Liste des participants
Jiri Bartek, Joan Brugge, Anne Dejean , Olivier Delattre, Jean Feunteun, Peter M. Howley (organisateur), Erich Huang, Adi Kimchi, Peter W. Laird, David M Livingston, James L. Manley, Moshe Oren, Pier Giuseppe Pelicci, Carol Prives, Claude Sardet, Mike Stratton, Maarten Van Lohuizen, Karen Vousden, Moshe Yaniv (organisateur)
Cancer: from fundamental research to prevention and therapy
by Peter Howley and Moshe Yaniv
20-25 juillet 2009
An intimate meeting was held at the Fondation des Treilles from July 20-25, 2009 focused on recent advances in cancer research with a focus on translational studies that have potential impact on new prevention strategies and therapy. The meeting was organized by Moshe Yaniv (Pasteur Institute), Peter Howley (Harvard Medical School) and Daniel Haber (Massachusetts General Hospital). Progress in basic cancer research and our understanding of the genetic and epigenetic changes that drive cancer progression has been fueled by major technical and conceptual advances in the field that highlight the potential for individualized cancer therapy strategies based on the genetic and epigenetic abnormalities that result in the specific cancers.
The meeting began with a presentation by Michael Stratton (The Sanger Centre, Cambridge, England) who reminded us that cancer is an evolutionary genetic process involving intrinsic mutations that are inherited, acquired mutations due to environmental and life style exposures, mutations that are generated due to the mutator phenotype of the precancerous lesions themselves and mutations that are the result of chemotherapy. He discussed the structural classes of somatic mutations in the cancer genome and presented his ongoing analysis of his cancer genome sequencing projects. He then discussed the mechanistic processes that underlie the generation of somatic mutations, genomic rearrangements, and genome copy number alterations. The sequencing efforts at the Sanger Centre in Cambridge have provided a comprehensive catalog of the mutations that can be seen in the cancer genomes. The next talk was by Erich Houang (Duke) who works with Joe Nevins and discussed their genomic strategies to dissect the complexity of cancer using rigorously controlled in vitro experiments with ectopic expression of known oncogenic activities to generate quantitative models of oncogenic pathway activation. They use Bayesian Factor Regression Models (BFRM) to create “modular” pathway models that break an overarching gene expression-based pathway model into subcomponents. Such a pathway model comprises a collection of component factors, or sub signatures. This provides flexibility in applying such models to different disease or therapeutic contexts in which some components of a particular pathway may be more or less important. When compared to linear pathway models, this non-linear approach is more accurate in modeling complex phenotypes such as response to pathway-specific inhibitors. They have employed this approach in using EGFR-based sub signatures to predict the response of Non-Small Cell Lung Cancer cell lines to Gefitinib, an EGFR-targeted tyrosine kinase inhibitor (TKI). The sub signature-based pathway models highlight intersections with other oncogenic activities, providing a strategy for objectively identifying combination therapies tailored to the characteristics of a particular tumor. They have employed this same strategy using SRC-based sub signatures to model response to Dasatinib, an SRC-targeted TKI and validate this approach in a clinical dataset of patients with AML treated primarily with Tipifarnib, a Ras-directed FTI.
The meeting continued with a focus on the cancer susceptibility gene, BRCA1, which is an established participant in breast and ovarian cancer suppression and in the error free repair of double strand DNA breaks (DSB). Indeed, abundant genetic evidence argues that this DNA damage defect in patients who have lost BRCA1 is key to their cancer susceptibility. However, little is known of whether or not BRCA1 contributes to other forms of DNA repair. David Livingston (Dana Farber Cancer Institute, Boston) presented data that argues that BRCA1 is indeed involved in other forms of DNA repair. Specifically he has found that BRCA1 operates in the response to UV damage, in the repair of the ss DNA gaps that emerge following either the elimination of pyrimidine photoproducts or that arise from stalling of replication forks at UV- induced DNA lesions. This newly detected function places BRCA1 at the center of cellular processes aimed at eliminating the abundant mutagenic DNA lesions that arise daily in human cells following exposure to naturally occurring and environmental mutagens. Certain carcinogenic estrogen metabolites would fall into the category of naturally occurring mutagens. His laboratory is now exploring whether BRCA1 contributes to the gap filling associated with the repair of estrogen metabolite-driven DNA damage and, if so, whether this function constitutes part of the breast and ovarian cancer specificity of BRCA1 tumor suppression function.
The afternoon session discussed the sex chromosomes in cancer and SUMO posttranslational modifications. Jean Feunteun (Institut Gustave-Roussy) discussed sex chromosomes and cancers. In mammals, the X and Y-chromosomes are unique within the chromosome set. In contrast to autosomes — for which two active copies are present — most of sex chromosomes linked genes display unisomy: XY male cells have genetic unisomy for X or Y linked genes and XX female cells have functional unisomy for most of the X linked genes because of the X inactivation process. This unisomy leads to specific genetic characteristics with regard to cancer genes located on X or Y-chromosomes. Oncogene activation behaves as a recessive trait when occurring on inactive X and tumor suppressor gene inactivation behaves as a dominant trait when occurring on active X. This genetic specificity was discussed in the context of melanoma progression. A CGH study revealed a specific pattern of X and Y chromosome losses associated with tumor progression. Among the females, losses in the X chromosome were significantly associated with distant metastasis free survival (DMFS). Feunteun observed that the affected X chromosome was always the inactive X. As the Y chromosome contains most of the genes located in the pseudo-autosomal region and escaping inactivation of the X chromosome escaping these genes, he investigated if there were also losses in the Y chromosome in males and if they were associated with DMFS. Among the males, losses in Y chromosome were significantly associated with DMFS. These observations define a locus target for deletion that fulfills three criteria: (I) located on the X chromosome in females, (ii) escaping inactivation of the Xi chromosome (iii) located on the Y chromosome in males. The best candidate genes are located in the pseudoautosomal PAR1 region on Xp22 in females and Yp11 in males. Anne Dejean (Pasteur Institute) then discussed the enzymology and molecular biology underlying sumoylation of proteins and the relevance to cancer and cellular senescence.
The PML-RAR alpha translocation is the causative event of promyelocytic leukemia. The tumor cells are blocked in their differentiation program and can be pushed to differentiate by treatment with high concentrations of retinoic acid or arsenic. In the later case she showed that the fusion protein undergoes poly-sumoylation followed by rapid degradation. PML has to undergo mono-sumoylation to assemble in nuclear bodies. Many proteins that are recruited to these nuclear PML bodies are also sumoylated and over 200 different substrates for SUMO have been identified. She has developed a mouse knock out of the E2 sumo conjugating protein ubc9, the homozygous knock out of which is very early embryonic lethal. Sumoylation is essential for nuclear envelope formation and normal division of early embryonic cells. Studying mice and immortalized embryonic fibroblasts that are hypomorph for ubc9, she could show that strong reduction in the sumoylation activity strongly reduced cell transformation by ras and inhibited intestinal tumor formation in an APC mouse model. Her studies suggest that inhibitors of sumoylation could become targets for anti-tumor therapies.
The meeting continued on Wednesday, July 22, with a session focused on tumor suppressor genes and cell death pathways. Adi Kimchi (Weizmann Institute of Science, Israel) discussed her work on the programmed cell death network that comprises three distinct functional modules, apoptosis, autophagy and programmed necrosis. Her work combines the focused analysis of genes already identified in this pathway (such as DAPk) and a systems level approach to assess the extent to which the inter-modular connectivity affects cell death performance. She discussed her recent work on the DAPk/Beclin-1 connection. Beclin-1, an essential autophagic protein was recently identified as a BH3-only protein that binds Bcl-2 anti-apoptotic family members. The dissociation of Beclin-1 from its Bcl-2 inhibitors is essential for its autophagic activity, and is tightly controlled by DAPk that regulates this process. The activated form of DAPk triggers autophagy in a Beclin-1 dependent manner through phosphorylation of Beclin-1. Her systems analysis is based on a platform that depends on RNAi-mediated perturbations targeting combinations of apoptotic and autophagic genes. The knock down of Caspase3 revealed a backup compensatory switch towards autophagic cell death requiring Atg5 or Beclin-1. Computational analysis of the protein-protein interactome suggests a biochemical pathway connection between Atg5 and Caspase3.
There were then a series of talks on the p53 tumor suppressor gene. Carole Prives (Columbia, New York) discussed the regulation of p53 and Mdm2. She identified several ribosomal proteins in a yeast two-hybrid screen using Mdm2, one of the E3 ligases responsible of p53 ubiquitylation. She focused on the small ribosomal subunit protein S7. She has found that the MDM2 homologue MDMX facilitates and may be required for the inhibition of MDM2 E3 ligase activity by S7. siRNA ablation of S7 or L11 inhibits MDM2 and p53 accumulation induced by multiple forms of DNA damage in some cell types indicating that ribosomal/nucleolar stress is likely a key integrating event in DNA damage signaling to p53. S7 is itself an excellent substrate for the E3 ligase activity of MDM2 both in vitro and in vivo. Further, an S7-ubiquitin fusion protein selectively inhibits Mdm2 degradation of p53 and is unaffected by MDMX, suggesting that MDM2 ubiquitylation of S7 is involved in sustaining the p53 response. She also discussed her work on the interaction of p53 with DNA in the context of chromatin when DNA is wrapped around a histone octamer. Optimal binding by unmodified p53 was seen with its binding site situated such that it was not in contact with the core histone octamer. Correspondingly, specific and efficient p53-dependent acetylation of mononucleosomal core histones by the p300 acetyl transferase required p53 association with its cognate site within the free DNA portion of the mononucleosome. Remarkably, however, when p53 itself was acetylated by p300, it acquired the ability to bind to its site even when in contact with the histone octamer. Further, mutational analysis of lysine residues indicated that both core and extreme C-terminal lysines contribute to this increased affinity for nucleosomal DNA. Her data indicate that in the context of chromatin, unmodified p53 is likely to bind to its recognition sites when they are present within naked DNA in the linker region between nucleosomes, although acetylation of p53 may increase the scope and availability of sites within nucleosomal DNA. Relevantly, mutation of the C-terminal lysines to arginine produces a version of p53 that, when expressed at physiological levels is partially impaired in activating some of its target genes. She has initiated studies to determine the density of nucleosomes at key p53 binding sites in untreated and DNA damaged cells. Her data reveal rather dramatic differences in nucleosome density and remodeling at these sites. It is therefore possible that p53 may be able to bind to nucleosomes in vivo in an acetylation dependent manner. Moshe Oren (Weizmann Institute of Science, Israel) followed with a discussion of cell autonomous tumor suppressor functions of p53 as well as non-cell autonomous activities of p53. In view of the importance of the cross-talk between tumor cells and their microenvironment, he hypothesized that p53 may also suppress tumorigenesis by affecting the behavior of the tumor microenvironment. In agreement with this conjecture, he has found that when co-injected into immunocompromised mice together with human PC3 tumor cells, fibroblasts derived from p53 knockout mice preferentially augment tumor growth in vivo. This was largely mediated by the ability of p53 to repress the production of the chemokine SDF-1 in fibroblasts. Indeed, knockdown of SDF-1 abrogated most of the tumor-stimulatory effect of p53 knockout fibroblasts. He further showed that human lung cancer-derived cells, but not non-transformed human lung epithelial cells, could repress p53 activation in adjacent fibroblasts. Furthermore, cancer-associated fibroblasts were preferentially sensitive to inhibition of their p53 by tumor cells. Together, these findings suggest that p53 is acting as a tumor suppressor also within stromal cells, and that “successful” tumor cells acquire an ability to quench this function of p53, thereby gaining a selective growth advantage. Reactivation of p53 function in the tumor microenvironment may therefore be considered as a goal for future anti-cancer therapies.
In the afternoon session, Karen Vousden (Beatson Institute, Glasgow) continued with a discussion on a role for mutant p53 in invasion and metastasis. Several approaches to the development of drugs to reactivate the p53 tumor suppressor protein as cancer therapies are being developed. These focus on the inhibition of Mdm2, the principal negative regulator of p53 that functions as an E3 ubiquitin ligase, leading to the proteasomal degradation of the p53 protein. Small molecules that block the binding of p53 to Mdm2, that inhibit the ubiquitin ligase activity of Mdm2 or that prevent p53 degradation at a post-ubiquitination step have been described, and each of these can activate p53 and drive the inhibition of cell proliferation in experimental systems. So far, however, the clinical efficacy of these drugs has not been established. Many human cancers show evidence for point mutation within p53, leading to the expression of a mutant protein that has lost normal tumor suppressor functions. In addition, these mutant p53 proteins show a gain of function that is independent of wild type p53, and contributes to increased invasive and metastatic behavior of cells both in vitro and in vivo. She has found that these types of mutant p53 acquire an ability to promote the recycling of integrins and the EGFR, through a Rab Coupling Protein dependent pathway. Treatment of mutant p53-expressing cells with an integrin blocking antibody, or a small molecule inhibitor of the EGFR, reversed the invasive behavior of these cells, suggesting types of therapy that may be particularly suited to the treatment of tumors with p53 mutations. The activity of mutant p53s may be related to their ability to interact with the p53-related protein p63. While mutant p53s are often expressed at very high levels in tumors, Mdm2 keeps them at a low level in normal tissue, like the wild type protein. Previous studies have suggested that many apparently normal tissues harbor p53 mutations, leading to the possibility that systemic treatment with Mdm2 inhibitors would result in the stabilization of these mutant p53s, with unanticipated, deleterious consequences.
Joan Brugge (Harvard, Boston) continued the session with a talk on the mechanisms regulating anchorage independence of tumor cells. One of the earliest recognized features of tumor cells in culture is their ability to proliferate and survive without attachment to extra cellular matrix. This ‘anchorage independence’ of tumor cells distinguishes their behavior from normal cells and is believed to be important in allowing tumor cells to proliferate outside of their natural niches during early stages of tumor formation as well as during invasion and metastasis. Oncogene pathways that regulate anchorage independence represent attractive targets for therapeutic intervention. Her presentation focused on a discussion of the relevance of this phenotype to different aspects of tumorigenesis and drug resistance, as well as findings from her laboratory on the mechanisms responsible for death of cells deprived of matrix and how oncogenes promote anchorage independence. She described that three distinct death processes – apoptosis, metabolic impairment, and a novel non-apoptotic mechanism, referred to as entosis, involving invasion of one cell within another and lysosomal degradation – contribute to the death of cells deprived of their appropriate matrix. The major focus of her presentation was on unpublished findings on metabolic pathways that are regulated by matrix attachment. She has found that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to loss of glucose transport. Over expression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and PI(3)K activation and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway (PPP). Interestingly, she found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation (FAO), which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an elevation in ROS in matrix-deprived cells in the luminal space of mammary acini and that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.
Jiri Bartek (Institute of Cancer Biology, Copenhagen) then discussed his work on the DNA damage response in cancer development and therapy. Recent work in the field of DNA damage recognition, signaling and repair has identified multiple protein modifications that operate in concert with the ‘classical’ phosphorylation/ dephosphorylation network governed by the ATM/ATR-regulated DNA damage response (DDR). His presentation summarized his recent published and unpublished data documenting the biological and pathophysiological role of the emerging ubiquitylation/ deubiquitylation cascade, including the RNF8, RNF168, HERC2/UBC13 and BRCA1 ubiquitin ligases, USP7 and other deubiquitylation enzymes and additional components, in DNA damage signaling and repair in human cells. The data included results from pan-genomic RNAi-based screens for novel DDR components, live-cell imaging of human cells to analyze the spatiotemporal orchestration of the key DDR pathways, and mechanistic insights into the cooperation between phosphorylation, ubiquitylation and protein-protein inter-actions in response to DNA double strand breaks. Then, recent results extending the concept of DDR as a tumorigenesis barrier in early human cancer development, and exploitation of DDR defects in tumors as predictive markers to guide individualized chemotherapy, were presented. He reported recent data on the genetic variant of NQO1 as a prognostic and predictive factor – the latter predicting resistance to anthracycline based chemotherapy of human breast cancer, particularly in cases with concomitant NQO1 unstable variant (as germ line feature) and mutant p53 in the tumor. Finally, new data on the predictive power of ATM and p53 status for chemotherapy resistance/sensitivity, and a novel synthetic lethality principle between ATM defects (ATM being connected with homologous recombination, HR, repair) and inhibitors of the DNA-PK (key component of the non-homologous end joining repair, that becomes dominant when ATM/HR are defective in tumors). These results were discussed in the light of potential applications for individualized treatment of cancer.
The morning of Thursday July 23 began with a presentation by Pier Giuseppe Pelicci (Institute of European Oncology, Milan) on the regulation of self-renewal in cancer stem cells and the hypothesis that the eradication of cancer stem cells was needed to affect a cure of the cancer. He then focused on normal hematopoeitic and leukemia stem cells and the potential role of p21 in the self-renewal of such cells. Contrary to normal HSC those lacking p21 are rapidly consumed during serial transfers in the mouse. Deletion of p21 do not affect the speed of appearance of leukemia in PML-RAR mice. However contrary to single PML-RAR leukemic mice, attempts to transplant leukemic stem cells from the double transgenic mice failed. These studies clearly demonstrate that tumor stem cells exist and that cell cycle regulators like p21 control their survival.
This was followed by a presentation by Maarten van Lohuizen (Netherlands Cancer Institute, Amsterdam) who discussed recent highlights from large-scale retroviral insertional mutagenesis screens done in collaborations with A. Berns and with D. Adams and A. Bradley (Sanger Institute, Cambridge) in cancer-predisposed mice. These included p15, p16, p21, p27 KO mice as well as p53 and p19Arf KO mice. The resulting dataset with over 500 common insertion sites marked known and unknown proto-oncogenes, tumor suppressor genes, and microRNAs. Many of these loci are skewed toward a specific genetic context of predisposing germ line and somatic mutations. There were associations between these loci and gender, age of tumor onset and with lymphocyte lineage (B or T cell). In addition, he observed highly specific concurrent and mutually exclusive insertions in tumors. Together these data highlight the importance of genetic context within large-scale mutation detection studies. The size of the dataset was of critical importance, illustrating the « added value » of performing these studies on a large scale and in defined genetic backgrounds. The approach is complementary to and can confirm the cancer-causing nature of genes identified by other approaches such as SNP analysis and high throughput sequencing of cancer genomes. Next, Maarten discussed the importance of Polycomb repressive complexes in controlling both proliferation and differentiation decisions in stem/progenitor cells. This involved both the histone methyltrasferase activity of EZH2 as well as a critical E3 ubiquitin ligase (Ring1b/Bmi1). Both in embryonic stem cells as well as in adult stem cells of the mammary epithelium polycomb repression dictated by the levels or activity of the regulatory factor Bmi1 sets the threshold for how stem/progenitor cells react to differentiation cues (such as pregnancy hormones in case of the mammary gland). When deregulated, aberrant stem/progenitor fate and proliferation is maintained, which contributes to a wide variety of cancers. Olivier Delattre (Institute Curie, Paris) concluded this session with a discussion of the genetics and biology of pediatric tumors. Ewing’s sarcoma is an undifferentiated tumor of bone that mainly occurs in teenagers. It is characterized by a specific chromosome fusion between EWS on the one hand and either of five ETS family members on the other hand. Recently a new fusion between EWS and NFATC2, a member of the NFAT family, was described. This therefore broadens the set of genes that can be fused to EWS in Ewing’s sarcoma. The cell of origin of Ewing’s sarcoma is a matter of debate since the initial description of this tumor in 1921 by James Ewing. Recent data based on the ability of EWS/FLI to transform mesenchymal progenitors and on the characteristics of Ewing’s cells in which EWS/FLI is inhibited by RNA interference suggest that the parental Ewing’s cell is related to mesenchymal stem cell. Recent microarrays and ChIP-Seq experiments highlight EWS/FLI downstream pathways whose targeting may constitute powerful new therapeutic approaches in Ewing’s sarcoma.
Claude Sardet (Institute of Molecular Genetics, Montpellier) was the first speaker on the final day of the meeting on July 24. His research explores the transcriptional and chromatin networks that control the mammalian cell cycle and cell survival, to understand how alterations of these networks contribute to tumorigenesis. His talk focused on E4F1, which like the E2F/pRB and p53 protein families, is a central player that controls cell cycle, survival, differentiation and transformation. These transcription factors gate the mammalian cell cycle via the control of genes that encode regulators of the cell cycle progression, apoptosis and development. They are directly targeted by various viral oncoproteins and their regulatory pathways are altered in numerous mammalian tumors. He discussed the physiological function E4F1 as revealed through conditional KO mouse models and has investigated the response to alterations of the cellular homeostasis and the molecular mechanisms by which E2F41 controls its target genes. Jim Manley (Columbia, New York) then discussed mRNA processing and links to cancer. Cancer cells avidly take up glucose and convert it to lactate while avoiding oxidative phosphorylation. This phenomenon is critical for maximal tumorigenicty and is in part explained by the almost universal reversion of tumors to the embryonic form of pyruvate kinase, PKM2. PKM2 and the adult isoform, PKM1, are produced from the same gene, and differ by a single mutually exclusive mRNA exon. Jim Manley showed the hnRNP proteins PTB, hnRNP A1 and hnRNP A2, bind repressively to sequences flanking the PKM1-specific exon, resulting in production of PKM2. He also demonstrated that the oncogenic transcription factor c-Myc up regulates PTB/A1/A2 ensuring a high PKM2:PKM1 ratio. Establishing a relevance to cancer, he showed that gliomas over express c-Myc and PTB/A1/A2 in a manner that correlates with PKM2 expression. These results demonstrated an important functional consequence for the observed over expression of PTB/A1/A2 in cancer, and identify an additional pathway through which c-Myc regulates tumor metabolism. Peter Howley (Harvard, Boston) then discussed the human papillomaviruses and cancer, from the standpoint of potential targets for the development of antiviral therapies. The current approved VLP based vaccines are preventive and have potential limitations given the fact that the major burden for HPV-associated cervical cancer is in the developing world. He presented data suggesting that both the E2 and E6 genes as potential antiviral targets. His laboratory has conducted siRNA and proteomic screens that have provided new insights into how expression of the E6 and E7 viral oncoproteins are regulated by the virus.
In the final session that afternoon, Peter Laird (USC, Los Angeles) discussed epigenetics and cancer. Epigenetics can have a powerful effect on cellular phenotype, as evidenced by the large diversity of genetically identical, but epigenetically distinct cell types in the human body. It seems logical that an opportunistic phenomenon like cancer would take advantage of epigenetic mechanisms to evolve. Many epigenetic alterations have been described in human tumors, but it has not been clear whether these changes were causal contributors or mere consequences of the cancer process. The causal role of DNA methylation in a cancer model system was demonstrated by showing that polyp formation in ApcMin/+ mice predisposed to intestinal neoplasia was completely blocked by genetically engineered reduced DNA methyltransferase levels. Genomic loci targeted by Polycomb Group Repressors in embryonic stem cells, and involved in cellular differentiation are frequently methylated in cancer cells, suggesting that an epigenetic block to cellular differentiation may sometimes be an initiating event in carcinogenesis. The very strong association between BRAF mutation and CpG Island Methylator Phenotype in colorectal cancer is consistent with an early role for DNA methylation alterations, providing a cellular context in which oncogene-induced senescence pathways have been inactivated. Advances in technology provide opportunities for clinical applications of epigenetics. These include the highly sensitive and specific detection of DNA methylation abnormalities in the serum and plasma of cancer patients by Digital MethyLight, while next-generation sequencing technologies provide single-base pair resolution DNA methylation maps by whole genome shotgun bisulfite sequencing.
Moshe Yaniv (Pasteur Institute, Paris) concluded the formal session with a presentation on the link of chromatin remodeling complexes involved in epigenetic control of gene expression and cancer. His presentation focused on SWI/SNF, an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position and stability in order to alter transcriptional programs within the cell. The SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and has recently been implicated in cancer development. The group of Olivier Delattre identified SNF5/Ini1, a non-enzymatic subunit of the complex, as a tumor suppressor gene mutated or deleted in malignant rhabdoid tumors of infants. Inactivation of this gene in mice results in very early lethality demonstrating the key role played by such a complex in controlling cell fate. Heterozygous animals survive but develop rhabdoid tumors that are indistinguishable from the human ones. The second copy of the gene is lost in these tumors. Conditional deletion of SNF5 in mouse fibroblasts results in DNA damage and mitotic failure followed by p53 dependent apoptosis explaining why SNF5 inactivation is associated with a rare type of tumor that can develop in the absence of this gene. The critical role of p53 in controlling the fate of SNF5 defective cells was confirmed by the spectacular acceleration of rhabdoid tumor formation in mice heterozygous for SNF5 and defective for p53.
David Livingston provided an inspiring summary where he explored how basic science can relate to drug discovery. Thus far targeted therapy has been more of a hope than a reality with a few notable exceptions such as Gleevac, herceptin and a few others. He summarized some of the highpoints of the meeting and concluded that tumor genome sequencing will undoubtedly serve as a powerful discovery and validation tool for drug targets. More insightful cancer biology however is necessary to lead to the identification of new drug targets.