on tumor volume (Tumor Volume Response).</p><p>Methods</p><p>Nu/nu mice bearing TNBC lesions of different size were evaluated with [¹⁸F]FDG and [¹⁸F]FLT PET before and after PTX treatment. SUV_max, Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) and Proliferation (TLP) were assessed using a graph-based random walk algorithm.</p><p>Results</p><p>We found that in our TNBC model the variation of [¹⁸F]FDG and [¹⁸F]FLT SUV_max similarly defined tumor response to therapy and that SUV_max variation represented the most accurate parameter. Response evaluation using Tumor Volume Response (TVR) showed that the effectiveness of NAC with PTX was completely independent from lesions size at baseline.</p><p>Conclusions</p><p>Our study provided interesting results in terms of sensitivity and specificity of PET in TNBC, revealing the similar performances of [¹⁸F]FDG and [¹⁸F]FLT in the identification of responders to Paclitaxel.</p></div

[¹⁸F]FDG and [¹⁸F]FLT uptake variations after treatment with PTX.

<p>[¹⁸F]FDG and [¹⁸F]FLT uptake expressed as percent variation (% change) in SUV_max (ΔSUV_max) between baseline and post-therapy in vehicle and treated mice categorized on the basis of TVR. One-way ANOVA multiple comparison, *p < 0.05, **p < 0.01 and ***p < 0.001.</p

Disruption of redox homeostasis for combinatorial drug eefficacy in K-Ras tumors as revealed by metabolic connectivity proling

Background Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Methods We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism. Conclusions Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology

Summary of tumor size of treated animals at baseline (pre) and at the end of PTX treatment (post) and the corresponding Tumor Volume Response (TVR) categorization.

<p>Summary of tumor size of treated animals at baseline (pre) and at the end of PTX treatment (post) and the corresponding Tumor Volume Response (TVR) categorization.</p

Histological and Ki67 immunohistochemical staining of tumors treated with PTX or vehicle.

<p>A) Representative images of histological morphology (H&E) and Ki67 staining of tumors receiving vehicle or PTX. B) Weights of tumors collected at the end of treatment significantly correlated with Ki67 P.I. values (r² = 0.707, p = 0.0006).</p

ROC curve of ΔSUV_max to predict MDA-MB-468 response.

<p>ROC analysis of [¹⁸F]FDG and [¹⁸F]FLT ΔSUV_max for prediction of different response to PTX therapy in the TNBC model. Optimal cut-off point was defined for [¹⁸F]FDG as -80.4% (89% sensitivity; 75% specificity) and for [¹⁸F]FLT as -70.7% (100% sensitivity; 50% specificity).</p