Consulter le programme

7
e
Journée
Roger Monier
Anti-tumor
drug design
& mode of action
14 MARS 2016
13h30 à 18h00
Amphithéâtre de l’Espace Maurice Tubiana
à Gustave Roussy / 114, rue édouard-Vaillant 94805 Villejuif
www.gustaveroussy.fr
www.curie.fr
Co-Organisée par Gustave Roussy et l’Institut Curie
«Designing chemical probes
and drugs for the cancer genome»
William Georges KAELIN
Diego di BERNARDO
TIGEM – Naples, Italie
« Computational approaches to drug
discovery and drug repositioning:
the “drug network »
Marc POIROT
Dana-Farber Cancer Institute – Boston, MA
Centre de recherche en cancérologie de Toulouse
« New Cancer Treatment Strategies
Emerging From Studies of the VHL
and IDH Proteins »
« From tamoxifen to dendrogenin
A: a rational discovery of the tumor
suppressor metabolite and drug
candidate dendrogenin A »
Organisation : Pr Jean Feunteun
Inscription : gratuite mais obligatoire
Formulaire d’inscription
Contact : [email protected]
Tél. 01 42 11 51 58
Conception : Direction de la Communication - Gustave Roussy -janvier 2016 - Impression : Reprographie GR
Paul WORKMAN
Institute of Cancer Research – Londres, UK
7ème JOURNÉE ROGER MONIER
« Anti-tumor drug design and mode of action »
LUNDI 14 MARS 2015 à 13h30
Amphithéâtre de l’Espace Maurice Tubiana
A Gustave Roussy - Villejuif
Co-organisée par Gustave Roussy et l’Institut Curie
Paul WORKMAN Institute of Cancer Research – Londres, UK
“Designing chemical probes and drugs for the cancer genome”
Precision genomic medicine is now a reality in the clinic. There are numerous successful
examples of ‘drugging the cancer genome’. However, only 5% of the cancer genome is
drugged. Furthermore, a major emerging challenge for drug design and use is the
inexorable development of resistance as a result of adaptive biochemical and
transcriptional feedback loops and the selection for genetically more aggressive and
resistant clones – the survival of the nastiest. There is an urgent need for innovative drug
discovery to explore the 95% of the cancer genome that remains undrugged, and to
discover new drugs and combinations that overcome drug resistance.
Since 2005, our Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer,
London has discovered 20 new drug candidates and progressed 8 of these into clinical
trials, almost all with our hospital partner the Royal Marsden Hospital. And out drug
abiraterone, designed and synthesised at ICR and initially trialled with RMH, was
approved in 2011 and has now been used to treat hundreds of thousands of men with
advanced prostate cancer.
I will describe case histories from our work that exemplify the role of academic drug
discovery efforts – often operating productively in partnership with biotech and pharma
companies. I will in particular illustrate the challenges of target selection and validation in
the post-genomic era; describe the power of structure-based drug design; demonstrate
the importance of target engagement biomarkers; and explore the promise and perils of
chemical probes for the cancer genome.
William Georges KAELIN Dana-Farber Cancer Institute – Boston, MA
”New cancer treatment strategies emerging from studies of the VHL and IDH proteins”
Loss of the VHL tumor suppressor protein (pVHL) is the truncal event in most kidney
cancers. pVHL is part an ubiquitin ligase that targets the alpha subunits of the HIF
transcription factor for degradation. Binding of pVHL to HIFα requires that HIFα be prolyl
hydroxylated by the EglN 2-oxoglutarate (2-OG)-dependent dioxygenases, which are
oxygen sensors. A drug that specifically inhibits HIF2α is efficacious in preclinical pVHLdefective kidney cancer models and has entered the clinic. Our recent work with
lenalidomide suggests another strategy for targeting transcription factors such as HIF2α:
small molecule mediated target destabilization. We are also identifying enzymes that
become more essential once pVHL is lost (synthetic lethality).
Some cancers, including some acute leukemias and gliomas, are caused by IDH1 or IDH2
mutations.
These mutations cause the accumulation of mM amounts of R-2
hydroxyglutarate (R-2HG). R-2HG can interfere with (usually inhibit) the activities of
various 2-OG-dependent enzymes, including the JmjC histone demethylases, the TET DNA
hydroxylases, and the EglN prolyl hydroxylases. We showed that the effects of R-2HG in
leukemia are reversible. Consistent with this, drugs that inhibit R-2HG production are
active in leukemia patients. It is less clear whether the effects of R-2HG will be reversible
in glioma. Nonetheless, we have identified vulnerabilities created by high R-2HG levels
that can be exploited in this setting.
Diego di BERNARDO TIGEM – Naples, Italie
“Computational approaches to drug discovery and drug repositioning: the “drug network"
“Big data” are a key feature of current research approaches in biomedicine, with gene
expression profiles (GEPs) being one of the most commonly available data types. GEPs
provide a snapshot of cell behaviour in disease or in a response to a genetic or chemical
perturbation (i.e. drug). I will present our recent results in the development and
application of advanced computational approaches to analyse the transcriptional
responses to genetic perturbations and drug treatments in order to elucidate drug mode
of action and for drug repositioning. I will then show how these computation approaches
can be used also to identify draggable targets and pathway with an application to
hepatocarcinoma.
Marc POIROT Centre de recherche en cancérologie de Toulouse
“From tamoxifen to dendrogenin A: a rational discovery of the tumor suppressor metabolite
and drug candidate dendrogenin A”
Our group is studying the pharmacology of Tamoxifen (Tam) since several years. Tam is
a cytostatic drug used since more than 30 years for the treatment of breast cancers
expressing estrogen receptors (ER). Tam was conceived as a blocker at the ER level of
the tumor promoting activity of 17β-estradiol. However, extensive studies showed that
Tam displays a more complex pharmacology than expected. This led to the
identification of supplementary targets responsible of ER-independent pharmacological
effects of Tam. Our team identified one of these targets known as the microsomal AntiEstrogen Binding Site (AEBS). We showed that the AEBS catalyzes the hydration of
cholesterol-5,6-epoxide to give cholestane-triol, establishing that the AEBS carried out
the cholesterol-5,6-epoxide hydrolase (ChEH) activity. We found that the inhibition of
ChEH by Tam, led to 5,6-EC accumulation, cancer cell differentiation and death. The
supposed reactivity of 5,6-EC suggested us the possible existence of a metabolic
pathway centered on 5,6-EC transformation. To test this hypothesis, we chemically
synthesized a conjugation product of 5,6α-EC with histamine which gave dendrogenin A
(DDA). DDA was found to induce in vitro and in vivo cell death and differentiation,
which made conceptually possible the existence of DDA as an endogenous metabolite.
We established later that DDA was a metabolite constitutively produced by mammalian
healthy tissues. Interestingly, its level was found strongly decreased in tumors,
suggesting a deregulation in DDA metabolism in cancers. Complementation of this DDA
deficiency in cancer cells implanted in mice established its anti-cancer efficacy. We
found that DDA induced cell death and differentiation in vivo. DDA kills tumor cells by
lethal autophagy, a cell death resulting from its dual targeting of ChEH and of a nuclear
receptor. This original mechanism of action makes of DDA a promising drug candidate
for the treatment of several cancers including acute myeloid leukemia. We established
that DDA is the first steroidal alkaloid found to date in mammals. Its discovery reveals
the existence of a new metabolic pathway in mammals at the crossroads of cholesterol
and histamine metabolism that leads to the production of a metabolic tumor
suppressor.
Further reading: Dalenc F, Poirot M and Silvente-Poirot S: (2015) Dendrogenin A: a
Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating
Properties. Curr Med Chem, vol 22(30): 3533-3549,