Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation.

Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor (CDK4 & 6i), approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease, and with endocrine therapy (ET) for initial treatment and after progression on ET. Abemaciclib has also shown clinical activity in combination with ET in patients with high risk early BC (EBC). Here, we examined the preclinical attributes of abemaciclib and other CDK4 & 6i using biochemical and cell-based assays. In vitro, abemaciclib preferentially inhibited CDK4 kinase activity versus CDK6, resulting in inhibition of cell proliferation in a panel of BC cell lines with higher average potency than palbociclib or ribociclib. Abemaciclib showed activity regardless of HER2 amplification and phosphatidylinositol 3-kinase (PI3KCA) gene mutation status. In human bone marrow progenitor cells, abemaciclib showed lower impact on myeloid maturation than other CDK4 & 6i when tested at unbound concentrations similar to those observed in clinical trials. Continuous abemaciclib treatment provided profound inhibition of cell proliferation, and triggered senescence and apoptosis. These preclinical results support the unique efficacy and safety profile of abemaciclib observed in clinical trials.

Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy.

Despite the biological and therapeutic relevance of CDK4/6 for the treatment of HR+, HER2- advanced breast cancer, the detailed mode of action of CDK4/6 inhibitors is not completely understood. Of particular interest, phosphorylation of CDK4 at T172 (pT172) is critical for generating the active conformation, yet no such crystal structure has been reported to date. We describe here the x-ray structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Furthermore, the effect of CDK4/6 inhibitors on CDK4 T172 phosphorylation has not been explored, despite its role as a potential biomarker of CDK4/6 inhibitor response. We show mechanistically that CDK4/6i stabilize primed (pT172) CDK4-cyclin D complex and selectively displace p21 in responsive tumor cells. Stabilization of active CDK4-cyclin D1 complex can lead to pathway reactivation following alternate dosing regimen. Consequently, sustained binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling. Overall, our study provides key insights demonstrating that prolonged treatment with CDK4/6 inhibitors and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib efficacy, with implications for this class of anticancer therapy.

Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy.

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.

Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene.

Loss-of-function mutations in the retinoblastoma gene RB1 are common in several treatment-refractory cancers such as small-cell lung cancer and triple-negative breast cancer. To identify drugs synthetic lethal with RB1 mutation (RB1 mut), we tested 36 cell-cycle inhibitors using a cancer cell panel profiling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest RB1 association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against RB1 mut cancer cells and leads to durable regression of RB1 mut tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identification of a synthetic lethal interaction between RB1 and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-deficient malignancies, including patients progressing on CDK4/6 inhibitors.See related commentary by Dick and Li, p. 169.This article is highlighted in the In This Issue feature, p. 151.

[Validity, Reliability and Associated Factors of the International Physical Activity Questionnaire Adapted to Elderly (IPAQ-E)]. / Medición de la actividad física en personas mayores de 65 años mediante el IPAQ-E: validez de contenido, fiabilidad y factores asociados.

OBJECTIVE: Physical activity contributes to improve health and reduce mortality in older people. The objective was to analyze the validity of content and reliability of the short version of IPAQ-E in elderly people who attended to Fernando el Católico health center between May 2013 and March 2015. METHODS: Validation study of the short version of the international physical activity questionnaire (IPAQ) adapted in Spanish elderly (IPAQ-E). Our sampling was for convenience. The short version of IPAQ in Spanish USA was used and its activities were adapted to Spanish elderly. Two measurements of IPAQ-E with 15 days between them were used to analyze the intraobserver reliability. The intraclass correlation coefficient was used to measure intraobserver reliability, Cronbach's alpha for internal consistency (CI) and Spearman correlation coefficients (CS) to analyze the correlation between IPAQ-E and the Short Physical Performance Battery (SPPB). RESULTS: The sample was 139 people, average age 73,18 years. Intraobserver reliability total was 0.914, besides exceeded 0.9 in the three dimensions of the questionnaire. The CI was 0.518; It exceeded 0.8 in the rest of dimensions of IPAQ-E. The CS between IPAQ-E Total and SPPB was (Rho 0.435), between the total scores SPPB and walking activity was (Rho 0.426), and the score vigorous activity was (Rho 0,248). CONCLUSIONS: The IPAQ-E is a valid and reliable instrument for measuring mobility in Spanish elderly. However, more studies about its validity will be required in the future.

OBJETIVO: La actividad física en las personas mayores contribuye a mejorar su estado de salud y a disminuir la mortalidad. El objetivo fue analizar la validez de contenido y fiabilidad de la versión corta del cuestionario internacional de la actividad física adaptado a personas mayores de 65 años (IPAQ-E) en el centro de salud Fernando el Católico de Zaragoza entre mayo 2013 y marzo de 2015. METODOS: Estudio de validez de contenido y fiabilidad del IPAQ-E. Se realizó muestreo por conveniencia. Se utilizó la versión corta del IPAQ en español de Estados Unidos y se adaptó a actividades realizadas por personas mayores españolas. Para analizar la fiabilidad intraobservador se realizaron dos mediciones del IPAQ-E con 15 días de diferencia. Se utilizó el coeficiente de correlación intraclase para la fiabilidad intraobservador, el alfa de Cronbach para la consistencia interna (CI) y el coeficiente de Spearman (CS) para analizar la correlación entre IPAQ-E y Short Physical Performance Battery (SPPB). RESULTADOS: Participaron 139 personas, edad media de 73,18 años. Fiabilidad intraobservador total 0,914 y superó el 0,9 en las tres dimensiones del cuestionario. CI 0,518; superó el 0,8 en el resto de dimensiones del IPAQ-E. CS entre IPAQ-E total y SPPB (Rho 0,435), y entre puntuaciones totales del SPPB con actividades caminar (Rho 0,426) y vigorosas (Rho 0,248). CONCLUSIONES: El IPAQ-E es un instrumento válido y fiable para medir la movilidad en personas mayores españolas. Son necesarios más estudios para añadir información sobre la validez de este instrumento.

Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation. Moreover, abemaciclib exposure led to durable inhibition of pRb, TopoIIα expression and DNA synthesis, which were maintained after drug removal. Treatment of ER+ breast cancer cells also led to a senescence response as indicated by accumulation of ß-galactosidase, formation of senescence-associated heterochromatin foci, and a decrease in FOXM1 positive cells. Continuous exposure to abemaciclib altered breast cancer cell metabolism and induced apoptosis. In a xenograft model of ER+ breast cancer, abemaciclib monotherapy caused regression of tumor growth. Overall these data indicate that abemaciclib is a CDK4 and CDK6 inhibitor that, as a single agent, blocks breast cancer cell progression, and upon longer treatment can lead to sustained antitumor effects through the induction of senescence, apoptosis, and alteration of cellular metabolism.

Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.

Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.

[Mobility assessment in elderly people. Description of measuring instruments for mobility: a review]. / Descripción de los instrumentos de medida de la movilidad en personas mayores de 65 años: revisión sistemática.

BACKGROUND: People over 65 are the ones who have higher levels of functional limitations. There are many instruments to measure mobility in this age range that causes a lack of international consensus on what are the most suitable for this purpose. The aim is to analyze and identify which instruments provide greater data reliability and validity in measuring mobility in elderly people. METHODS: Systematic review of the instruments used to measure mobility in people over 65 years published between 2001-2013, conducted in PubMed and Science Direct. RESULTS: The 34 items selected instruments were grouped into 4 categories: doubly labeled water (DLW), motion detectors, objective measures of mobility and questionnaires. We identified, 23 are questionnaires, 4 accelerometers, 3 to objective measures of mobility and 2 both pedometers as DLW. The other 2 to combined analysis of different instruments. CONCLUSIONS: We conclude that assessing objective and subjective data obtains the most accurate measures of mobility. To obtain objective data, objective measures of mobility will be opposed to pedometers and accelerometers, while questionnaires were selected for subjective data due to its ease of use and sociodemographic data that provides. Among these instruments, the Short Physical Performance Battery (SPPB) and Minnesota Leisure Time are the most appropriate instruments to estimate the mobility of the elderly in Spain.

Funcionalidad familiar y estilos de vida saludable en pacientes con linfoma Hodgkin en Bogotá / Family functionality and healthy lifestyles in patients with Hodgkin lymphoma, Bogota / Funcionalidade familiar e estilos de vida saudável em pacientes com linfoma de Hodgkin, em Bogota

Se realizó una investigación cuantitativa descriptiva y transversal en un grupo de pacientes con linfoma Hodgkin para determinar \r\nla relación entre funcionalidad familiar y los estilos de vida saludable. Se usaron los instrumentos Escala de Evaluación de la Funcio\r\n-\r\nnalidad Familiar y el Health Promoting Lifestyle Profile II, los dos en su versión en español. El informante familiar fue el paciente con \r\ndiagnóstico de linfoma Hodgkin. Se encontró predominio de un nivel bajo de funcionalidad familiar y frecuencia de estilos de \r\nvida saludable A veces y Frecuentemente; se determinó que solo hubo correlación con significancia estadística entre la dimensión \r\nRelaciones interpersonales\r\n, perteneciente a los estilos de vida saludable, y la funcionalidad familiar. Se requiere profundizar en esta \r\ntemática con otros grupos de pacientes para lograr un mejor conocimiento al respecto.

A descriptive and cross-quantitative investigation in a group \r\nof patients with Hodgkin lymphoma was conducted to \r\ndetermine the relationship between family functionality \r\nand healthy lifestyles. The instruments Evaluation Scale of \r\nFamily Functionality in Spanish and the Health Promoting \r\nLifestyle Profile II in its version of the Spanish language were \r\nused, the family informant was the patient diagnosed with \r\nHodgkin lymphoma. Predominance of a low level of family \r\nfunctionality and frequent healthy lifestyles of "Sometimes" \r\nand "Often" was found; it was determined that there were \r\nonly statistically significant correlation for the dimension of \r\ninterpersonal relationships\r\n, pertaining to healthy lifestyles, with \r\nfamily functionality. It is required to deepen this subject, with \r\nother patient groups to achieve a better knowledge about it.

Uma pesquisa descritiva e cross-quantitativa em um grupo de \r\npacientes com linfoma de Hodgkin foi realizado para deter\r\n-\r\nminar a relação entre o funcionamento familiar e estilos de \r\nvida saudáveis. Os instrumentos Escala de Avaliação da Família \r\nfuncionalidade em espanhol e promoção da saúde Lifestyle \r\nProfile II, na sua versão em espanhol utilizado, o informante da \r\nfamília era o paciente diagnosticado com linfoma de Hodgkin. \r\nPredominância de uma baixa frequência de funcionamento \r\nfamiliar e estilos de vida saudáveis "às vezes" e "Muitas vezes" \r\nfoi encontrado; determinou-se que havia apenas estatisti\r\n-\r\ncamente dimensão correlação significativa para as \r\nrelações \r\ninterpessoais\r\n, pertencentes a estilos de vida saudáveis, com o \r\nfuncionamento familiar. É necessário aprofundar este assunto, \r\ncom outros grupos de pacientes para alcançar um melhor \r\nconhecimento sobre o assunto.