vendredi 30 mars 2012

Press Review (March 31, 2012) – Revue de presse (31 mars 2012)




Drug candidates derailed in case of mistaken identity
PARP inhibitor that wasn’t highlights widespread flaws in preclinical studies.
By Heidi Ledford. In Nature

Cancer Rates Decline Overall, but Obesity and Tanning Lead to Upticks
Rates of many cancers have continued to fall in the U.S., according to a national report, but the authors say that obesity and persistent use of tanning beds are contributing to increases in related cancers.
By Mike Stobbe. In TIME.

Even a Little Drinking May Raise Breast Cancer Risk: Study
Heavy consumption increases risk up to 50 percent, new review finds.
By Kathleen Doheny. In U.S. News & World Report

HPV Vaccine May Help Women With Cervical Conditions
Study suggests immunization can reduce their risk for cervical disease later on.
In U.S. News & World Report

Some Triple-Negative Breast Cancers Express Androgen Receptor
Triple-negative breast tumors are notorious for their ability to evade hormonal agents and targeted therapies. But a subset of these intractable tumors expresses androgen receptors, and may be vulnerable to antiandrogen drugs, investigators suggested at the symposium of the Society of Surgical Oncology.
By Neil Osterweil. In The Oncology Report

Britain is failing to care for older people with cancer
Older people diagnosed with cancer are being under treated because of their age. This is discrimination and must stop.
By Ciaràn Devane. In The Guardian

New more-sensitive blood test catches recurring breast cancer a year earlier
A new blood test is twice as sensitive and can detect breast cancer recurrence a full year earlier than current blood tests, according to a scientist who reported here today at the 243rd National Meeting & Exposition of the American Chemical Society (ACS). The report was among more than 11,000 presentations on new developments in science scheduled this week at the meeting, held by the world's largest scientific society.
In EurekAlert (press release)

Breast cancer fundraising lags after abortion dispute
U.S. breast cancer charity Susan G. Komen for the Cure is feeling a pinch on donations following a controversy over its funding for Planned Parenthood, a leading provider of birth-control and abortion services.
By David Morgan and Anna Yukhananov. In Reuters

Roche to file T-DM1 (trastuzumab emtansine) breast cancer drug on good data
Roche said patients with an aggressive type of breast cancer lived longer after taking its experimental "armed antibody" drug without the disease worsening than those on a mix of GlaxoSmithKline drug Tykerb and Roche's Xeloda.
By Katharina Bart. In Reuters

Provenge: New Doubts About Prostate Cancer Vaccine
Prostate cancer vaccine Provenge has long incited passions unlike any other cancer therapy. Doctors who raised doubts about it received death threats. Health regulators and lawmakers faced loud protests at their offices.
By Sharon Begley. In Huffington Post

Threshold Pharmaceuticals Announces Multiple Data Presentations on TH-302 at the 2012 AACR Annual Meeting
Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that TH-302 will be featured in four presentations, including a late-breaking clinical trial session, at the American Association for Cancer Research (AACR) Annual Meeting, to be held on March 31 - April 4, 2012, in Chicago, IL.
In Healthcare Global (press release)

Kidney cancers: Major rise 'linked to obesity'
Obesity is fuelling a major increase in the number of cases of kidney cancers diagnosed in Britain, experts say.
In BBC News

Huge Cancer Knowledge Resource Made Public
Bringing the goal of personalized medicine a step closer, scientists who design anti-cancer treatments and clinical trials now have access to a huge cancer knowledge resource, thanks to a collaboration between industry and academia. A report in the 28 March online issue of Nature describes how the Cancer Cell Line Encyclopedia (CCLE) brings together genome data and predictors of drug response for 947 cancer cell lines.
In Medical News Today




L'autopalpation des testicules inutile pour prévenir un cancer
Les appels de célébrités destinés à encourager les mâles britanniques à se palper régulièrement les testicules afin de détecter des signes précoces du cancer sont une perte de temps, selon l'opinion d'un médecin.
RTBF

Cancer : un seul médicament fait régresser la plupart des tumeurs
Un anticorps dirigé contre une protéine (CD47) exprimée par la plupart des cellules tumorales pourrait faire reculer, voire soigner, sept cancers différents, du sein à la prostate en passant par le foie et le cerveau. Les premiers résultats des essais cliniques sont espérés dans les deux prochaines années.
Par Janlou Chaput. Dans Futura-Sciences

Une encyclopédie génétique du cancer
La recherche sur le cancer s'oriente vers la personnalisation du traitement. Chaque tumeur a des caractéristiques génétiques propres. Les thérapeutiques anticancéreuses doivent désormais être adaptées au plus près du type tumoral, lorsque c'est possible. Déjà dans certaines formes de cancer du sein ou du poumon, la présence de gènes particuliers au sein des cellules malades conduisent à l'utilisation de certaines chimiothérapies qui ne sont efficaces que lorsque ces gènes sont présents. La revue scientifiqueNature publie ce jeudi 28 mars la première encyclopédie génétique cellulaire du cancer (The Cancer Cell Line Encyclopedia), qui présente le génome décrypté de 1000 types de cancers différents.
Par Martine Perez. Dans Le Figaro

Le cancer de la peau, multiplié par 2000% en 70 ans !
Le risque d'attraper un cancer de la peau touche désormais une personne sur 75 en 2012, contre une sur 1500 en 1940. Les raisons de cette augmentation fulgurante ? Une baisse des dépistages et une utilisation sommaire des protections solaires.
Par Audrey Kazadi & Gina Tarlayan. Dans Cosmopolitan.fr

Prix du cancer: la double peine‎‎
Si la maladie entraîne un choc psychologique, elle pèse également lourdement sur la santé financière des patients. Une double peine dénoncée par Emmanuel Jammes, de la Ligue contre le cancer.
Par Anthony Lieures. Dans L’Express

Le cancer, une maladie des cellules qui devient une maladie des gènes
Au cours des 30 dernières années, grâce à la Recherche fondamentale, notre vision du cancer s'est radicalement modifiée. Ces prochaines années seront celles où ces découvertes théoriques vont bouleverser la classification des tumeurs et les modes de traitement. La France, comme les autres pays, doit se préparer stratégiquement à cette nouvelle révolution médicale.
Par Thomas Tursz. Dans Le Huffington Post

Les traitements personnalisés des cancers‎
Les progrès de la génétique moléculaire depuis 20 ans ont modifié de fond en comble notre compréhension des mécanismes de la transformation des cellules cancéreuses et de la progression tumorale. La découverte dans le génome des cellules tumorales de mutations ou d'activations anormales de gènes clés gouvernant les mécanismes et le contrôle de la prolifération des cellules normales a fait émerger les concepts d'oncogènes et de gènes suppresseurs de tumeurs. L'analyse de la structure et des fonctions de ces gènes mutés dans les cellules cancéreuses a conduit au développement de nouveaux médicaments ciblés, dont l'action spécifique n'est plus de tuer toutes les cellules de l'organisme se divisant rapidement, sans reconnaitre clairement les cellules cancéreuses, comme le font les agents de la chimiothérapie conventionnelle, mais bien d'inhiber spécifiquement telle ou telle fonction de la protéine produite par les gènes anormaux présents dans les cellules cancéreuses.
Par Thomas Tursz. Dans Le Huffington Post

Les associations entre médicaments: conséquences médico-économiques
Quand on pense à la lenteur et au prix de revient du développement d'un nouveau médicament en cancérologie (8 à 10 ans pour un budget de 800 à 950 000 000 $) avant même son autorisation de mise sur le marché (AMM), et qu'on sait que toutes ces nouvelles drogues sont développées par des firmes concurrentes et engagées dans une compétition mondiale acharnée sur un marché en plein développement, on conçoit qu'aujourd'hui la stratégie des grandes firmes industrielles est de développer individuellement chaque drogue jusqu'à l'obtention de l'AMM, en évitant le plus longtemps possible toute comparaison et de fait toute combinaison avec une drogue peut-être complémentaire, mais développée par une firme concurrente. Aujourd'hui, les intérêts de court terme du marketing l'emportent sur l'intérêt médical de long terme dont dépendra de fait la pérennité du médicament. La stratégie industrielle actuelle est dispersée, peu efficace, lente et surtout génératrice de surcoûts qui pourraient rapidement devenir insupportables pour les dépenses de santé, surtout en Europe.
Par Thomas Tursz. Dans Le Huffington Post

Cancer : les essais cliniques en augmentation en France‎‎
En 2010, 34.000 patients atteints de cancer ont été inclus dans des essais cliniques en France, contre près de 22.000 en 2008, soit une augmentation de plus de 50%, selon un bilan de l'Institut national du cancer (INCa).
Dans AFP

Focus: Drug candidates derailed in case of mistaken identity



PARP inhibitor that wasn’t highlights widespread flaws in preclinical studies.


DRUG
STAGE
CANCER



Olaparib (AZD-2281)
Phase I
Solid tumors
Veliparib (ABT-888)
Phase I, II

Prostate, colorectal, leukemias, solid tumors
CEP-9722
Phase I, II
Solid tumors, lymphoma
Rucaparib (CO-338)
Phase I, II
BRCA1/2 mutant cancers, solid tumors
E7016
Phase I
Solid tumors
BMN-673
Phase I
Leukemias, solid tumors



Table: Despite flagging enthusiasm, several PARP-inhibitor drugs are still making their way through clinical trials.
Source: ClinicalTrials.gov, data accessed 29 March 2012.


Source: Drug candidates derailed in case of mistaken identity. Heidi Ledford. Nature 29 March 2012, volume 483, 519.


jeudi 29 mars 2012

Focus: Combining immunotherapy and targeted therapies in cancer treatment.

Abstract | During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.


Table: Effects of approved and experimental targeted agents on tumour cells and immune cells

Drug
Effect on tumour
Effect on the immune system



Trastuzumab

Blocks growth signalling through HER2
Primes anti-tumour CTLs, and boosts NK cell secretion of IFNγ and ADCC
Bevacizumab

Neutralizing antibody against VEGF: blocks angiogenesis
Increases DC maturation, shifts DC differentiation towards mature DCs instead of MDSCs and increases DC priming of T cells
Cetuximab

Neutralizing antibody against EGFR: blocks growth signals
• Immune activating: complement fixation, ADCC, increases MHC class I and MHC class II expression and augments DC priming of tumour-specific CTLs
• Immunosuppressive: activates M2 macrophages
Temsirolimus, rapamycin
and other mTOR inhibitors

Blocks mTOR pathway

• Immunostimulatory: enhances CD8+ T cell activation and IFNγ production, augments CD8+ T cell differentiation into memory T cells, impairs the homeostasis of TReg cells and decreases IDO expression
• Immunosuppressive: augments the responsiveness of TReg cells to antigen
Sunitinib

Blocks multiple tumour-associated tyrosine kinases, including VEGFR and PDGFR
Blocks STAT3, decreases numbers and effectiveness of MDSCs and TReg cells, and blocks VEGF signalling
Imatinib

Blocks multiple tumour-associated tyrosine kinases, including ABL and KIT
Blocks IDO, decreases numbers and effectiveness
of TReg cells, promotes DC cell–NK cell crosstalk, and increases the numbers of B1 B cells and the amount of ‘natural’ anti-tumour carbohydrate antibodies
Vemurafenib

Blocks BRAFV600E
Increases expression of gp100, MART1 and other antigens, and decreases tumour secretion of immunosuppressive cytokines
Bortezomib

Blocks 26S subunit of the proteasome
Sensitizes tumour cells to CTL-mediated lysis, sensitizes tumour cells to NK cell-mediated lysis by
downregulating MHC class I molecule expression and boosts antigen-specific T cell response to vaccination
JAK2
inhibitors

Block JAK2 signalling in tumour cells

Enhances DC maturation, bolsters DCmediated antigen presentation and T cell priming, decreases immunosuppressive STAT3 signalling, decreases
IAP expression and decreases tumour cell PDL1
expression
HSP90
inhibitors

Blocks HSP90, which increases unfolded protein-associated stress in tumour cells

• Immunostimulatory: increases expression of NKG2D ligands and boosts CTL recognition of tumour cells
• Immunosuppressive: decreases cytokine secretion from macrophages and T cells, decreases expression of co-stimulatory molecules on DCs and decreases antigen presentation by DCs
PI3K–AKT
inhibitors

Decreases PI3K–AKT signalling in tumour cells

Increases tumour susceptibility to perforin and granzyme-mediated lysis (mediated by CTLs and NK cells), decreases pro-survival signalling and decreases tumour-promoting inflammation
Lenalidomide

Not well understood
Pleiotropic: increases co-stimulatory molecules on tumour cells, modulates SOCS1 expression to increase cytokine secretion, decreases PDL1 expression on tumour cells, increases NK cell cytotoxicity and cytokine secretion, and increases NKG2D ligand expression
GSK3β
inhibitors

Blocks GSK3β-mediated signalling of tumour cell growth

Facilitates differentiation towards ‘stem-cell’ memory T cell population and augments TLR4 signalling
IAP inhibitors

Sensitizes tumour cells to apoptosis
Increases T cell, NK cell and NKT cell responses to stimulation



ADCC, antibody-dependent cellular cytotoxicity; CTL, cytotoxic T lymphocyte; DC, dendritic cell; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumour; GMCSF, granulocyte–macrophage colony-stimulating factor; GSK3β, glycogen synthase kinase 3β; HSP90, heat shock protein 90; IAP, inhibitor of apoptosis protein; IDO, indoleamine-pyrrole 2,3-dioxygenase; IFN, interferon; JAK2, janus kinase 2; MART1, melanoma antigen recognized by T cells 1; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NK, natural killer; NKG2D, natural killer group 2, member D; PD1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PDL1, PD1 ligand 1; STAT3, signal transducer and activator of transcription 3; SOCS1, suppressor of cytokine signalling 1; TLR4, Toll-like receptor 4; TReg cells, regulatory T cells; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.


Source: Combining immunotherapy and targeted therapies in cancer treatment. Matthew Vanneman and Glenn Dranoff. Nature Reviews Cancer. Volume 12 April 2012  237-251.
Free paper available at:


mardi 27 mars 2012

Focus: Antibody therapy of cancer



Abstract | The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody–drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.


Monoclonal antibodies currently FDA approved in oncology and their mechanisms of action

Naked antibodies: solid malignancies



Trastuzumab (Herceptin)
Inhibition of ERBB2 signalling and antibody-dependent cellular cytotoxicity (ADCC)
Bevacizumab (Avastin)
Inhibition of VEGF signalling
Cetuximab (Erbitux)
Inhibition of EGFR signalling and ADCC
Panitumumab (Vectibix)
Inhibition of EGFR signalling
Ipilimumab (Yervoy)
Inhibition of CTLA4 signalling


Naked antibodies: haematological malignancies



Rituximab (Mabthera)
ADCC, direct induction of apoptosis and complement-dependent cytotoxicity (CDC)
Alemtuzumab (Campath)
Direct induction of apoptosis and CDC
Ofatumumab (Arzerra)
ADCC and CDC


Conjugated antibodies: haematological malignancies



Gemtuzumab ozogamicin (Mylotarg)
Delivery of toxic payload, calicheamicin toxin
Brentuximab vedotin (Adcetris)
Delivery of toxic payload, auristatin toxin
90Y-labelled ibritumomab-tiuxetan (Zevalin)
Delivery of the radioisotope 90Y
131I-labelled tositumomab (Bexxar)
Delivery of the radioisotope 131I, ADCC and direct induction of apoptosis




Source: Antibody therapy of cancer. Andrew M. Scott (andrew.scott@ludwig.edu.au), Jedd D. Wolchok and Lloyd J. Old. Nature Reviews Cancer Volume 12 | Avril 2012 | 278-287.
Free paper available at :