Hernández, C. (Carlos)

Filtering

20202

Settings

Author search.filters.isAuthorOfPublication.68e53601-57fa-4c2b-b8cd-70a92647b1f7

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics
    (2020) Kochan, G. (Grazyna); Chocarro, L. (Luisa); Gato-Cañas, M. (María); Bocanegra, A. (Ana); López, P. (Paúl); Hernández, C. (Carlos); Zuazo, M. (Miren); Morilla, I. (Idoia); Fernández-Hinojal, G. (Gonzalo); Arasanz, H. (Hugo); Hernández, B. (Berta); Alberdi, N. (Nerea); Teijeira, L. (Lucía); Escors, D. (David); Martinez-Aguillo, M. (M.); Vera, R. (Ruth)
    Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.
  • Thumbnail Image
    Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition
    (MDPI AG, 2020) Kochan, G. (Grazyna); Chocarro, L. (Luisa); Gato-Cañas, M. (María); Blanco-Luquin, I. (Idoia); Bocanegra, A. (Ana); Hernández, C. (Carlos); Fernandez-Irigoyen, J. (Joaquín); Zuazo, M. (Miren); Arasanz, H. (Hugo); Santamaría, E. (Eva); Fernandez, G. (Gonzalo); Escors, D. (David); Rodríguez, C. (Carlos); Santamaria, E. (Enrique); Ausin, K. (Karina); Vera, R. (Ruth)
    Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.