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Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma

The introduction of immunomodulatory drugs (IMiDs) (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib) as first-line therapy and after relapse has improved response rates and survival multiple myeloma (MM) patients.

However, MM remains incurable and the majority of patients relapse and become refractory to available therapies. There are currently four approved lenalidomide-based and two proteasome inhibitor-based combinations for patients relapsing after 1-3 previous lines of therapy. The choice of treatment at relapse is based on age and comorbidities, the efficacy and toxicity of previous treatments, the duration of previous remission, and the circumstances of relapse. It is important to have an effective therapy for MM patients at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage.

This multicenter, phase II trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in MM patients in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). A total of 100 patients were enrolled between April 2014 and February 2017. The trial was conducted in 30 hospitals in France.

The primary objective was to evaluate the rate of partial remission or better after four cycles of PCD in patients previously treated with RVD, with or without upfront ASCT. The secondary objectives was to evaluate the time to response, duration of response, safety of PCD, and to assess progression-free survival and overall survival.

Results show that relatively cost-effective PCD was highly effective and safe as second-line treatment in RVD-exposed patients. Addition of a monoclonal antibody could increase its efficacy further.

 

Authors

Laurent Garderet & Frederique Kuhnowski

INSERM, APHP, Hôpital Saint Antoine, Sorbonne Université, Institut Curie

Sources

Blood Journal, Nov. 2018: Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma

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Microtubules – the critical highways of neurons – must stay “clear” for good traffic and neuronal survival

abstract_magda_06_test_export_depuis_applati_et_niveaux

The excess of tubulin polyglutamylation perturbs transport in primary hippocampal neurons and causes extensive neurodegeneration in mice and humans.

Researchers from Carsten Janke’s group from Institut Curie have recently published two articles of important relevance in the field of Neurobiology.

Neurobiology is the branch of biology, which explores neurons, these tentacle cells also known as nerve cells, which are the primary components of our Nervous System.

A typical neuron1 consists of a cell body, dendrites and an axon2 (see images 1 and 3) 1,4. Most neurons receive signals via the dendrites and send out signals down the axon. However, to allow the spreading of those signals, materials have to be transported to the right place at the right time in the axons.

“Scientists are amazed that microscopic materials can be transported more than several feet along one neuron that goes from the spinal cord to the foot. This is equivalent scale to a person carrying a package walking along the wall of China” 3.

Neuronal cells have to transport mitochondria, vesicles and other materials from one side to the other for their correct functionality. This means from the neuronal cell body to the end of the axon (synaptic terminal) and vice versa. In order to do this, neurons use microtubules as highways along the vast length of their axon.

Image 3

Image 2

Image 3

Image 1, 2 and 3. From top to bottom: 1A typical neuronal cell with its nucleus in pink and axon and dendrites in blue. 3Great Wall of China, represents the analogy with axons of some neurons. Those axons are so long, that the material travelling along them can be compared to the transport of a package along the Great Wall of China. 3Main parts of a neuron: cell body, dendrites and axon.

Many neurodegenerative diseases can be related to the dysfunction of microtubules. Therefore, studying the mechanisms that can influence and alter the properties and functions of microtubules is of important interest since they could play a role in neuronal disorders.

One of the mechanisms that alter the properties of microtubules, and how things move on them, are “tubulin posttranslational modifications”. But, what does this exactly mean? And what is tubulin? Let’s start answering the second question! In cells, there are big structures, polymers, built from small elements, or monomers, like a big structure built from small Lego bricks. Microtubules are one such polymer, and their Lego bricks are the tubulin proteins. Meaning one tubulin after another tubulin, after another tubulin, after another tubulin… form a microtubule! (see figure 4) 5.

image 4

Figure 4. The analogy between microtubules and a Lego structure. Lego blocks assembled as an example of how monomers (a single Lego blocks or tubulin) form a polymer (a Lego structure or a microtubule). Left image: a Lego structure, right image: a 3D model of a microtubule.

Regarding the first question – what are posttranslational modifications? – we need to imagine a factory chain. In this factory, the manufacturers produce tubulin, and, as in every factory, the products undergo several steps in the whole production chain. After the first step of protein production, tubulin assembles into microtubules, which then undergo some changes, meaning that at the end of its assembly line, microtubules are modified (see figure 5) 6.

Image 5

Figure 5. Image adapted to show the different steps of the maturation of the protein tubulin. In this case the posttranslational modification that is common on neuronal microtubules is named polyglutamylation.

The scientists of this discovery, focused particularly in a modification named “polyglutamylation”, that consists in the addition of glutamate groups to the tubulins forming the microtubules.

In general, as many things in life, balance is good and excess of something can have bad consequences. In this study, scientists, using mouse models, have discovered how neurodegeneration occurs as a direct cause of an excess of polyglutamylation. In other words, when microtubules get too much of these glutamate groups (in red in the diagram), they change they properties in the axons of neurons, disturbing the transport and therefore leading to the degeneration of a variety of neurons in the central nervous system (see figure 6)7.

image 6

Figure 6. Image showing the analogy between transport of materials on microtubules in cells and traffic of cars on roads. Balanced microtubule polyglutamylation in neurons would be the case of good car traffic. However, the excess of polyglutamylation provokes a disruption in the traffic and leads to neurodegeneration in neurons.

Importantly in this research, the authors Magiera and collaborators were able to reverse the neurodegeneration by inhibiting the process of polyglutamylation, a discovery holding the promise that specific inhibitors could be used in the near future as potential therapeutic agents to treat disabling and often, fatal neurodegeneration, for which so far, no treatment is available.

Their second article – Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration – in which they analyzed 13 patients, makes the important discovery that dysregulated microtubule polyglutamylation is also detrimental to human neurons. This gives more value to their discovery in mice and entails more strongly this “posttranslational modification” as a potential target for drug development for human neurodegenerative disorders.

REFERENCES:

Abstract: Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

1.       Image 1. Nature Communication (2016). Lifestyle, Health and Wellbeing: 3D technology enriches nerve cells for transplants to brain. Image taken from https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/180316/3d-technology-enriches-nerve-cells-for-transplants-to-brain.html
2.       Katja Hoehn (2018). Biology Reference. Neuron – Biology Encyclopedia. Taken from: http://www.biologyreference.com/Mo-Nu/Neuron.html
3.       Image 2. Blog Searching for the Mind with Jon Lieff, M.D. (2014). Medical Xpress: The Enormous Complexity of Transport Along the Axon. Image taken from http://jonlieffmd.com/blog/the-enormous-complexity-of-transport-along-the-axon
4.       Image 3. Cell Press (2014). Medical Xpress: Researchers provide first peek at how neurons multitask. University of Michigan. Image adapted from https://medicalxpress.com/news/2014-11-peek-neurons-multitask.html
5.       Image 4. Image (Lego) taken from https://pixers.no/lerretsbilder/lego-farge-blokk-trapp-9472402
Image (microtubule) adapted from  https://fr.123rf.com/photo_84820589_microtubule-isolé-sur-fond-blanc-illustration-3d-un-polymère-composé-d-une-protéine-tubuline-c-est-un-.html
6.       Figure 5. Image adapted from http://canvart.club/atmose-11_09_18.html
7.       Figure 6. Image adapted from http://www.qstormlegacy.org/glossary-2/axonal-transport-2/

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The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA

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Centromeres are the chromosomal domains required to ensure faithful transmission of the genome during cell division. They have a central role in preventing aneuploidy, by orchestrating the assembly of several components required for chromosome separation. However, centromeres also adopt a complex structure that makes them susceptible to being sites of chromosome rearrangements. Therefore, preservation of centromere integrity is a difficult, but important task for the cell. In this review, we discuss how centromeres could potentially be a source of genome instability and how centromere aberrations and rearrangements are linked with human diseases such as cancer.

Find out more

Nature Communications, Oct. 2018 : The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA

Authors : V. Barra & Daniele Fachinetti 

Nature Communications, doi:10.1038/s41467-018-06545-y

Nature Communications, doi:10.1038/s41467-018-06545-y

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NONO, the “red flag system” that detects HIV

« Sentinelles de l’organisme », les cellules dendritiques, ci-dessus en vert, reconnaissent les pathogènes dans nos tissus et les dégradent jusqu’à en isoler des fragments caractéristiques. En même temps, elles se dirigent vers les organes lymphoides les plus proches pour présenter ces fragments aux lymphocytes, soldats du système immunitaire. C’est ainsi que pourra se mettre en place une réponse immune spécifiquement ciblée contre ce pathogène.

There is not one but several types of HIV. Although HIV-1, which is the most common, wreaks havoc in infected populations, this is not the case for HIV-2 which less frequently leads to the development of AIDS. But why does the immune system do a better job of fighting this version of the virus? Researchers from Inserm and Institut Curie looked at this question, and identified the NONO protein, a detector which is more sensitive to HIV-2 and responsible for direct recognition of the virus by the immune system. This work, published in the journal Cell, provides a better understanding of the natural control of HIV and paves the way for new progress in the search for a vaccine for this virus.

AIDS develops when the immune system of an HIV-positive individual becomes unable to fight infection and becomes dramatically weak. The majority of people infected and not treated develop fatal AIDS. But in some cases AIDS does not develop in certain untreated HIV-positive individuals. This explains the existence of several forms of HIV.

Although HIV-1, which affects 25 million people, without treatment leads to AIDS in 99% of cases, this is not the case for HIV-2. This particular form of HIV is very close to HIV-1 but differs in terms of genetics. It is found mostly in West Africa and affects 1 million people. HIV-2 leads to the development of AIDS in fewer than 25% of cases, has no impact on the life expectancy of most people infected, and proves to be difficult to transmit to others. Furthermore, HIV-positive individuals with the HIV-2 form of the virus, and who also contract HIV-1, show improved resistance to the latter.

Researchers from Inserm and Institut Curie in Unit 932 Immunity and Cancer (Inserm/Institut Curie/PSL University/Paris Descartes University) studied the reasons for the immune system’s better control of HIV-2.

In 2010, this research team had already shown that dendritic cells – the immune system’s “sentinel” cells – were able to detect HIV-2 much more efficiently than HIV-1. In order for the immune response to be effective, there needs to be good immune recognition.

Based on this observation, the researchers sought to understand the molecular mechanisms involved in the dendritic cells’ recognition of HIV-2, and to find out why this recognition is effective in comparison to that of HIV-1.

They thus discovered that the NONO protein, located in the dendritic cells, acted as a detector able to recognize the internal casing (or capsid) of HIV-2 a lot better than that of HIV-1, and as a result to trigger an immune response to fight the virus. The capsid – which surrounds the genetic material of viruses – is made up of proteins, and NONO is apparently able to recognize a specific protein pattern of the capsid of HIV-2.

This study provides a better understanding of the natural mechanisms involved in infection control by HIV. According to Nicolas Manel, Inserm researcher in charge of the study: “the next step in this research project is to understand how this detection system works at the molecular level and how this detection triggers the immune response. We are developing innovative vaccine strategies in the lab, and this discovery paves the way for the new studies needed to develop a new generation of vaccines capable of “imitating” the HIV-2 capsid, and as a result triggering an immune response in people infected with the HIV-1 virus.”

 

Sources

NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation

Xavier Lahaye1 Matteo Gentili1 Aymeric Silvin1 Cécile Conrad,1 Léa Picard2,3 Mabel Jouve1 Elina Zueva1 Mathieu Maurin1 Francesca Nadalin1 Gavin J. Knott4 Baoyu Zhao5 Fenglei Du,5 Marlène Rio6,7 Jeanne Amiel6,7 Archa H. Fox4,8,9 Pingwei Li5 Lucie Etienne2 Charles S. Bond4 Laurence Colleaux6,7 and Nicolas Manel1,10

1 Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932,

75005 Paris, France

2 CIRI – International Center for Infectiology Research, Inserm U1111, CNRS UMR5308, École

Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Univ Lyon, 69007, Lyon, France

3 LBBE – Laboratoire de Biométrie et Biologie Evolutive CNRS UMR 5558, Université Lyon 1,

Univ Lyon, 69622, Villeurbanne, France

4 School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia

6009, Australia

5 Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas

77843, USA

6 INSERM UMR 1163, Paris-Descartes-Sorbonne Paris Cité University, Institut IMAGINE,

Necker-Enfants Malades Hospital, 75015 Paris, France

7 Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France

8 School of Human Sciences, The University of Western Australia, Crawley, Western Australia

6009, Australia

9 The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western

Australia 6009, Australia

10 Lead contact

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Combining Homologous Recombination and phosphopeptide-binding assays to predict the impact of BRCA1 BRCT variants on cancer risk

caputo

BRCA1 mutations have been identified that increase the risk of developing hereditary breast/ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, in order to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected.

We present a high-throughput structural and functional analysis of a large set of BRCA1 VUS. Information on both cellular localization and homology-directed DNA-repair (HR) capacity was obtained for the 78 BRCT missense variants of the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT domains.

This extensive analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects.

A classification is presented that is based on mutated BRCT-domain solubility, phosphopeptide-binding properties as well as VUS cellular localization and HR capacity. We propose that HR-defective variants, which always present, in addition, BRCT domains either insoluble in bacteria or defective for phosphopeptide-binding, lead to an increased cancer risk. On the opposite, variants with a WT HR activity and WT phosphopeptide-binding properties are likely neutral. The case of variants with WT HR activity and defective phosphopeptide-binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis.

More information

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New plan of action against ovarian cancer

Fatima Mechta-Grigoriou, chef de l'équipe "Stress et cancer" au sein de l'unité 830 Inserm "Génétique et biologie des cancers" à l'Institut Curie.

Fatima Mechta-Grigoriou’s team from Institut Curie just identified a brand new mecanism on ovarian cancer’s treatment. Her work just got published in the prestigious scientific journal Cell Metabolism.

“Our work is challenging the 100-year-old notion that all cancers, including ovarian cancer, are addicted to glucose,” applauds Fatima Mechta-Grigoriou, head of the Stress and Cancer team at Institut Curie (Inserm unit U830, a team certified by the Ligue Nationale Contre le Cancer). These researchers have applied an array of cutting-edge techniques – including proteomics, metabolomics and bioenergetics – to ovarian cancer cells to discover the secrets that they hold; namely the proteins they contain, the chemical reactions that take place and the source of their energy. They have been able to uncover information about high-grade serous cancers, the most formidable of ovarian cancers.

And it turns out that, against all expectations, some of these tumors do not feed on glucose but prefer fatty acids and glutamine (an amino acid made up of proteins). The research team has thus shed light on an innovative molecular mechanism by identifying the very surprising role of a PML (ProMyelocytic Leukemia) protein which is well known in leukemia.  And better still, the scientists have discovered that their original metabolism makes these cancers more vulnerable to certain types of chemotherapy, namely taxanes and platinum derivatives.

Once again, this work was made possible by the contributions of Basic research to knowledge of cancer, aided by the location of the “Stress and cancer” laboratory at Institut Curie Research Center in proximity to the Hospital Group. This enabled access to biological material from the hospital and fostered exchanges on medical observations and scientific hypotheses.

Fatima Mechta-Grigoriou now hopes that “physicians will seize these new discoveries to launch clinical trials”. First up, a molecular diagnosis of these tumors to ascertain their different types, followed by new and more effective treatments against cancer. This is crucial given that we know that ovarian cancer kills more than 3,000 women each year in France.

Reference of the publication

High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOC rely on oxidative phosphorylation, supported by glutamine- and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1a axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1a. Active PGC-1a increases synthesis of electron transport chain complexes thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOC exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1a-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.

Sources : Cell Metabolism, September, 20th – PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers