MAYOR SUPERVIVENCIA GLOBAL EN EL CÁNCER DE PRÓSTATA AVANZADO GRACIAS A LOS AVANCES TERAPÉUTICOS

La supervivencia en cáncer de próstata avanzado en los últimos 15 años se ha triplicado gracias al desarrollo de nuevos agentes hormonales, quimioterapia o radiofármacos, pasando de 12-18 meses en 2005, cuando sólo se disponía de quimioterapia, a los 32-36 meses actuales. Además, los inhibidores de PARP han demostrado beneficio en supervivencia en pacientes con cáncer de próstata avanzado, previamente tratados con otras líneas de tratamiento y alteraciones en genes implicados en la reparación del DNA, siendo los más frecuentes BRCA1 y BRCA. Por su parte, las combinaciones de nuevos fármacos con agentes inmunoterápicos representa otra prometedora estrategia terapéutica en el cáncer de próstata avanzado.

En pacientes con carcinoma de próstata resistente a la castración que todavía no han desarrollado metástasis, diferentes agentes hormonales de nueva generación han demostrado retrasar la aparición de metástasis en aproximadamente dos años, disminuir el riesgo de aparición de síntomas en más de un 50% y, además, en el Congreso de la Sociedad Americana de Oncología Médica (ASCO) recientemente celebrado, han demostrado ser capaces de mejorar la supervivencia de los pacientes.

En el marco de la campaña de comunicación “En Oncología cada AVANCE se escribe en Mayúsculas”, SEOM da a conocer la evolución y LOS avances médicos que se han sucedido en estas últimas décadas en el tratamiento de los diferentes tumores. Coincidiendo con el Día Mundial del Cáncer de Próstata que se celebra este jueves, 11 de junio, destacamos los avances más importantes en cáncer de próstata, el segundo cáncer más diagnosticado en nuestro entorno (primero en varones), con una estimación de 35.126 nuevos casos en España en 2020, según el informe de SEOM “Las cifras del cáncer en España” de 2020.  

Además, el cáncer de próstata es el tumor de mayor prevalencia en varones con una estimación para el año 2018 de 106.941 pacientes afectos (25,8%), según los últimos datos disponibles recogidos en el citado informe de SEOM. Sin embargo, ocupa el tercer lugar como responsable del número de fallecimientos por cáncer en varones en España, habiéndose reducido la tasa de mortalidad un 1,6% en 2018 respecto a 2017. La supervivencia neta a cinco años de los pacientes diagnosticados en el periodo 2008-2013 fue de 89,8%, la más elevada entre los tumores frecuentes.

En la actualidad, la inmensa mayoría de casos de cáncer de próstata se diagnostica en estadios iniciales, mientras que sólo el 5-10% corresponde a casos avanzados (metastásicos) al diagnóstico. En estadios iniciales, el cáncer de próstata es curable en una gran mayoría de casos mediante técnicas actuales de cirugía, radioterapia / braquiterapia con o sin la adición de hormonoterapia.

En una proporción de casos, sin embargo, la enfermedad desarrolla resistencia al tratamiento hormonal (resistencia a la castración) con el eventual desarrollo de metástasis, situación denominada cáncer de próstata resistente a la castración metastásico. En otras ocasiones, sin embargo, los pacientes presentan metástasis en el momento del diagnóstico, situación denominada cáncer de próstata hormono sensible metastásico, no subsidiario ya de opciones curativas como la cirugía y la radioterapia. En estos casos, los objetivos del tratamiento son prolongar la supervivencia, preservar la calidad de vida y prevenir eventos óseos.

Es en estos casos avanzados (resistencia a la castración y enfermedad hormonosensible metastásica) donde se ha realizado la mayoría de avances en el tratamiento de la enfermedad. Entre los años 2011 y 2014, el desarrollo de nuevos agentes hormonales (abiraterona, enzalutamida), quimioterapia (cabazitaxel) o radiofármacos (Ra-223) ha permitido aumentar la supervivencia desde los 12-18 meses en 2005, cuando sólo estaba disponible la quimioterapia con docetaxel, a los 32-36 meses actuales. Además, en el último año, se han presentado los resultados de un estudio fase III con olaparib, un inhibidor de PARP, que ha demostrado beneficio en supervivencia en pacientes con cáncer de próstata avanzado y previamente tratado con otras líneas de tratamiento y alteraciones en genes implicados en la reparación del DNA, siendo los más frecuentes BRCA1 y BRCA2. Otros inhibidores de PARP como rucaparib, talazoparib o niraparib, están siendo también estudiados en otros contextos del cáncer de próstata, tanto en monoterapia como en combinación con otros fármacos. Por otro lado, las combinaciones de nuevos fármacos con agentes inmunoterápicos representa otra prometedora estrategia terapéutica en el cáncer de próstata avanzado, actualmente en evaluación dentro de ensayos clínicos.

Por otro lado, en pacientes con carcinoma de próstata resistente a la castración que todavía no han desarrollado metástasis, tanto apalutamida como enzalutamida y darolutamida, todos ellos nuevos agentes hormonales, han demostrado retrasar la aparición de metástasis en aproximadamente dos años, disminuir el riesgo de aparición de síntomas en más de un 50% y, además, en el Congreso de la Sociedad Americana de Oncología Médica recientemente celebrado, han demostrado ser capaces de mejorar la supervivencia de los pacientes.

Además, nuevos estudios han confirmado el valor del tratamiento tanto de quimioterapia como de estos nuevos agentes hormonales, como la abiraterona, enzalutamida o apalutamida, en combinación con la deprivación androgénica (hormonoterapia), en pacientes con enfermedad metastásica al diagnóstico. A través de diferentes ensayos clínicos, estos agentes han demostrado una reducción del riesgo de muerte de hasta un 38%, incluso en pacientes de alto riesgo, y un incremento de la mediana de supervivencia desde los 32 hasta los 50 meses.

We are more than just Brits - DNA sheds light on our mixed ancestry

Where are you from? It’s a simple question most of us answer without hesitation. A global survey conducted among 7,200 people in 18 countries, including 400 Brits, now shows that 6 out of 10 Brits think the most you can trace their ancestry back to is two countries. But if you think you’re from just two countries, you’re likely mistaken.

DNA analysis: We are more diverse than most people think

According to Brad Argent, spokesperson at AncestryDNA - the world’s largest provider of personal DNA testing, our origin and inner geographical map is far more complex.

Argent states: "The findings from the survey confirms our experience with people who want to understand their DNA genealogy profile. Most people are very surprised when they find out their geographical background is more diverse than expected. We, on average, have genetic roots in four global regions, which far exceeds the general notion of two countries."

And momondo is pleased DNA insights can lend context to its global survey.

"With the survey we wanted to find out whether people knew of their ancestry. We hypothesized people may have underestimated their ancestral diversity. It all indicates we are more connected to the rest of the world than we realise – it is our aim to focus on this message," says Lasse Skole Hansen from momondo.

Hansen further elaborates: "We have therefore initiated a project with AncestryDNA to give people from all over the world the opportunity to take a DNA test and thus find out where they actually come from,” concludes Lasse Skole Hansen.

DNA Journey: Visit the countries you originate from

As part of the initiative, momondo in April 2016 invited 67 ordinary people from all over the world to take part in a project, which was documented on film. People were offered to take a DNA test to find out more about their ancestry. And they spoke of their hopes of what the tests would uncover. Some weeks later they were invited back, and their results were revealed.

"The project confirmed many of us do not know our full ancestry. It also showed knowing how diverse we in fact are can be an eye-opener and even change our view of who we are and who people from other nations are," says Lasse Skole Hansen from momondo.

Find out your own DNA

Now 500 people worldwide will get the opportunity to take a DNA test, reveal their own DNA genetic origins and thus find out where they come from. Among them, one winner will get the opportunity to take a DNA journey and visit the regions from which they originate.

https://www.youtube.com/watch?v=tyaEQEmt5ls

Researchers find why depression and ageing linked to increased disease risk

 Psychological stress and stress-related psychiatric disorders are associated with increased risk for aging-related diseases, but the molecular mechanisms underlying this relation are unknown. Understanding these mechanisms may contribute to the development of targeted preventive strategies and new or improved treatments for these devastating diseases. This work is presented at the European College of Neuropsychopharmacology congress in Berlin.

Now an international group of researchers from Germany and the US has found that both ageing and depression are associated with changes in the FKBP5 gene. Genes can be regulated by the addition or removal of methyl (CH3) groups to an area of the gene.  The researchers found that ageing can decrease this methylation process, causing the FKBP5 gene to be overexpressed. They also found that when someone is depressed, this demethylation process is accelerated even further.

In a second finding they found that this increased FKBP5 expression is associated with increases in biochemical markers of inflammation and cardiovascular risk.

According to lead researcher, Dr Anthony Zannas (Max Planck Institute of Psychiatry, Munich):

“We found that both aging and depression seem to lead to changes in how DNA is processed, and that this can control the expression of genes that regulate how we respond to stress. These changes are associated with increased inflammation, and we believe that this may lead to the increased risk for several aging-related diseases, such as cardiovascular diseases and neuropsychiatric disorders, that has been observed in chronically stressed and depressed individuals.

Our work shows that risk for aging-related diseases could be conferred by epigenetic changes of stress-related genes and resultant increases in the expression of inflammation markers. It’s too early to say that we are seeing a cause and effect, so we need to confirm the findings by using larger samples and uncover the mechanisms using animal models. If we can do that, we may have the opportunity to develop tests for age-related diseases and new ways to prevent the harmful effects of stress”.

The FKBP5 gene is found on chromosome 6 in humans. It codes the FK506 binding protein 5, also known as FKBP5. This protein is known to play a role in stress responses, immune regulation and basic cellular processes involving protein folding.

Commenting on the work for the ECNP, Professor Bill Deakin (Manchester) said:

“There is a growing realisation that depression is one expression of a set of vulnerabilities for a range of disorders associated with age including obesity, diabetes, cerebro-vascular disease and dementia. Zannas and colleagues are now beginning to unpick some of the first molecular mechanisms of the shared risk. The focus is on FKBP5 a protein transcription factor that regulates several genes relevant to depression (via stress hormones) and to disorders such as Alzheimer’s disease.

Experiencing trauma in childhood and ageing have long-term influences on activity of the gene for FKBP5. This epigenetic regulation is abnormal in people with depression. It is early days and these findings need to be confirmed in definitively large populations. Nevertheless, the results point the way to finding molecular subtypes of depression with specific treatments targeted on transcription factors and epigenetic mechanisms”.

DNA sequencing consortium unveils patterns of mutations in autism

It has long been recognized that autism runs in families, suggesting a substantial genetic component to the disease. Yet few genes have so far been identified and the underlying genetic architecture of autism -- that is, how many genes contribute and to what extent they influence a person's chances of developing the disorder -- remains poorly understood. Now, a consortium led by researchers from the Broad Institute, Massachusetts General Hospital (MGH), and six other organizations has taken a step toward addressing these questions by searching for mutations in the fraction of the human genome that codes for proteins. The researchers sequenced this region, known as the "exome," in 175 autism patients and their unaffected parents, looking for single-letter DNA changes present only in the children. Their results, along with simultaneously published findings from two other research groups, suggest modest roles for hundreds of genes in the development of autism and pinpoint a few specific genes as genuine risk factors. The work is described in a paper that appears online April 4 in the journal Nature.
"Autism, like many heritable disorders, results from the action of many genes -- not simply a single gene as in cystic fibrosis or Huntington's disease," said senior author Mark Daly, chief of the Analytic and Translational Genetics Unit at MGH, a senior associate member of the Broad Institute and co-director of its Program in Medical and Population Genetics, and a member of the Broad Institute's Stanley Center for Psychiatric Research. "These genes hold key insights into the true biological causes of autism -- insights we have been unable to gain through other lines of research."
Autism is a common neurodevelopmental disorder characterized by impaired social, behavioral, and communication abilities. Compared to other complex diseases, which are caused by a complicated mix of genetic, environmental, and other factors, autism is highly heritable -- genetics accounts for roughly 80-90% of the risk of developing autism. Yet the majority of autism cases cannot be attributed to known inherited causes.
Researchers in the ARRA Autism Sequencing Collaborative (AASC) -- formed by researchers from the Broad Institute, MGH, Baylor College of Medicine, Mount Sinai School of Medicine, Vanderbilt University, University of Pennsylvania, Carnegie Mellon University, and University of Pittsburgh -- used massively parallel sequencing to help shed light on the genes that influence autism risk. Concordant findings from separate studies by two other groups, from Yale University and the University of Washington respectively, also appear in Nature.
The AASC team focused its attention on a particular set of mutations, specifically single-letter mutations that are not present in the parents' DNA but instead appeared spontaneously in the children -- so-called de novo point mutations. Although it is not yet clear exactly when these changes arise, such genetic variations tend to be rare but also more severe in their impact on gene function. With such extreme effects, they can serve as important signposts toward genes involved in autism.
"The idea is that these de novo mutations can help identify candidate genes much more precisely because a newly arisen point mutation is considered really strong evidence that the mutation -- and the gene it resides in -- is involved in autism," said first author Benjamin Neale, a research affiliate at the Broad Institute and an assistant in genetics at MGH.
The researchers found that less than half of the autism cases studied carried a potentially protein-altering de novo point mutation. While this was only slightly higher than the number expected based on the rate of mutation in the general population, these events are sufficiently rare that they could be used to uncover specific risk genes.
"These data suggest that there is a role for de novo point mutations in the coding region of the genome for autism, but they do not constitute a sufficient cause," said Neale. "That is to say, most de novo variants do not fully explain the disorder in an individual."
To learn more about these mutations and the genes in which they reside, the scientists looked for any meaningful connections among them. Such connections, among different proteins for example, might reveal important biological networks or pathways that underlie autism. By mining these data, Daly, Neale, and their colleagues found that the mutated genes are more connected to each other and to previously identified autism genes than expected. Specifically, the results suggest that some of the proteins encoded by these genes physically interact with each other.
As described in their paper, Daly and his colleagues pooled their data with those published in the other two Nature papers, revealing 18 candidate genes with multiple functional de novo point mutations. Considering the severity of the mutations, the collective results pointed to three genes as strong autism candidates: KATNAL2, a gene whose function is unknown; SCN2A, which encodes a brain protein that forms a channel for sodium ions; and CHD8, a gene that regulates gene transcription and modifies chromatin (the network of proteins that surrounds DNA).

**Source: Broad Institute of MIT and Harvard