Molecular Targeted Therapy in Oncology Focusing on DNA Repair Mechanisms.

DNA repair mechanisms are essential for maintaining cellular homeostasis. Malfunction of these repair mechanisms leads to cellular DNA mutations, carcinogenic transformation, and cell death. These same defects also create vulnerabilities that are relatively specific to cancer cells, and which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The targeted therapy based on inhibiting the DNA damage response (DDR) opens a new therapeutic landscape for patients with deficient DDR. Currently there are two DNA repair mechanisms that are used as targets for molecular therapies: Mitsmach Repair (MMR) and Homologous Recombination Repair (HRR). These molecular targets allow for immunotherapy treatments based on "checkpoint inhibitors" (ICIs) drugs and "PARP inhibitor" (PARPi) drugs in different solid tumors. In this review we will describe the state of the art of this interesting mechanism and explain the options for treatment based on these alterations. Moreover, many clinical trials are currently underway exploring better treatment options for dMMR and HRD patients with different solid tumours.

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma.

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.

Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer.

BACKGROUND AND AIMS: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. METHODS: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). RESULTS: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. CONCLUSIONS: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Immunotherapy maintenance therapy for advanced urothelial carcinoma (aUC): a comprehensive review.

Immunotherapy has revolutionized the systemic treatment of solid tumors, including advanced urothelial carcinoma (aUC), providing durable responses with a favorable safety profile. Multiple immune checkpoint inhibitor agents have been approved in monotherapy in second-line setting, and for a selected group of chemo-naïve cisplatin-ineligible patients with high PD-L1 expression. Despite the incorporation of immunotherapy to the systemic treatment landscape of aUC, platinum-based chemotherapy remains the standard of care in frontline setting for vast majority of patients. Urothelial carcinoma is a chemosensitive disease with response rates of up to 50% to frontline chemotherapy. However, the response to chemotherapy is short lasting with vast majority of patients experiencing disease progression and death within months. In this context, maintenance therapy constitutes an attractive therapeutic strategy to maximize the time to treatment failure. Different cytotoxic and targeted agents have been investigated as maintenance therapy for aUC but have not shown an impact on survival. Avelumab has become the first and only drug to improve overall survival as maintenance therapy after frontline platinum-based therapy in aUC patients and the first drug to be approved in this setting. This article will review the rational for maintenance therapy, the different drugs investigated as maintenance therapy for aUC, and the impact of avelumab maintenance therapy as a new standard of care in the management of aUC.

Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.

BACKGROUND: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. METHODS: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. RESULTS: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. CONCLUSIONS: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

Phase II Trial of Palbociclib in Recurrent Retinoblastoma-Positive Anaplastic Oligodendroglioma: A Study from the Spanish Group for Research in Neuro-Oncology (GEINO).

BACKGROUND: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). OBJECTIVE: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. RESULTS: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6-3.1] and the median overall survival was 32.1 months (95% CI 5.1-59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. CONCLUSION: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).

Induction of oxidative stress as a possible mechanism by which geraniol affects the proliferation of human A549 and HepG2 tumor cells.

Geraniol (GOH), like other plant-derived natural bioactive compounds, has been found to possess antiproliferative properties that are essential to cope with malignant tumors. However, the mechanisms of molecular action of GOH are not fully elucidated. The aim of this study was to evaluate the effect of GOH on some oxidative parameters in human tumor cell lines (HepG2 and A549). Cytotoxicity evaluated in cell lines by the MTT assay, genotoxicity by the comet assay, and lipid peroxidation by the TBARS. The activities of antioxidant the enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST), were also analyzed. Additionally, intracellular reactive oxygen species (ROS), nitric oxide, and lactate production were determined in HepG2 cells. Both tumor cell lines showed a clear concentration-dependent response to GOH in several of the parameters evaluated. Lipids turned out to be more sensitive than DNA to oxidative damage induced by GOH. TBARS levels increased with respect to control (p < 0.05) by 33% and 122% in HepG2 and A549 cells, respectively treated with 200 µM GOH. However, GOH caused a statistically significant decrease in SOD and CAT activities in HepG2 cells only. GST was not affected in any cell lines. GOH induced the production of ROS but not nitric oxide in HepG2, which shows that ROS were mainly responsible for oxidative damage. Lactate release increased statistically significantly compared to control (p < 0.001), by 41% and 86% at 200 and 800 µM GOH respectively, showing that this monoterpene also affected the glycolytic pathway in HepG2 cells. These results suggest that oxidative stress could mediate the anti-proliferative effects of GOH in HepG2 and A549 cells.

An Experimental Study of Mortars with Recycled Ceramic Aggregates: Deduction and Prediction of the Stress-Strain.

The difficult current environmental situation, caused by construction industry residues containing ceramic materials, could be improved by using these materials as recycled aggregates in mortars, with their processing causing a reduction in their use in landfill, contributing to recycling and also minimizing the consumption of virgin materials. Although some research is currently being carried out into recycled mortars, little is known about their stress-strain (σ-ε); therefore, this work will provide the experimental results obtained from recycled mortars with recycled ceramic aggregates (with contents of 0%, 10%, 20%, 30%, 50% and 100%), such as the density and compression strength, as well as the σ-ε curves representative of their behavior. The values obtained from the analytical process of the results in order to finally obtain, through numerical analysis, the equations to predict their behavior (related to their recycled content) are those of: σ (elastic ranges and failure maximum), ε (elastic ranges and failure maximum), and Resilience and Toughness. At the end of the investigation, it is established that mortars with recycled ceramic aggregate contents of up to 20% could be assimilated just like mortars with the usual aggregates, and the obtained prediction equations could be used in cases of similar applications.

Impacto de una intervención alimentaria con un concentrado proteico de Medicago sativa L (alfalfa), en niños pre escolares con desnutrición crónica / Nourishing intervention impact with Medicago sativa L (alfalfa) protein extract in chronically undernourished preschool children

Introducción: Estudios realizados a nivel preclínico han demostrado el valor biológico del concentrado proteico obtenido de Medicago sativa L, alfalfa (CPA), por lo que este producto puede ser una alternativa para reducir la desnutrición. Objetivo: Evaluar el efecto del consumo de CPA por niños preescolares con desnutrición crónica, mediante indicadores bioquímicos y hematológicos. Diseño: Estudio analítico de intervención, de tipo longitudinal y prospectivo. Institución: Centro de Investigación de Bioquímica y Nutrición, Facultad de Medicina, Universidad Nacional Mayor de San Marcos. Participantes: Niños preescolares con desnutrición crónica, provenientes de una comunidad de Pampas, Huancavelica, Perú. Intervenciones: Previo consentimiento informado de los padres, se evaluó el estado alimentario-nutricional, bioquímico y hematológico de 23 niños menores de seis años, para establecer la condición de desnutrición. Luego, se desarrolló una intervención alimentario nutricional con el CPA como complemento alimenticio, por 25 días, en niños seleccionados. Finalmente, se repitió la evaluación una vez concluido el período de intervención. Las determinaciones bioquímicas fueron hemoglobina, proteínas totales, albúmina y globulina, creatinina, transaminasas, y las hematológicas, hematocrito, recuento de reticulocitos. Se utilizó el programa Excel y t-student, a fin de obtener la inferencia en los resultados. Resultados: Para el indicador talla/edad, 84,5% de los niños padecía desnutrición crónica; respecto a calorías y nutrientes consumidos por los niños, los valores de energía estuvieron entre 563 kcal y 2 597 kcal; de proteína, 9,7 g a 78 g; de grasas, 5,1 g a 53,8 g; carbohidratos, 79,8 g a 495,1 g; calcio, entre 180,9 mg y 986 mg; y hierro, 1,9 mg y 21,5 mg. Los valores de hemoglobina, proteínas totales, globulinas, creatinina, transaminasas y hematocrito obtenidos antes y después de la ingesta de CPA, no presentaron variaciones (p>0,05); pero, los valores de albúmina y recuento de reticulocitos se incrementaron significativamente después de la ingesta (p<0,05). Conclusiones: El consumo diario de CPA por niños con desnutrición crónica por 25 días aumentó significativamente los valores de recuento de reticulocitos, así como los niveles de albúmina sérica.

Introduction: Studies made at preclinical level have demonstrated the Medicago sativa L, alfalfa (CPA)Æs concentrated protein biological value; as such this product could be an alternative to reduce undernourishment. Objective: To determine CPA consuming effects in kindergarten children with chronic undernourishment by biochemical and hematologic indicators. Design: Intervention analytical, longitudinal and prospective study. Setting: Biochemistry and Nutrition Research Center, Faculty of Medicine, Universidad Nacional Mayor de San Marcos. Participants: Pampas, Huancavelica, Peru, preschool children with chronic undernourishment. Interventions: Previous parents informed consent we determined the nourishment-nutritional, biochemical and hematologic status of 23 less than six year-old children in order to establish undernourishment. Then a CPA nutritional nourishment intervention in the chronically undernourished children was developed for 25 days and finally the initial evaluation was repeated. Biochemical -hemoglobin, total proteins, albumin and globulin, creatinine, transaminases- and hematologic -hematocrit, reticulocytes count- determinations were done before and after providing the CPA nutritional complement. Excel program and t-student were used in order to obtain results inference. Results: By stature/age indicator 84,5% of the children suffered chronic undernourishment. With respect to calorie and nutrients consumed by the children, energy values were between 563 kcal and 2 597 kcal, protein 9,7 g to 78 g, lipids 5,1 g to 53,8 g, carbohydrates from 79,8 g to 495,1 g, calcium between 180,9 mg and 986 mg, and iron from 1,9 mg to 21,5 mg. Hemoglobin, total proteins, globulins, creatinine, transaminases and hematocrit before and after CPA ingestion did not display variations (p>0,05) but albumin and reticulocytes count increased significantly following ingestión (p<0,05). Conclusions: CPA daily consumption for 25 days CPA by children with chronic undernourishment significantly increased reticulocytes count and albumin levels.

Gestational weight gain as predicted by pregestational body mass index and gestational age in Mexican women.

OBJECTIVE: To develop a reference pattern to evaluate gestational weight according to pregestational body mass index (BMI) and gestational age, using current longitudinal information from healthy pregnant women. SUBJECTS AND METHODS: We followed 438 women with singleton pregnancies between weeks 16 and 36 of pregnancy Women were excluded if they developed pathologic conditions during gestation, delivered malformed or dead fetuses, or delivered babies with a birthweight of less than 2500 or more than 4200 g or with a gestational age of less than 37 or more than 41 weeks. Weight, biochemical indicators, and clinical indicators were recorded every 4 weeks throughout the pregnancy. Data were analyzed by sequential regressions. RESULTS: Four equations for maternal predicted weight across categories of pregestational BMI (underweight, normal, overweight, and obese) and gestational ages were developed and synthesized in a table of reference values. CONCLUSIONS: Optimal weight and weight gain during pregnancy can be estimated with our equations, which are corrected for pregestational BMI and gestational age.

Adolescents with adequate birth weight newborns diminish energy expenditure and cease growth.

Maternal energy requirements increase during pregnancy but the magnitude of this increment is unknown among adolescents. We determined the effects of maternal age and weight status on adjustments in gestational weight gain, resting energy expenditure (REE), and growth among adolescents. Weight, and growth rates of pregnant adolescents (PA) < or =17 y during late pregnancy were compared with changes in nonpregnant adolescents (NPA) over a 5-mo period. REE was also measured monthly in the PA group. Paired t-tests and general linear models for repeated measures were used for the analysis; height was included as a confounding variable. Weight, height, and BMI of the PA and NPA women did not differ at baseline. During the follow-up period, NPA grew 0.94 +/- 30 cm; growth rate was greater in adolescents < or =14 y of age (P < 0.001) than in the older subjects. No growth occurred in the PA group. REE tended to increase linearly between 20 and 36 wk of gestation (P = 0.164); the net change in women >14 y (25%) tended (P = 0.164) to be greater than that of younger adolescents (7%). The mean increment of REE from wk 20 to wk 36 was 230 +/- 30 kcal/d (962 +/- 126 kJ/d) and the smallest increase occurred in women with BMI <20 (P = 0.010). Women with BMI <20 had a decrease in REE/kg that was greater than that of normal weight (BMI 20-25) or overweight (BMI > or =25) women (within subject, P = 0.010; between subject, P = 0.001). In conclusion, PA appear to adjust their resting energy needs by ceasing growth.

Nutrición materna, crecimiento fetal en gestaciones con dos productos y resultado perinatal / Maternal nutritional status, fetal growth in twin pregnancies and perinatal outcome

Objetivo: Determinar el efecto de la nutrición materna sobre el crecimiento fetal en gestaciones múltiples con resultado perinatal adecuado. Material y métodos: Se realizó un estudio de cohorte con gestantes de 20 semanas de embarazo, sin patología agregada. Mensualmente se evaluó peso, fondo uterino (FU) y gasto energético en reposo (GER). Para el análisis de los cambios en peso, FU y GER se utilizó la prueba de ANOVA para datos repetidos, las diferencias intrasujetos fueron con base en la edad gestacional y las diferencias intersujetos en función al tipo de embarazo e IMC pregestacional (IMCp). Resultados: La muestra estuvo constituida por 39 gestantes (19 EM y 20 EU). Se tomaron los eventos exitosos (10 EM como casos y 11 EU como controles). El peso corporal incrementó significativamente entre la semana 0-32 y existió una interacción tiempo de gestación e IMCp (p < 0.05). El FU mostró un incremento significativo a lo largo de la gestación (p < 0.001), que fue dependiente del tipo de embarazo (p < 0.001) y no se vio afectado por el IMCp (p > 0.05). El GER mostró un incremento lineal significativo (p < 0.05), que fue independiente del tipo de gestación (p > 0.05), pero dependiente del IMCp (p < 0.05). Cuando se analizó el GER/kg de peso, se encontró un menor gasto/kg en las mujeres con sobrepeso (p < 0.05). Conclusiones: Los determinantes de la nutrición materna de la semana 20 y hasta la semana 32 de gestación, dependen del IMCp y no del tipo de embarazo; a diferencia del de crecimiento fetal que depende del tipo de embarazo.

Objetive: To determine the effect of maternal nutritional status on fetal growth in twin pregnancies with good perinatal outcome. Material y methods: A cohort conformed by 39 healthy pregnant women with 20 weeks of gestation or less(19 with twin pregnancy (TP)and 20 with singleton pregnancy (SP)). Every four weeks height, weight, uterine fundus height (UFH)and resting energy expenditure (REE) were measured. General Lineal Models for repeated measures were used to evaluate longitudinal changes in body weight, REE, and UFH at 20, 24, 28, and 32 weeks of pregnancy (within subjects) The group was divided by pregnancy type or BMI (< 25, and > 25) (between subjects) in order to evaluate their effect on weight, uterine fundus height and REE changes. Results: The successful deliveries were uses for the analysis (10TP as cases and 11 SP as controls). Weight gain increased significantly between 0 and 32 weeks of gestation with an interaction between gestational age and prepregnancy body mass index (pBMI) (p < 0.05). The UFH also increased significantly during gestation (p < 0.001); this increase was dependant on pregnancy type (p < 0.001) and it was not affected by the pBMI (p > 0.05). REE showed a linear increase (p < 0.05) that depended on the pBMI (p < 0.05) but not on pregnancy type (p > 0.05). When the REE/kg was analyzed, the weight showed a lower energy expenditure per kg in overweight women (p < 0.05). Conclusions: Maternal nutritional determining factors from 20 to 32 weeks of gestation depends on the pBMI and did not depend on pregnancy type, while fetal growth did.

Twin pregnancies: eating for three? Maternal nutrition update.

The incidence of multifetal pregnancies has increased, mainly because of assisted reproduction treatments. This trend is reflected in increased maternal and neonatal morbidity and mortality. While the optimum maternal nutrition and weight gain patterns for singleton pregnancies is well documented, there is a paucity of information for twin pregnancies. Although it is assumed that optimum nutritional requirements and weight gains would be greater for twin than for singleton gestations, research is needed to establish the optima. This article is a collation of available recommendations for maternal nutrition and weight gain patterns in twin pregnancies.