Birinapant, demcizumab, etirinotecan pegol, mafodotin, pexastimogene devacirepvec, rabusertib, rimilogene galvacirepvec, vintafolide, vorsetuzumab

Recently adopted names for antitumoral compounds (April 2012) - Noms d’antitumoraux adoptés récemment (avril 2012)

Birinapant, demcizumab, etirinotecan pegol, mafodotin, pexastimogene devacirepvec, rabusertib, rimilogene galvacirepvec, vintafolide, vorsetuzumab

Name (nom)	Code name	Type	Target(s)
birinapant	TL32711	Synthetic small peptidomimetic molecule	Smac ( Second mitochondrial-derived activator of caspases)
demcizumab	OMP-21M18	Monoclonal antibody	Delta-like 4 ligand (DLL4), an activator of Notch signaling
etirinotecan pegol	NKTR-102	Irinotecan conjugate (natural product-derived small molecule)	Topoisomerase I
mafodotin	mc-MMAF, mcMMAF, SGD-1269, monomethyl auristatin F	Peptide	Tubulin
pexastimogene devacirepvec	JX-594, TG6006	Thymidine kinase-deleted oncolytic poxvirus	Cancer cells
rabusertib	LY2603618, IC-83	Small inhibitory molecule	Cell cycle checkpoint kinase  (chk)
rimilogene galvacirepvec	Prostvac-V	Recombinant vaccinia virus vaccine	Prostate-specific antigen (PSA)
vintafolide	EC145	Vinca alkaloid conjugate	Microtubules
vorsetuzumab	SGN-70	Monoclonal antibody	CD70

Focus: Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma.

BACKGROUND:

Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions.

METHODS:

The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data.

RESULTS:

The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient's death.

CONCLUSION:

The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e., metastases from metastases, are irrelevant in terms of total tumour mass. Hence metastases seeded from metastases are clinically irrelevant in our model system. Only the first metastases seeded from the primary tumour contribute significantly to the tumour burden and thus cause the patient's death.

Source: Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma. Bethge A, Schumacher U, Wree A, Wedemann G. PLoS One. 2012;7(4):e35689.

Free paper available at:

http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0035689&representation=PDF

Press Review (May 5, 2012) – Revue de presse (5 mai 2012)

Fight Cancer With Facebook

How do you value Facebook? For my part, it's helping me get through cancer. And for me, that's invaluable.

By Gabe Canales. In Huffington Post (blog)

http://www.huffingtonpost.com/gabe-canales/cancer-support_b_1468729.html

Many Breast Cancer Patients in Their 40s Aren't 'High-Risk': Study

Researchers favor annual mammograms even with no family history.

By Kathleen Doheny. In U.S. News & World Report

http://health.usnews.com/health-news/news/articles/2012/05/03/many-breast-cancer-patients-in-their-40s-arent-high-risk-study

More women need breasts removed after brachytherapy‎‎

Women who got seed radiation as part of their breast cancer treatment were more likely to have an infection or breast pain than those who were treated with whole-breast irradiation, in a new study.

In Reuters.

http://www.reuters.com/article/2012/05/01/us-women-brachytherapy-idUSBRE8401FG20120501

Insight: Cancer in Africa: Fighting a nameless enemy

In Emanuel Adu's language, Twi, people call the skin cancer that is invading his cheek and nose "sasabro". It means a disease that eats away at you.

By Kate Kelland. In Reuters.

http://www.reuters.com/article/2012/05/01/us-cancer-africa-ghana-idUSBRE8400ET20120501

UC Santa Cruz builds national data center for cancer genome research‎

The emerging field of "personalized" or "precision" medicine holds great promise in the fight against cancer. If scientists can identify the genetic changes that drive each patient's cancer cells, they can use that information to develop targeted treatments. But achieving this goal will require massive amounts of genomic and clinical data and a sophisticated infrastructure to manage and analyze the data.

In Medical XPress

http://medicalxpress.com/news/2012-05-uc-santa-cruz-national-center.html

Life, Interrupted: Cancer Is Awkward

Disease has a way of invading your social space, forcing your hand. Will you tell your family and close friends only? What about acquaintances and work mates? Will you share your diagnosis on Facebook? Who knew cancer needed a social consultant?

By Suleika Jaouad. In New York Times (blog)

http://well.blogs.nytimes.com/2012/05/03/life-interrupted-cancer-is-awkward/

Lower-Dose Radioiodine Effective Against Thyroid Cancer

Patients may be able to skip high doses of radiation, painful thyroid hormone withdrawal, studies find.

By Carina Storrs. In U.S. News & World Report

http://health.usnews.com/health-news/news/articles/2012/05/02/lower-dose-radioiodine-effective-against-thyroid-cancer

Aveo says cancer drug not better than existing therapy‎

Aveo Pharmaceuticals Inc said a combination of its experimental drug (ficlatuzumab) to treat a type of lung cancer and the standard of care did not significantly improve the response and survival rate in a mid-stage study.

In Reuters

http://www.reuters.com/article/2012/05/02/us-aveopharmaceuticals-idUSBRE8410OC20120502

An ABSOLUTEly new view of the cancer genome

Scientists hoping to unlock cancer’s secrets face a formidable challenge. Sophisticated research tools have allowed them to peer into the genomes of cancer cells and identify many DNA alterations that may underlie malignancy, yet quantifying those changes is no simple task.

In Medical XPress

http://medicalxpress.com/news/2012-05-absolutely-view-cancer-genome.html

New data improve understanding of breast cancer's multiple varieties ‎

Presentations at the 4th IMPAKT Breast Cancer Conference.

In EurekAlert

http://www.eurekalert.org/pub_releases/2012-05/esfm-ndi050112.php

Le cancer synonyme de baisse des revenus‎‎

Le cancer entraîne pour de nombreux malades de moindre rentrées d'argent, des frais supplémentaires et des difficultés pour se réinsérer dans le monde du travail, selon une enquête diffusée mercredi par la Ligue contre le cancer.

Dans Le Figaro

http://sante.lefigaro.fr/actualite/2012/05/03/18113-cancer-synonyme-baisse-revenus

Cancer du sein : les progestatifs augmenteraient le risque‎‎‎

Utilisés comme contraceptifs, des progestatifs multiplieraient le risque par deux chez les femmes de moins de 44 ans, selon une étude.

Par Anne Prigent. Dans Le Figaro

http://sante.lefigaro.fr/actualite/2012/04/29/18098-cancers-seinle-risque-certains-contraceptifs

Cancer de la thyroïde: Un nouveau traitement aussi efficace et mieux vécu‎

Cette étude menée par une équipe de l’Institut de cancérologie Gustave Roussy (IGR) de Villejuif sur 4 stratégies thérapeutiques de traitement par l’iode 131 après chirurgie complète de la thyroïde pour les patients atteints de cancers de la thyroïde à faible risque, montre qu’un des traitements est mieux toléré, avec une moindre dose d’irradiation pour l’organisme. Ces résultats publiés dans l’édition du 3 mai du New England Journal of Medicine précisent les meilleures modalités de traitement.

Dans SantéLog

http://www.santelog.com/news/cancerologie/cancer-de-la-thyro-de-un-nouveau-traitement-aussi-efficace-et-mieux-vecu_8202_lirelasuite.htm

Une saine alimentation augmente les chances de survie après un cancer‎‎

L'American Cancer Society a lancé un guide pour les survivants du cancer dans lequel on apporte encore une fois la preuve que de saines habitudes de vie réduisent les risques d'une rechute et améliorent donc les chances de survie.

Dans Canoë

http://fr.canoe.ca/sante/archives/2012/05/20120502-162441.html

L'Etat devra indemniser un agriculteur exposé à des substances toxiques‎

L'Etat a été condamné par une juridiction d'Epinal à indemniser un agriculteur ayant développé un cancer à cause des substances toxiques contenues dans des pesticides et herbicides. "Ce qui constitue une première judiciaire en France", selon l'avocat du plaignant.

Dans Le Monde

http://www.lemonde.fr/planete/article/2012/04/27/l-etat-devra-indemniser-un-agriculteur-expose-a-des-substances-toxiques_1692613_3244.html

Amiante: la justice reconnaît la faute de Sanofi après la mort d'un salarié‎

La justice a reconnu jeudi la "faute inexcusable" commise par Sanofi-Chimie en exposant à l'amiante un ex-salarié de son site de Vitry-sur-Seine (Val-de-Marne), mort en 2010 d'un cancer broncho-pulmonaire, a annoncé à l'AFP sa fille Soraya Berkane.

Dans Le Nouvel Observateur

http://tempsreel.nouvelobs.com/societe/20120503.AFP5101/amiante-la-justice-reconnait-la-faute-de-sanofi-apres-la-mort-d-un-salarie.html

Mutated genes in cancer (68) – PTEN

PTEN

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 5728 or PTEN

● Ensembl (http://www.ensembl.org/index.html): ENSG00000185920

● UniProt (http://www.uniprot.org/): P60484

● OMIM (http://www.ncbi.nlm.nih.gov/omim): 601728

● GeneCards (http://www.genecards.org/): PTEN

● HGNC (http://www.genenames.org/): 9588 or PTEN

● Enzyme Number (IUBMB): EC 3.1.3.16, EC 3.1.3.48, EC 3.1.3.67

Gene locus :

10q23

Protein name:

Phosphatase and tensin homolog

Protein Size:

403 amino acids; about 47 kDa

Function:

PTEN acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and  threonine-phosphorylated proteins. It also acts as a lipid phosphatase, an activity that is critical for its tumor suppressor function. By negatively regulating intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells, PTEN antagonizes the PI3K-AKT/PKB signaling pathway, thereby modulating cell cycle progression and cell survival.

Cancer-related alterations:

Germinal PTEN mutations have been documented in Cowden disease and in Bannayan-Riley-Ruvalcaba phenotype; they are observed along the various exons of the gene except the 9th (never described) and the 1st (very few reports); a mutational hot spot is observed in exon 5 (amino acids 130-131 and 173) in relation with the catalytic core motif; in the great majority of the cases, inactivating mutations are observed, either by protein truncation, or by “missense” mutation within the phosphatase domain.

Somatic PTEN mutations are observed in several tumor types, notably those affecting vulva, endometrium, salivary glands, CNS (glioma), prostate, skin (malignant melanoma); they lead to a biallelic inactivation of the gene either by homozygous deletion, or by a combination of point mutation (mainly substitution) and a large deletion of the second allele. As with germinal mutations, mutational hot spots correspond to aminoacids 130-131 and 173.

Defects in PTEN are a cause of Cowden disease (CD), which is an autosomal dominant cancer predisposition syndrome associated with elevated risk for tumors of the breast, thyroid and skin. The predominant phenotype for CD is multiple hamartoma syndrome, in many organ systems including the breast (70% of CD patients), thyroid (40-60%), skin, CNS (40%), gastrointestinal tract. Affected individuals are at an increased risk of both breast and thyroid cancers. Trichilemmomas (benign tumors of the hair follicle infundibulum), and mucocutaneous papillomatosis (99%) are hallmarks of CD.

Defects in PTEN are the cause of Lhermitte-Duclos disease (LDD), which is characterized by dysplastic gangliocytoma of the cerebellum which often results in cerebellar signs and seizures. LDD and CD seem to be the same entity, and are considered as hamartoma-neoplasia syndromes.

Defects in PTEN are a cause of Bannayan-Zonana syndrome (BZS), also known as Bannayan-Riley-Ruvalcaba syndrome (BRRS). In BZS there seems not to be an increased risk of malignancy. It has a partial clinical overlap with CD. BZS is characterized by the classic triad of macrocephaly, lipomatosis and pigmented macules of the gland penis.

Defects in PTEN are a cause of Proteus syndrome. Proteus syndrome is a hamartomatous disorder characterized by overgrowth of multiple tissues, connective tissue and epidermal naevi, and vascular malformations. Tumors, mostly benign but some malignant, have also been reported in Proteus syndrome, generally presenting by the age of 20 years and including papillary adenocarcinoma of the testis, meningioma, and cystadenoma of the ovaries.

A microdeletion of chromosome 10q23 involving PTEN and BMPR1A is a cause of chromosome 10q23 deletion syndrome. This syndrome shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.

References (open access):

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA. Aging (Albany NY). 2011 Mar;3(3):192-222.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091517/pdf/aging-03-192.pdf

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control. Georgescu MM. Genes Cancer. 2010 Dec;1(12):1170-7.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092286/pdf/10.1177_1947601911407325.pdf

Characterisation of the PTEN inhibitor VO-OHpic. Mak LH, Vilar R, Woscholski R. J Chem Biol. 2010 Oct;3(4):157-63.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957887/pdf/12154_2010_Article_41.pdf

The PTEN phosphatase controls intestinal epithelial cell polarity and barrier function: role in colorectal cancer progression. Langlois MJ, Bergeron S, Bernatchez G, Boudreau F, Saucier C, Perreault N, Carrier JC, Rivard N. PLoS One. 2010 Dec 23;5(12):e15742.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009737/pdf/pone.0015742.pdf

Anticancer molecules (85) – Molécules anticancéreuses (85) - PEGASPARGASE

PEGASPARGASE

Name: pegaspargase

Commercial name: Oncaspar

Pharmacological class: asparagine-related enzyme

Therapeutic class: antineoplastic

Action: pegaspargase, more effective than asparaginase, converts asparagine to aspartic acid and ammonia. It facilitates production of oxaloacetate which is needed for general cellular metabolism. Some malignant cells lose the ability to produce asparagine and so the loss of exogenous sources of asparagine leads to cell death.

In 2011, pegaspargase is approved:

            ● for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multi-agent chemotherapy regimen.

***

Nom: pegaspargase

Nom commercial: Oncaspar

Classe pharmacologique: enzyme en relation avec l’asparagine

Classe thérapeutique: antinéoplasiques

Action: la pegaspargase, plus efficace que l’asparaginase, convertit l’asparagine en acide aspartique et ammoniac. L’enzyme facilite la production de l'oxaloacétate qui est nécessaire au métabolisme cellulaire en général. Certaines cellules malignes perdent la capacité de produire l’asparagine ; en conséquence, la perte de sources exogènes de l'asparagine conduit à la mort cellulaire.

En 2011, la pegaspargase est approuvée:

            ● pour le traitement de première ligne de patients atteints de leucémie aiguë lymphoblastique (LAL), en tant que composante d'une chimiothérapie multi-agents

Focus: Treatment of HER2-positive breast cancer: current status and future perspectives

Abstract | The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer.

Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.

Source: Treatment of HER2-positive breast cancer: current status and future perspectives. Carlos L. Arteaga, Mark X. Sliwkowski, C. Kent Osborne, Edith A. Perez, Fabio Puglisi and Luca Gianni (gianni.luca@hsr.it). Nat. Rev. Clin. Oncol. 9, 16–32 (2012)

Free article available at:

http://www.nature.com/nrclinonc/journal/v9/n1/pdf/nrclinonc.2011.177.pdf

Résumé | L'avènement de thérapies dirigées contre la molécule HER2 a considérablement amélioré les perspectives pour les patients ayant un cancer du sein HER2-positif au stade précoce. Toutefois, une proportion significative de ces patients rechutent et meurent du cancer du sein. Les essais visant à définir, affiner et optimiser l'utilisation des deux agents ciblant HER2 approuvés (trastuzumab et du lapatinib) chez les patients ayant un cancer du sein HER2-positif au stade précoce sont en cours. En outre, de nouvelles approches prometteuses sont développés, notamment 1) le développement d’anticorps monoclonaux et de petites molécules inhibitrices de tyrosine kinase ciblant HER2 ou d'autres membres de sa famille, 2) le développement d’anticorps liés à des fragments cytotoxiques ou modifiés pour améliorer leur fonction immunologique, 3) le développement de peptides immunostimulants, et 4) le ciblage des voies de la PI3K et de l'IGF-1R. Une meilleure compréhension de la voie de signalisation de HER2, de ses relations avec les autres voies de signalisation et des mécanismes de résistance a conduit également à des polythérapies rationnelles et à une meilleure compréhension de la réponse au traitement chez les patients avec un cancer du sein HER2-positif.

Basé sur des résultats prometteurs obtenus avec de nouveaux agents dans les cancers du sein HER2-positif au stade avancé, une série d'études de grande envergure en traitements adjuvant et néoadjuvant sont prévues ou en cours. Cette revue se concentre sur le traitement actuel des patients atteints de cancer du sein HER2-positif et vise à actualiser les connaissances des cliniciens sur les évolutions futures probables dans le traitement de cette maladie, selon les essais cliniques et la recherche translationnelle.

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

http://www.nature.com/nrclinonc/journal/v9/n1/pdf/nrclinonc.2011.177.pdf

FDA approves Votrient for advanced soft tissue sarcoma

            The U.S. Food and Drug Administration recently approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.

            Votrient works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.

            A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.

            “Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”

            Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.

            Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Source: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302065.htm