Publishable executive summary|
Summary description of project objectives
Ovarian cancer is the fifth most common cause of death from cancer in women. The standard first-line treatment is a combination of paclitaxel and carboplatin (DDP) or carboplatin alone. In the case of progressive disease or drug resistance treatment with platinum, either alone or in combination, especially investigational compounds should be used. The mechanisms behind acquired resistance to cDDP and its derivatives are not clear yet, although it is evident that the process is multifactorial including, enhanced DNA repair. In the human ovarian carcinoma cell line A2780, a 3-fold-DDP-resistance was associated with cross-resistance to the thymidylate synthase (TS) inhibitor 5-fluorouracil and to methotrexate, a 2.5-fold increase in TS, and an increase in the intracellular pools of the TS cofactor 5, 10-methylentetrahydrofolate and of tetrahydrofolate. The ultimate goal of LIGHTS is to directly halt tumour progression and the development of drug resistance upon treatment with platinum derived drugs by inhibiting the protein regulatory function of monomeric TS through small molecule cellular perturbation. The scientific and technological objectives will be to design small-ligand libraries to bind to the TS monomer (dimer interface) and thereby disrupt TS. The strategy will include, protein SH and X -labelling to identify low-affinity ligands, peptide mimic design & synthesis, and filtering for ADME properties. The multidisciplinary approach will be carried out by a consortium integrating Molecular modelling, Chemistry, Chemoinformatics, Structural Biology and Pharmacology, and will apply the knowledge being created by genomics and other fields of basic research to the problem of discovery of anticancer. agents. The consortium consists of six groups from five different countries, including three SMEs.
The intermediate objectives are based on employing novel medicinal chemistry strategies to identify potential drug candidates with new mechanisms of action. LIGHTS specifically addresses early phase medicinal chemistry issues that can critically influence the time schedule for obtaining an investigational drug candidate. Nevertheless it is also expected as a products of our project that potential drug candidate(s) with high quality in vitro activity profile can be obtained ready for in vivo pharmacology profiling. Intellectual property issues, searching for out-licensing and/or co-operative opportunities for the inventive aspects of the project.
These goals will be translated into the below described objectives.
1. Derivation of small-ligand libraries with ligands design to bind to the Thymidylate synthase monomer /monomer interface affecting dimer formation and TS- TSmRNA interactions.
2. Validation of the integrated, multidisciplinary drug design strategy necessary to achieve objective 1, which poses a highly challenging design problem. The strategy including systems pathway studies, protein cysteine SH-labelling to identify low-affinity ligands, peptide mimetic design, and filtering for ADME properties.
3. Identification of small-ligands identified in a chemical-biology approach as effective perturbing agents to investigate the mechanism of resistance against a panel of cis-platinum resistant ovarian carcinoma cell lines.
4. Provide potential drug candidate(s) with new mechanism of action for further development as safer therapeutic agent(s) for the treatment of ovarian carcinoma.
To achieve these objectives 7 workpackages (WP) have been organized, oriented to specific aims and involve 6 partners in a collaborative team which has to achive the planned work.
WP1. management activity.
WP2: Protein and peptide design and mutagenesis
The overall goals of this WP are: 1. The detection of small ligands that may bind too weakly to be identified by traditional means to the surface of humanTS that participates in the formation of the active dimeric form of the enzyme by using protein labelling tecniques. 2. The optimization of the binding of peptides that have been identified to bind to monomeric TS 3. Understand the regulatory mechanism relating the TS monomer-dimer balance and TS mRNA binding through protein mutagenesis and small-molecule perturbationThese objectives will be achieved by a combination of computational and experimental approaches.
WP3: Chemioinfo, ADME-tox properties evaluation and validation The overall goals of this WP are: Chemioinfo, ADME-tox properties evaluation and validation
1. Calculate molecular properties of compound libraries including ADME –tox in silico studies
2. Measure molecular properties (pK, logP, solubility, membrane permeability, Ligand efficiency, promiscuous inhibition properties, albumin binding).
3. Data analysis, scoring the experimental versus in silico data, comparative scoring, software implementation through appropriate algorithm.
WP4: Library design and compound selection (virtual screening, scaffold selection, library design).
The overall goals of this WP are: Library design and compound selection (virtual screening, scaffold selection, library design) The aim is to design compounds to interfere with TS dimerization by binding to the TS monomer-monomer interface. The design strategy will be two-pronged:
1. Design of peptides and peptidomimetics based on knowledge that peptides from the sequence of TS can affect dimerization and bind to the TS monomer. These peptides will be further optimized for binding to the TS monomer and libraries of peptidomimetics will be designed.
2. Fragment based de novo ligand design to identify low-affinity ligand/fragments by cysteine tethering and to optimize these to obtain high-affinity ligands. To aid the ligand design, modelling and simulation will also be performed, for the interaction of TS with its mRNA and the effect of small ligands on this interaction. All ligand design, will be accompanied by in silico ADME screening (see WP4). All design studies will target the human TS, and involve comparison with the homologous TSs from microorganisms.
WP5: Scaffold chemistry validation. In parallel/combichem synthesis and new synthetic tools.
The overall goals of this WP are: Scaffold chemistry validation. In parallel/combichem synthesis and new synthetic tools.
1. Scaffold synthesis evaluation for scaffold validation for one to two derivatization points.
2. Library synthesis and synthetic cycle refinement.
3. Peptide/peptide mimetic library synthesis.
4. Development of synthetic strategies for selected compounds and preparation of the same.
5. Lead optimisation and synthesis of drug candidates.
WP6: SH-labelling and ligand-protein interaction studies
The overall goals of this WP are: SH-labelling and ligand-protein interaction studies
1. Identification of the highest affinity hits and low affinity ligands in solution. Protein (monomeric form/dimeric form-wt and mutant) fishing out of the best affinity inhibitor.
2. Structural characterization of protein-ligand complexes with compounds. SH-labelling from WP6 for structure-based drug design. Covalent and non covalent complexes. 3. Characterization of the energetics of the interaction small molecule hit-protein, lead-protein (TS monomeric/dimeric form-wild type and mutant).
WP7: Cellular/molecular pharmacology.
In vivo evaluation of the monomer-monomer interface inhibitors against enzymes biolibrary and wt and resistant ovarian carcinoma cell line.Objectives
1. Enzyme bio-library preparation, enzyme purification
2. Compounds library rapid screening assay
3. Examination of cytotoxic effects of compounds designed to limit the intracellular levels of TS protein in cDDP-sensitive and cDDP-resistant cell lines and in a non-carcinoma cell line (VERO cells).
4. Evaluation of cell growth effects of TS monomer-monomer interface inhibitors in combination with cisplatin.
5. Characterization of the intracellular molecular mechanisms involved in the action of inhibitors.
6. Evaluation of transcription levels of the folate dependent enzymes in ovarian human cell lines (ATCC).
7. Identification of molecules competing with TS for their binding to mRNA.
Work performed and end results
We aim at restore the sensitivity to Platinum-based drugs through a direct inhibition of TS without affecting TS-mRNA interaction that leads to TS protein synthesis modulation/alteration. In order to tune this process we need to study the effect of our compounds on three biological processes:
a. capability to directly inhibit TS activity at the enzyme level;
b. capability to directly inhibit TS expression or do not induce TS ( and other folate dependent biomolecules as DHFR) at the cellular level (TS activity and level, DHFR activity and level);
c. capability to downregulate or do not overexpress TS- and DHFR- mRNA levels;
d. capability to restore the sensitivity to Pt-based drugs on Pt drugs induced resistance cancer cell lines and to show collateral sensitivity (sensitivity to new TS inhibitors and synergy with platinum-based drugs).
These biological parameters/markers should not be considered independently but in a pathway related study. Only compounds that can selectively demonstrate this profile can be considered positively for our pourposes. If one compound shows all the four biological markers, then it can affect/modulate the TS related pathway. This may impact the toxicity profile of the compound at the cellular level, and this model can be considered predictive for a lead candidate that shows limited off-target effects. Moreover, if the compounds is active against the resistance cells and not on the sensitive cells, it is also possible that the mechanism of action in the resistant cell is specific and some biological differences between the sensitive and resistant cancer cell lines may be exploited. It may also happen that one compound is active against normal cancer cells and not against resistant cells. Due to the fact that the overall aim of the project is related to halt ovarian cancer progression, we have not discarded any compound with more classical in vitro profile but that show some efficacy against ovarian cancer cell lines. Due to the ambitious aims of the project, we may not have enough effort available within LIGHTS to study the cellular mechanism of action of the compounds we have discovered. This will be part of future projects. We mechanistically demonstrated the genuinely new mechanism of TS inhibition of some peptides we have discovered within the LIGHTS project. This opens new strategies to overcome ovarian cancer inhibition. On the other hands, we have discovered new leads and candidates that can affect the TS activity, reduce/block ovarian cancer cell growth both in sensitive and cis-platin resistant cell models. At least one of these lead can enter the pharamcokinetic and animal pre-clinical studies.
Our target protein was Thyimidylate synthase dimeric interface. During the 42 months of the project we were able to:
1. characterize our target protein: dimer-monomer equilibrium, monomeric protein interface, structure-function properties relationship of TS interface surface. We have designed and obtained a number of interface mutants in which the residues identified hot spots on the protein dimeric interface. We also used this information to set up a highthrouput test to detect monomer/monomer protein interface inhibitors.
2. improve our knowledge of the TS related pathway in terms of structure-function both at the protein level and cellular level. We could measure the protein levels in the cells and the activity of the compounds at the protein level upon cell treatment with some of the compounds that we have identified. We were able to detect the TSmRNA levels and Dhydrofolate reductase levels and understand that these biological markers are related and the compounds are effective cytotoxic agents and modulators of the folate cycle.
3. validate our multidisciplinary approach to the discovery of new hits/leads that takes advantage of theoretical and experimental approaches combined in a feed-back informations exchange. We have performed this work during the first period (1-18th months) with the initial compounds we had and we continued also during these second period. We have studied their mechanism of action against the hTS protein. This second aspect requests the setting up of an efficient analytical assay able to characterize the interference with the dimer/monomer equilibrium, that is currently ongoing. (validation of the dissociative inhibition mechanism at the enzyme level). (FRET assay).
4. we set up a product pipeline at dfferent level of development:
4. we have filed 5 patents on our findings.
Intentions for use and impact
1. Innovation-related aspects
The project has innovative aspects, which lie in:
1. the identification of candidate drugs acting against platinum-drugs resistant cancer cell lines, showing novel mechanism of action;
2 identification of candidate drugs that restore the sensitivity to Pt-based drugs on Pt-drugs induced resistance ovarian cancer cell lines;
3. improvement of the quality of the in silico and in vitro studies to obtain better profiled leads, showing lower toxicity and reduced side effects;
4. introducing early phase ADMETox studies and validating our methods and strategies at the cellular level to produce low toxicity drugs candidates at the cellular level, ready to pass to the pre-clinical studies (pre-clinical studies are out of the scope of this project).
5. improving the know how on the TS related metabolic pathway as drug targets; validation of the strategies and methods employed to achive this knowledge.
2. Ovarian Cancer: social impact.
In western countries, ovarian cancer is the fourth most common cause of cancer-related death among women. It is estimated that 22,200 new cases will be diagnosed and approximately 16,210 women will die of this disease in the United States during 2005, while around 6,900 women are diagnosed with ovarian cancer each year in the UK, that is one of the highest incidence in Europe (Jemal A, et al., Cancer statistics 2005. CA J Clin 2005; 55:10-30). Ovarian cancer is more frequently diagnosed among elderly women. The age-specific incidence of ovarian cancer peaks in the eighth decade. Seventy percent of women with ovarian cancer are diagnosed with advanced stage disease, and approximately 60% of them will die within 5 years. Among all gynecologic malignancies, ovarian cancer is the deadliest, with an overall 5-year survival estimate of 37% (Ries LAG et al., editors. SEER cancer statistics review, 1975-2001, national cancer Institute, Bethesda, MD). Significant prognostic factors for ovarian cancer include tumor stage, volume of residual disease, and histologic grade. When diagnosed in Stage I, however, the cure rate can approach 90% with currently cytoreductive surgery and combination chemotherapy (Hoskins WJ. Prospective on ovarian cancer: why prevent? J Cell Biochem, Suppl 1995;23:189-99). However, at present, less than 25% of ovarian cancer cases in the U.S. are diagnosed in Stage I. As with most cancers, the risk of developing ovarian cancer increases with age. Apart from getting older, the risk of ovarian cancer may be increased by family history or having breast cancer, being infertile or having fertility treatment, the age when ovulatory periods started and stopped, by using talcum powder, etc. Instead, risk of ovarian cancer may be lowered by taking the contraceptive pill, having had children or not, breast feeding, having hysterectomy or tubal ligation, diet, aspirin. Ovarian cancer treatment typically consists of aggressive surgical debulking combined with adjuvant chemotherapy, that is a combination of platinum drugs and taxane. Patients with advanced disease undergoing optimal debulking surgery to less than a centimeter residual have a median survival of just over 4 years after adjuvant chemotherapy (Ozols RF et al., J Clin Oncol 2003;21(17):3194-200). Unfortunately, almost all such a women ultimately develop recurrent ovarian cancer and die of progressive disease primarily as a result or the development of chemotherapy resistant clones. Thus, novel non-cross resistant chemotherapeutic drugs are urgently needed in this disease. LIGHTS project can support the discovery of new potential anticancer drugs against cross resistant Pt-based drugs with non-cross resistant profiles.
The focus of LIGHTS is on inhibiting the protein regulatory function of TS through small molecules cellular perturbation. This requires the design of novel small molecules that can interact with the dimer interface of TS, which is an obligate dimer, thus interfering with the binding of monomeric TS to its mRNA. The interactions of these molecules and mRNA with TS will be characterized using structural, biophysical and computational biology methods, as well as in studies of the effects of compounds on in vitro and in vivo tumour cell lines. An interdisciplinary team is essential for achieving the goals of the project.
Methodology and techniques
The LIGHTS Consortium has provided the necessary and complementary expertise to carry out the above-described activities in an integrated manner. Our team includes the following expertises: Analysis of biochemical pathway networks, modeling to guide ligand and protein design and experiments; iterative refinement of models and testing against experiment, Protein, peptide design and mutagenesis: protein synthesis, purification and characterization, including Mass spectrometry experiments. Library design and compound selection through chemioinformatic & experimental tools, iterative refinement ADMEtox in silico evaluations. Validation of “in silico” molecular properties prediction and implementation of scoring for predictive compound bioavailability. In parallel/combinatorial synthesis and new synthetic tools for synthetic route implementations. Structural biology X-ray Crystallography. In vitro evaluation of the monomer-monomer interface inhibitors against enzymes bio-library and wild type and resistant ovarian carcinoma cell line. The results of this project do not only provide novel insights into the inhibition of this important enzyme but also illuminate the basis for drug networking phenomena by providing experimentally-grounded mathematical models of the inhibition mechanism of the protein through our novel inhibitors. This will give a feedback that will guide tto the next step: understanding the network among the levels of TS protein, TSmRNA and small molecules. We expect that our results will also provide conceptual insights of broad relevance, on chemical biology design strategies for such proteins, as well as the discovery of effective new leads with acceptable cellular pharmacokinetic properties. This involves practical demonstrations of new techniques such as screening for protein ligands.
The project is oriented to directly halt the progression of ovarian cancer and interfere with the development of drug resistance upon treatment with platinum-derived drugs by inhibiting the protein regulatory function of monomeric TS. The intermediate objectives are based on employing novel medicinal chemistry strategies to identify potential drug candidates with new mechanisms of action. LIGHTS specifically addresses early phase medicinal chemistry issues that can critically influence the time schedule for obtaining an investigational drug candidate. Nevertheless it is also expected as a products of our project that potential drug candidate(s) with high quality in vitro activity profile can be obtained ready for in vivo pharmacology profiling. Intellectual property issues, searching for out-licensing and/or co-operative opportunities for the inventive aspects of the project.
Overview of general project objectives and current relation to the state-of-the-art.
The above described goals will be translated into the below described objectives.
1 Derivation of small-ligand libraries with ligands design to bind to the Thymidylate synthase monomer /monomer interface affecting dimer formation and TS-TSmRNA interactions.
The first approach was to characterize aour main target: the TS dimer interface. To this objective WP2, WP3, WP4 and WP5 contribute in a concerted action. In particular WP2 performs protein and peptide design and mutagenesis studies (over 20-25 mutants single and double mutants have been provided);
WP3 performs library design and WP4, virtual screening and molecular modelling in general, scaffold selection for library design; WP5 perform scaffold chemistry validation and the different synthetic methodologies. We will deliver a few compound classes (pyrazole-quinoxaline, Lt004 compounds, berberine derivatives, C4 and E7) that will be able to bind to the monomer/monomer interface of TS, affecting the dimer formation: small molecules and peptides/peptides mimetic. The work is performed combining and integrating theoretical and experimental approaches. Small molecules libraries are designed following WP3 indications. These results are obtained following experimental feedback on ligand library for SH-labelling experiments. WP4 is fully involved in the design work of both the compound classes and in details the following objectives are considered: scaffold synthesis evaluation for scaffold validation for one to two derivatization points; library synthesis and synthetic cycle refinement; peptide/peptide mimetic library synthesis; development of synthetic strategies for selected compounds and preparation of the same; lead optimisation and synthesis of drug candidates. This integrated work provides peptides, first libraries and follow up implementation of small molecules (SH and SH-labelled compounds) and peptide libraries in an iterative fashion on biological evaluation feed-back basis.. All this section is implemented during all the project duration, on a feed-back evaluation basis to give as milestone results compounds library enzyme profile, peptide mimic enzyme profile, identification of drugs with cell growth inhibitory activity against human ovarian cancer, synergistic, or at least additive effects, of drug combinations in vitro, description of the molecular mechanisms of the identified inhibitors, which overcome resistance.
Recent discoveries in the field.
In the latest two years (3/2008-3/2010), no significative advance in this area has been produced in relation to the identification of molecules that can interfere with TS dimerization. Two papers, instead, have been published on two TS mutants related to stable inactive form of the TS protein by Lebioda (1: Lovelace LL, Johnson SR, Gibson LM, Bell BJ, Berger SH, Lebioda L. Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation. Protein Sci. 2009. 2: Huang X, Gibson LM, Bell BJ, Lovelace LL, Peña MM, Berger FG, Berger SH, Lebioda L. Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability.Biochemistry. 2010 Mar 23;49(11):2475-82).
2 Validation of the integrated, multidisciplinary drug design strategy necessary to achieve objective 1, which poses a highly challenging design problem.
The strategy include protein cysteine SH-labelling to identify low-affinity ligands, peptide mimetic design, and filtering for ADME properties.
Validation of the successful integration of the multidisciplinary approach to drug design with the goal to derive small ligands libraries. The validation of the approach is performed combining theoretical and experimental studies. In particular molecular modelling and chemioinformatic methodologies and techniques are applied. The chemioinformatic approach is validated anticipately and in the due course with molecular properties evaluation experiments. These experimental results is fully integrated in the chemioinformatic tools and contribute to the software implementation. WP3 and WP4 contribute specifically to this objective and milestone results is related to strategy for the design of peptidomimetics and decision on improvements to library and design strategy to obtain high-affinity ligands following experimental feedback on ligand library for SH-labelling experiments, implemented score for compound selection and implemented software for compound selection. We have been able to set up a new FRET based assay aimed at identify dissociative inhibitors that affect the dimer-monomer equilibrium.
Recent discoveries in the field.
This approach was already well described at the beginning of the project as a standard approach. It was not applied to TS interface specifically. Alternative strategies have been proposed to identify low affinity ligands through X-protein labelling techniques. Among these (Dynamic Combinatorial Mass Spectrometry Leads to Metallo-lactamase Inhibitors Benoît M. R). Regarding the ADMETox propetise prediction, our partner Molecular Discovery, is world leader in the field and this record is maintained and even improved in the participation to the LIGHTS project.
3. Identification of small-ligands identified in a chemical-biology approach as effective perturbing agents to investigate the mechanism of resistance against a panel of cis-platinum resistant ovarian carcinoma cell lines.
This objective is related to the identification of the “effective perturbing agents” of the mentioned resistance mechanism. This work is performed in WP6 and WP7. It required two sequential approaches: ligand target interaction studies, sub-cellular studies and cell-based studies. Ligand-target interaction studies specifically aimed to the identification of the highest affinity hits and low affinity ligands in solution; protein (monomeric form/dimeric form-wt and mutant) fishing out of the best affinity inhibitor; structural characterization of protein-ligand complexes with compounds. SH-labelling from WP5 for structure-based drug design. Characterization of the energetics of the interaction small molecule hit-protein, lead-protein (TS monomeric/dimeric form-wild type and mutant). Milestone results for this section are related to low affinity ligand through Mass Spectrometry techniques available, X-ray crystallographic complex of SH-labelled compounds, non SH-labelled compounds and library, complex of peptide mimic compounds, energetics and biophysics of the interaction of the best hit/ lead with the monomeric protein. We have obtained at least 10 X-ray crystal structure of our new inhibitors with the hTS proteins and 15 more with bacterial or yeast TS as model enzyme proteins.
The cell-based approach in this objective has required Enzyme bio-library preparation, enzyme purification; compounds library rapid screening assay, examination of cytotoxic effects of compounds designed to limit the intracellular levels of TS protein in cDDP-sensitive and cDDP-resistant cell lines and in a non-carcinoma cell line (VERO cells), evaluation of cell growth effects of TS monomer-monomer interface inhibitors in combination with cisplatin.
Milestone results are related to compounds library enzyme profile and peptide mimic enzyme profile. Peptides and peptides library have been obtained that work at the enzyme level and at the cellular level.
Recent discoveries in the field.
There were no specific publication in the area.
4.Provide potential drug candidate(s) with new mechanism of action for further development as safer therapeutic agent(s) for the treatment of ovarian carcinoma.
The specific objective within the WP7 are related to the characterization of the intracellular molecular mechanisms involved in the action of inhibitors. Evaluation of transcription levels of the folate dependent enzymes in ovarian human cell lines (ATCC). Identification of molecules competing with TS for their binding to mRNA. This objective is at the core of the whole project and represents the conclusive part of the project. It is the most complex objective to achieve passing from model non-cellular system to complicate cellular system. At the cellular level unexpected complications arises related to membrane translation inside the cell of the different compounds, multitargeting of the compounds inside the cell. These effects can mask the final achievement and may need re-iteration of the design process at a refinement level. The WP involved (mainly WP7) in this work have validate the experimental process from the beginning and step by step along the whole process. All the WP, in particular WP4 and WP5 have been continuously connected to WP7 results to perform new design/synthesis round. Milestone results are related to the identification of leads candidates with cell growth inhibitory activity against human ovarian cancer, synergistic, or at least additive effects, of drug combinations in vitro, description of the molecular mechanisms of the identified inhibitors, which overcome resistance.
Recent discoveries in the field.
In the recent years no specific compounds have been promoted to the final stage of the drug discovery with this profile. New insights on the difference between sensitive and resistant cell lines have been exploited through proteomic approach, but no inhibitors/drugs have been identified, yet.
Summary of the final results
We have reached almost all the expected objectives.
One crucial point was the development of computational technicques for the improvement of early phase discovered compounds with a better pharmacological profile (efficacy and toxicity).
We have effectively developed these new methods during the project, however for some of new methods that have reached their validation at the end of the project, this was not practically possible. Instead we have successfully combined the two approaches - experimental and computational - to reach our cellular activity against ovarian cancer.
We have characterized the dimeric protein interface of hTS protein.
We have set up a novel assay, validated to identify compounds that can interfere with the protein dimeric assembly.
We have discovered new compounds, of peptidic or non peptidic nature that can inhibit the protein directly with a novel mechanism and effectively block the growth of sensitive and cis-platin resitant ovarian cancer cells in cell model system. At the end of the project we had at least 8 ovarian cancer cells models, sensitive and resistant. At least one class of the compounds we have discovered, is ready to enter the pharmacokinetic study and animal pre-clinical study.
All our findings have resulted in published and on going publications and 5 patents.
Our results opens new avenues to the inhibition strategies of the folate pathway, provides evidence that resistance developed by TS targeting drugs may be buffered and reversed by candidates designed to interfere with a the protein dimeric assembly and not with the direct active site inhibition of the protein.
However, we have also shown that non-folate analogs, differently from the classical TS inhibitors nowadays in therapy, can downregulate the TS pathway and block ovarian cancer cell growth.
We have reasonably enlarged the pipeline of candidates that can be specifically directed to ovarian cancer, in this project. The level of tumor-specificity has to be assessed and is an important issue. Most important is that it maybe possible to test our compounds also on other tumor types that specifically express high TS levels and TS related biomolecules (pathways) that represents important biomarkers for the tumor type growth (predictive biomarker).
SME have been highly collaborative and achieved IP results by the end of the project, thus improving their own potential.
Educational purposes have also fully reached in that the 70% of the participants were young researchers at the early stage of their careear.
LIGands to interfere with Human TS - LIGHTS is a STREP project within the 6FP.
Lights is focused on ovarian cancer and carried out by a consortium of six partners:|
University of Modena and Reggio Emilia (I) - University di Paris Sud (FR) - European Media Laboratories (D) Molecular Discovery (UK) - Naxospharma (I) - University of California San Francisco (UCSF)
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