jeudi 31 mai 2012

Focus: Targeting Autophagy Addiction in Cancer





Autophagy inhibition is a novel cancer therapeutic strategy in the early stages of clinical trial testing. The initial rationale for using autophagy inhibition was generated by research revealing that autophagy is upregulated in response to external stresses, including chemotherapy and radiotherapy. Combining autophagy inhibition with agents that induce autophagy as a pro-survival response may therefore increase their therapeutic efficacy. Recent research has shown that some cancer cells, particularly those driven by the K-Ras oncogene, also depend on elevated levels of autophagy for survival even in the absence of external stressors. In multiple in vitro as well as in vivo systems, oncogenic Ras-mediated transformation and tumor growth are dependent on autophagy to evade metabolic stress and cell death. These studies have subsequently led to further early phase clinical testing whether autophagy inhibition is a viable and effective strategy for targeting Ras-driven tumors. Even before the clinical results are available from these ongoing clinical trials, much work remains to optimally develop the approach of autophagy inhibition clinically; most notably reliably detecting levels of autophagy in human tumor samples, pharmacodynamics of currently available autophagy inhibitors (chloroquine and the derivative hydroxychloroquine), and new target identification and drug development.

Source: Targeting Autophagy Addiction in Cancer. Mancias JD, Kimmelman AC (Alec_Kimmelman@DFCI.HARVARD.edu). Oncotarget. 2011 Dec 19.
Free paper available at:

L'inhibition de l'autophagie est une nouvelle stratégie thérapeutique du cancer actuellement en essais cliniques de premiers stades. La raison initiale de ces tentatives  d'inhibition de l’autophagie provient d’études révélant que l'autophagie est régulée à la hausse en réponse à des contraintes externes, en ce compris la chimiothérapie et la radiothérapie. La combinaison de l'inhibition de l'autophagie avec des agents qui induisent l'autophagie comme une réponse pro-survie peut donc accroître l’efficacité thérapeutique de ceux-ci. Des recherches récentes ont montré que certaines cellules cancéreuses, en particulier celles dépendant l'oncogène K-Ras, dépendent également de niveaux élevés d'autophagie pour leur survie, même en l'absence de facteurs de stress extérieurs. Dans de nombreux systèmes in vitro ainsi que in vivo, la transformation cellulaire médiée par Ras et la croissance tumorale sont dépendentes de l’autophagie pour se soustraire au stress métabolique et à la mort cellulaire. Ces études ont conduit récemment à des essais de développement clinique au stade précoce afin de voir si l'inhibition de l’autophagie est une stratégie viable et efficace pour cibler des tumeurs « Ras-dépendantes ». Bien avant que les résultats cliniques de ces essais soient disponibles, beaucoup de travail subsiste, notamment afin de détecter de manière fiable les niveaux de l'autophagie dans des échantillons de tumeurs, la pharmacodynamie des inhibiteurs d’autophagie actuellement disponibles (la chloroquine et son dérivé l'hydroxychloroquine), identifier des cibles et déveolpper de nouveaux médicaments.

Article (en anglais) librement accessible à l’adresse:


mercredi 30 mai 2012

Mutated genes in cancer (73) – RUNX1





RUNX1

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 861 or RUNX1
● Ensembl (http://www.ensembl.org/index.html): ENSG00000159216
● UniProt (http://www.uniprot.org/): Q01196
● GeneCards (http://www.genecards.org/): RUNX1
● HGNC (http://www.genenames.org/): 10471 or RUNX1

Gene locus:

21q22.3

Protein name:

Runt-related transcription factor 1

Protein Size:

453 amino acids; about 49 kDa

Function:

The protein encoded by RUNX1 is a transcription factor associated with acute myeloid leukemia (AML). It belongs to the Runt-related transcription factor (RUNX) family of genes which are also called core binding factor-α (CBFα). RUNX proteins form a heterodimeric complex with CBFβ which confers increased DNA binding and stability to the complex. RUNX1 is thought to be involved in the development of normal hematopoiesis.

Cancer-related alterations:

Somatic RUNX1 mutations (deletion, insertion, point mutations) have been observed in tumors of haematopoietic/lymphoid tissue and CNS.  There are no mutational hot spots.
RUNX1 is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML).

Chromosomal alterations involving RUNX1 and leading to fusion genes are well-documented and have been associated with several types of leukemia.



ins(8;21)(q22;q22q22) leads to RUNX1-RUNX1T1 in AML
ins(21;8)(q22;q13q22) leads to RUNX1-RUNX1T1 in AML
ins(21;8)(q22;q21q22) leads to RUNX1-RUNX1T1 in AML
t(1;21)(p35;q22) leads to RUNX1-YTHDF2 in AML
t(1;21)(p36;q22) leads to RUNX1-PRDM16 in AMLt, MDS
t(1;21)(q21;q22) leads to RUNX1-ZNF687 in AML
t(2;21)(q11;q22) leads to RUNX1-AFF3 in T-ALL
t(3;21)(q26;q22) leads to RUNX1-RPL22P1 in CML, AML, MDS
t(3;21)(q26;q22) leads to RUNX1-MDS1 in AMLt, MDSt
t(3;21)(q26;q22) leads to RUNX1-EVI1 in CML, MDSt, AML, AMLt
t(4;21)(q31;q22) leads to RUNX1-SH3D19 in AML
t(7;21)(p22;q22) leads to RUNX1-USP42 in AML
t(8;21)(q21-q22;q22) leads to RUNX1-RUNX1T1 in AML
t(8;21)(q23;q22) leads to ZFPM2-RUNX1 in RAEB
t(8;21)(q24;q22) leads to RUNX1-TRPS1 in T-ALL, AML
t(11;21)(q13;q22) leads to MACROD1-RUNX in AML, CML, MDS
t(12;21)(p13;q22) leads to ETV6-RUNX1  in B-ALL
t(12;21)(q12;q22) leads to RUNX1-CPNE8 in AML
t(16;21)(q24;q22) leads to RUNX1-CBFA2T3 in MDS, AML, AMLt
t(X;21)(p22;q22) leads to RUNX1-PRDX4 in AML

Abbreviations: AML: acute myeloid leukemia; AMLt: acute myelogenous leukemia, primarily treatment associated; MDS: myelodysplastic syndrome; T-ALL: T-cell acute lymphocytic leukemia; CML: chronic myeloid leukemia; MDSt: myelodysplastic syndrome, primarily treatment associated; RAEB: refractory anemia with excess blasts; B-ALL: B-cell acute lymphocytic leukaemia.


RUNX1 genetic alterations are the cause of familial platelet disorder with associated myeloid malignancy (FPD-AML or FPDMM), which is an autosomal dominant disease characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukemia.

References (open access) :

Familial myelodysplastic syndromes - a review of the literature. Liew E, Owen CJ. Haematologica. 2011 May 23

Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, Tadrist Z, Olschwang S, Vey N, Birnbaum D, Gelsi-Boyer V, Mozziconacci MJ. BMC Cancer. 2010 Aug 2;10:401.

RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia. Edwards H, Xie C, LaFiura KM, Dombkowski AA, Buck SA, Boerner JL, Taub JW, Matherly LH, Ge Y. Blood. 2009 Sep 24;114(13):2744-52.

Integrative analysis of RUNX1 downstream pathways and target genes. Michaud J, Simpson KM, Escher R, Buchet-Poyau K, Beissbarth T, Carmichael C, Ritchie ME, Schütz F, Cannon P, Liu M, Shen X, Ito Y, Raskind WH, Horwitz MS, Osato M, Turner DR, Speed TP, Kavallaris M, Smyth GK, Scott HS. BMC Genomics. 2008 Jul 31;9:363.



mardi 29 mai 2012

Anticancer molecules (87) – Molécules anticancéreuses (87) - PALIFERMIN





PALIFERMIN


Name: palifermin
Commercial name: Kepivance
Pharmacological class: keratinocyte growth factor (recombinant)
Therapeutic class: biologic and immunologic agent
Action: palifermin binds to the human keratinocyte growth factor (KGF) receptor found on buccal cell surfaces. The binding activates a signaling pathway which leads to the transcriptional activation of many proteins important for cell growth and survival.

In 2011, palifermin is approved:

            ● to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue.

***

Nom: palifermine
Nom commercial: Kepivance
Classe pharmacologique: facteur de croissance des kératinocytes (recombinant)
Classe thérapeutique: agent biologique et immunologique
Action: la palifermine se lie aux récepteurs du facteur de croissance des kératinocytes (« KGF ») présents à la surface des cellules buccales. La liaison active une voie de signalisation qui conduit à favoriser l’expression de plusieurs protéines importantes pour la croissance et la survie cellulaire.

En 2011, la palifermine est approuvée:

            ● pour diminuer l'incidence et la durée de la mucosite buccale sévère chez les patients atteints d'hémopathies malignes qui reçoivent de fortes doses de chimiothérapie et de radiothérapie suivies d’un traitement aux cellules souches reconstituantes.




lundi 28 mai 2012

Focus: The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression




It is becoming increasingly clear that the tumour microenvironment has a very important role in tumour progression and drug resistance. Many different cell types within the tumour stroma have an effect on tumour progression either in a positive or in a negative way. Mesenchymal stem cells (MSCs) are a distinct population of cells that have been linked with tumour growth. Mesenchymal stem cells can home to tumours where they modulate the immune system and facilitate tumour growth, angiogenesis and metastasis. Recent studies have shown that MSCs also have an important role in the resistance to various anti-cancer drugs. This mini-review provides an overview of the functional properties of MSCs in tumour progression and drug resistance.

Source: The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression JM Houthuijzen, LGM Daenen, JML Roodhart and EE Voest. British Journal of Cancer advance online publication 17 May 2012
Free paper available at:

Il est de plus en plus clair que le microenvironnement d’une tumeur joue un rôle très important dans la progression tumorale et la résistance aux médicaments. De nombreux types différents de cellules dans le stroma tumoral ont un effet sur ​​la progression tumorale, dans un sens positif ou dans un sens négatif. Les cellules souches mésenchymateuses (CSM) sont une population distincte des cellules qui ont été précédemment liées à la croissance tumorale. Les cellules souches mésenchymateuses peuvent pénétrer les tumeurs où elles modulent le système immunitaire et favorisent la croissance tumorale, l'angiogenèse et la métastase. Des études récentes ont montré que les CSM ont également un rôle important dans la résistance à divers médicaments anti-cancéreux. Cette mini-revue donne un aperçu des propriétés fonctionnelles des cellules souches mésenchymateuses dans la progression tumorale et la résistance aux médicaments.

Article (en anglais) librement accessible à l’adresse :


vendredi 25 mai 2012

Press Review (May 26, 2012) – Revue de presse (26 mai 2012)




Sleep Apnea Tied to Increased Cancer Risk‎‎
Two new studies have found that people with sleep apnea, a common disorder that causes snoring, fatigue and dangerous pauses in breathing at night, have a higher risk of cancer. The new research marks the first time that sleep apnea has been linked to cancer in humans.
By Anahad O’Conner. In New York Times (blog)

Lung cancer tests advised for some heavy smokers‎
New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a high risk of false positive tests.
By Genevra Pittman. In Reuters

Sigmoidoscopy an option for colon cancer screening‎‎
Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests.
By Genevra Pittman. In Reuters

Folic acid tied to lower child cancer risks‎‎
Rates of two rare childhood cancers (Wilms tumor -a type of kidney cancer-, and primary neuroectodermal tumor) declined after the U.S. began requiring grain products to be fortified with the B vitamin folic acid, a new study finds.
By Amy Norton. In Reuters

Cancer Research Should Be a National Priority
If a terrorist targeted almost two million Americans per year and killed over half a million of them, the U.S. would almost certainly declare war. Why, then, have we not put the same effort into fighting cancer that we have into fighting wars?
Cancer kills more people every day than terrorists killed on September 11, 2001. Yet our country fails to prioritize cancer as a national issue.
By Sierra Alef-Defoe. In Huffington Post

Celldex breast cancer drug (CDX-011) shrinks some tumors: study‎‎‎
Interim results from a mid-stage trial of Celldex Therapeutics Inc's experimental drug showed trends toward reducing tumors in patients with advanced breast cancer, with rates improving for those patients with high levels of a key protein.
In Reuters

Pancreatic Cancer Vaccine Shows Promise‎
A vaccine to treat deadly pancreatic cancer could be available within a couple years.
By Jason Koebler. In U.S. News & World Report

Panel advises against PSA cancer screening‎‎‎
Doctors should no longer offer the PSA prostate cancer screening test to healthy men because they're more likely to be harmed by the blood draw — and the chain of medical interventions that often follows — than be helped, according to government advisory panel's final report.
By Liz Szabo. In USA Today.

Art competition helps cancer patients tell their stories‎‎
The American Cancer Society reports that there are nearly 12 million cancer survivors alive today in the U.S. alone. In addition, there are millions more who love and care for them. The common thread that unites them is the fact that each person is on a cancer journey with a story to tell that can inspire others.
In Milwaukee Journal Sentinel

Professor writes about painful effects of ovarian cancer‎‎
After learning she had advanced ovarian cancer, Susan Gubar felt the need to reassure her two grown daughters that not even death could separate them.
By Liz Szabo. In USA Today.

Not Letting Cancer Define Us‎ ‎
It is how we face obstacles that define us and those obstacles can vary in size or matter. They can be trying to hit a curve ball in Little League, passing a math test or as common as trying to curb your appetite so that you can shed 10 pounds. Sometimes in life, what seems to be an obstacle is not. If you face these small obstacles with positive focus and bravery, the so-called obstacle will never define you -- in fact, you can actually define it.
By David Plotkin. In Huffington Post

Anti-Psychotic Drug Pushes Cancer Stem Cells Over the Edge‎ ‎
An anti-psychotic drug used to treat schizophrenia appears to get rid of cancer stem cells by helping them differentiate into less threatening cell types. The discovery reported in the Cell Press journal Cell on May 24th comes after researchers screened hundreds of compounds in search of those that would selectively inhibit human cancer stem cells, and it may lead rather swiftly to a clinical trial.
In ScienceDaily

New clues about cancer cell metabolism emerge‎ ‎
For almost a century, researchers have known that cancer cells have peculiar appetites, devouring glucose in ways that normal cells do not. But glucose uptake may tell only part of cancer's metabolic story. Researchers from the Broad Institute and Massachusetts General Hospital looked across 60 well-studied cancer cell lines, analyzing which of more than 200 metabolites were consumed or released by the fastest dividing cells. Their research yields the first large-scale atlas of cancer metabolism and points to a key role for the smallest amino acid, glycine, in cancer cell proliferation. Their results appear in the May 25 issue of the journal Science.
In ScienceCodex
Why People Stick with Cancer Screening, Even When It Causes Harm‎ ‎
When it comes to complex medical decisions, cold hard statistics may hold little sway over patients in the face of a single, compelling anecdote.
By Maia Szalavitz. In TIME




Cancer de la peau: les cabines à UV dans le collimateur du gouvernement‎‎‎‎
Face à la multiplication des cancers de la peau en France, le gouvernement a décidé de durcir la réglementation des cabines à bronzage artificiel, tenus pour responsables de plusieurs dizaines de décès chaque année par mélanomes.
Par Olivier Thibault. Dans AFP

Les cas de cancer de la peau en forte hausse depuis 1980 en France‎‎‎
Quelque 80.000 cancers de la peau sont signalés chaque année dans l'Hexagone, d'après des données présentées par l'Institut national du cancer (INCa), l'Institut national de prévention et d'éducation pour la santé (Inpes) et le ministère de la Santé, mercredi 23 mai. Près de 9.780 nouveaux cas de mélanomes, le plus dangereux des cancers de la peau, ont été diagnostiqués en 2011. L'incidence de cette forme de cancer de la peau a ainsi plus que triplé entre 1980 et 2005.
Dans Le Parisien

Cancer: des chercheurs explorent la piste d'un médicament aimanté‎
Des chercheurs grenoblois spécialisés dans les sciences du neutron espèrent contribuer par leurs travaux à la mise au point d'un médicament liquide aimanté pour traiter le cancer, qui ne devrait cependant pas voir le jour avant plusieurs années.
Dans AFP

Cancer: des molécules "faussaires" pour doper l'effet de la radiothérapie‎
Des molécules "leurres" qui trompent les cellules cancéreuses et les poussent au suicide sont testées pour doper la radiothérapie chez des patients atteints de mélanome cutané avec présence de métastases à proximité sur la peau, selon l'Institut Curie.
Dans AFP

Ronfler augmenterait les risques de cancer
Les personnes souffrant de troubles graves de la respiration pendant le sommeil (SDB), ont presque 5 fois plus de risques de développer un cancer.
Dans Atlantico.fr

Quand l'immunité protège aussi du cancer‎‎
AVIS D'EXPERT- Sebastian Amigorena, biologiste et membre de l'Académie des sciences nous explique que le système immunitaire peut nous protéger, au moins partiellement, contre le développement des tumeurs cancéreuses malignes.
Par Sebastian Amigorena. Dans Le Figaro

Une poupée Barbie chauve‎‎
La compagnie Mattel va fabriquer dès 2013 une poupée Barbie chauve pour sensibiliser les enfants au cancer.
Dans Canoé

Vers un nouveau traitement contre le cancer de la prostate‎‎‎
Des chercheurs américains ont démontré qu'un médicament, nommé le "Zytiga", avait la capacité de d'enrayer la tumeur cancéreuse chez les hommes souffrant d'un cancer de la prostate, avance Le Parisien / Aujourd'hui en France, lundi 21 mai. Cette molécule agirait en bloquant la production de testostérone.
Dans Le Parisien


Mutated genes in cancer (72) – IDH1/IDH2





IDH1 and IDH2

IDH1

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 3417 or IDH1
● Ensembl (http://www.ensembl.org/index.html): ENSG00000138413
● UniProt (http://www.uniprot.org/): O75874
● GeneCards (http://www.genecards.org/): IDH1
● HGNC (http://www.genenames.org/): 5382 or IDH1
● Enzyme Number (IUBMB): EC 1.1.1.42

Gene locus :

2q33.3

Protein name:

Isocitrate dehydrogenase 1 (NADP+), soluble

Protein Size:

414 amino acids; about 47 kDa



IDH2

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 3418 or IDH2
● Ensembl (http://www.ensembl.org/index.html): ENSG00000182054
● UniProt (http://www.uniprot.org/): P48735
● GeneCards (http://www.genecards.org/): IDH2
● HGNC (http://www.genenames.org/): 5383 or IDH2
● Enzyme Number (IUBMB): EC 1.1.1.42

Gene locus:

15q26.1

Protein name:

Isocitrate dehydrogenase 2 (NADP+), mitochondrial

Protein Size:

452 amino acids; about 51 kDa




Function:

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 localizes to the cytoplasm and peroxisomes, and acts as a NADP-dependent protein that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate. The homologous isocitrate dehydrogenase 2 (IDH2) is the only protein homologous to IDH1 that also utilizes NADP; however IDH2 localizes to the mitochondria. IDH2 plays an important role in controlling the mitochondrial redox balance, and in providing protection from oxidative damage similar to IDH1.

Cancer-related alterations:

Several recent studies have identified a genetic alteration in the IDH1 or IDH2 genes of malignant brain tumors. While IDH1 or IDH2 mutations are observed in the majority of grade II and III astrocytomas and oligodendrogliomas, glioblastomas and low grade astrocytic tumors demonstrate an absence or low frequency of mutations.
All IDH alterations are point mutations resulting in a “missense” change at codon 132 of IDH1, and codons 140 or 172 of IDH2. Residues 132 of IDH1 and 172 of IDH2 are analogous between genes, and occur in exon 4 at a highly conserved region of the isocitrate binding site. The mutation is thought to down-regulate or even eliminate enzyme activity, leading to increased cellular oxidative stress and damage.

IDH1 or IDH2 mutations have also been observed in about 10% of acute myeloid leukemia (AML) cases.

References (open access):

Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Reitman ZJ, Yan H. J Natl Cancer Inst. 2010 Jul 7;102(13):932-41.

Mutant metabolic enzymes are at the origin of gliomas. Yan H, Bigner DD, Velculescu V, Parsons DW. Cancer Res. 2009 Dec 15;69(24):9157-9.

Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. Krell D, Assoku M, Galloway M, Mulholland P, Tomlinson I, Bardella C. PLoS One. 2011;6(5):e19868.

IDH1 and IDH2 mutations in myeloid neoplasms--novel paradigms and clinical implications. Cazzola M. Haematologica. 2010 Oct;95(10):1623-7.

IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D, Holland KB, Whitman SP, Becker H, Schwind S, Metzeler KH, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD. J Clin Oncol. 2010 May 10;28(14):2348-55.