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NAD+ metabolism, sternness, the immune response, and cancer

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Signal Transduction and Targeted Therapy 2021年第2期6卷 257-276页

作者： Lola ENavas Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocioUniversidad de SevillaConsejo Superior de Investigaciones CientificasSevillaSpain CIBER de Cancer SevillaSpain

NAD+was discovered during yeast fermentation,and since its discovery,its important roles in redox metabolism,aging,and longevity,the immune system and DNA repair have been highlighted.A deregulation of the NAD+levels has been associated with metabolic diseases and aging-related diseases,including neurodegeneration,defective immune responses,and cancer.NAD+acts as a cofactor through its interplay with NADH,playing an essential role in many enzymatic reactions of energy metabolism,such as glycolysis,oxidative phosphorylation,fatty acid oxidation,and the TCA cycle.NAD+also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins.Finally,different NAD hydrolase proteins also consume NAD+while converting it into ADP-ribose or its cyclic counterpart.Some of these proteins,such as CD38,seem to be extensively involved in the immune response.Since NAD cannot be taken directly from food,NAD metabolism is essential,and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools.Because of the complex network of pathways in which NAD+is essential,the important role of NAD+and its key ge nerating enzyme,NAMPT,in cancer is understandable.In the present work,we review the role of NAD+and NAMPT in the ways that they may influence cancer metabolism,the immune system,stemness,aging,and cancer.Finally,we review some ongoing research on therapeutic approaches.

关键词： metabolism cancer diseases

Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 697-709页

作者： Marco Perez JoséManuel García-Heredia Blanca Felipe-Abrio Sandra Muñoz-Galván Javier Martín-Broto Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocíoUniversidad de SevillaConsejo Superior de Investigaciones CientíficasSevillaSpain Ciber de Cancer IS Carlos IIIMadridSpain Departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain Departamento de Anatomía Patológica Hospital Universitario Virgen del RocíoSevillaSpain

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.Despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

关键词： H2AX doxorubicin treatment

A new treatment for sarcoma extracted from combination of miRNA deregulation and gene association rules

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3221-3224页

作者： JoséManuel García-Heredia Marco Pérez Eva M.Verdugo-Sivianes María M.Martínez-Ballesteros Sara M.Ortega-Campos Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS)/HUVR/Universidad de Sevilla/CSIC SevillaSpain Departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain CIBERONC IS Carlos IIIMadridSpain Departamento de Anatomía Patológica HUVRSevillaSpain Departamento de Lenguajes y Sistemas Informáticos Escuela Superior de Ingeniería InformáticaUniversidad de SevillaSevillaSpain

Dear Editor Sarcomas are a group of heterogeneous mesodermic rare tumors with high incidence in children,reaching up to 20%of neoplasms.Standard treatment for sarcomas is surgical resection,and only some patients are treated with chemotherapy and/or radiation therapy.The 5-year relative survival rate for patients with metastatic sarcoma is only 15%.

关键词： neoplasms chemotherapy treatment

Phase Ⅱ trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5518-5527页

作者： Javier Martin-Broto Jeronimo Martinez-Garcia David SMoura Andres Redondo Antonio Gutierrez Antonio Lopez-Pousa Javier Martinez-Trufero Isabel Sevilla Roberto Diaz-Beveridge Maria Pilar Solis-Hernandez Amancio Carnero Marco Perez David Marcilla Jesus Garcia-Foncillas Pablo Romero Javier Fernandez-Jara Daniel Lopez-Lopez Ivan Arribas Nadia Hindi Health Research Institute-Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid(IIS-FJDUAM)28040MadridSpain Medical Oncology Department Fundación Jimenez Diaz University Hospital28040MadridSpain General de Villalba University Hospital 28400MadridSpain Medical Oncology Department University Hospital Virgen de la Arrixaca30120MurciaSpain Department of Medical Oncology Hospital Universitario La Paz-IdiPAZP.Castellana26128046MadridSpain Hematology Department University Hospital Son Espases07120MallorcaSpain Medical Oncology Department Sant Pau Hospital08025BarcelonaSpain Medical Oncology Department University Hospital Miguel Servet50009ZaragozaSpain Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Malaga(IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria de Malaga MalagaSpain Medical Oncology Department Hospital Universitari i Politècnic La Fe46026ValenciaSpain Medical Oncology Department Central University Hospital of Asturias33011OviedoSpain Instituto de Biomedicina de Sevilla(IBiS HUVRCSICUS)41013SevillaSpain Pathology Department Virgen del Rocio University Hospital41013SevillaSpain Radiology Department Fundación Jimenez Diaz University Hospital28040MadridSpain Computational Medicine Platform Fundación progreso y salud(FPS)Hospital Virgen del Rocío41013SevilleSpain Bioinformatics in Rare Diseases(BiER).Centro de Investigación Biomédica en Red de Enfermedades Raras(CIBERER) FPSHospital Virgen del RocioSevillaSpain Universitat de València-ERI-CES 46010ValenciaSpain

Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.

关键词： CDKN2A sarcoma CDK4