News Article | September 20, 2016
A Ludwig Cancer Research study published online September 14th in Nature reports a novel technique to map specific chemical (or "epigenetic") modifications made to the protein packaging of DNA using a small population of cells. Such epigenetic marks play a central role in the regulation of the genome's expression. Led jointly by Ludwig San Diego's Bing Ren and Arne Klungland of the University of Oslo, the authors describe their application of this method to unravel a key mystery of the earliest stage of development. The new technique, named μChIP-seq, is also likely to be of notable relevance to cancer research. Very soon after fertilization, the control of embryonic development shifts from pre-existing maternal gene products to the products of genes encoded by the early embryo (or zygote). This passing of the genetic baton, called the maternal-to-zygotic transition (MZT), is poorly understood because existing technologies have generally been too insensitive to capture the full scale of the epigenetic changes it entails across the zygotic genome. The improved sensitivity of μChIP-seq, developed jointly by Klugland, Ren and John Arne Dahl of Oslo University, led to "some remarkable discoveries that have completely changed our view of epigenetic inheritance mechanisms," says Ren. In the current paper, Ren and his colleagues describe their use of μChIP-seq to investigate how epigenetic information is passed from one generation to the next to orchestrate the MZT. To that end, they examined in mouse embryos the global distribution of an epigenetic mark known to play a critical role in regulating the activity of genes. This mark (H3K4me3) modifies chromatin—the complex of DNA and its protein packaging—by adding three identical molecules known as methyl groups at a specific place on a packaging protein known as histone 3. Dahl, a visiting scholar in Ren's lab and co-first author on the Nature paper, fine-tuned the technique for mapping such epigenetic tags to where only a few hundred embryos or cells were needed for each experiment. Previous methods required up to 10,000 cells to conduct similar analyses. The other first author, Inkyung Jung, a Ludwig postdoc in Ren's lab, contributed significantly to the computational analysis of the resulting data. When the scientists compared H3K4me3 distribution in immature mouse egg cells they found something unexpected: broad but distinct domains of the immature egg cell's genome, representing some 22% of the whole, are heavily marked by H3K4me3. These domains rapidly decrease in size in 2-cell embryos and eventually shrink to about 1% to 2% of the genome. "The key lesson we learned was that the genes that are destined to be turned on specifically in the fertilized egg are covered by this unique chromatin domain structure," says Ren. Those marks have to be removed by specialized enzymes to activate the zygotic genome. "This mark is a mechanism for the oocyte to influence which genes in the zygote are activated. It is an epigenetic mechanism for the passage of information from the maternal oocyte to the zygote." The ability to map "epigenomes" using such a small number of cells will be valuable to cancer research, since the epigenetic landscape is dramatically rearranged in cancer and contributes to phenomena driven by small subpopulations of cells, such as drug resistance and metastasis. "With a better understanding of the epigenetic landscapes in cancers, we are going to have more tools to study the basis of tumorigenesis," says Ren. "We still have a long way to go, but our goal is to have a thorough understanding of gene regulatory programs so we can use that knowledge to treat cancer and develop diagnostic tools."
News Article | March 2, 2017
Ludwig researchers have shown that triple-negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy and that targeting this pathway could undermine their resistance to such therapies. MARCH 2, 2017, New York -- A team of researchers led by Alex Toker of the Ludwig Center at Harvard has discovered a metabolic weakness in triple-negative breast cancer (TNBC) cells that may be exploited to quell their resistance to chemotherapy. TNBC is notoriously aggressive and is difficult to treat because its cells lack the targetable receptors found in other forms of breast cancer. Only about 30 percent of TNBC patients achieve a pathologic complete response, or a complete eradication of active cancer cells, following chemotherapy. Those who do frequently relapse shortly afterward. "Trying to understand the mechanisms that contribute to cancer's resistance to therapy is a major mission here at the Ludwig Center at Harvard," said Alex Toker. In the new study, published online in the journal Cancer Discovery, Toker, an investigator at the Ludwig Center at Harvard Medical School, and his team including lead author Kristin Brown, formerly of the Ludwig Center at Harvard and now at Peter MacCallum Cancer Center in Melbourne, Australia, outline a newly discovered chink in the armor of TNBC cells. This "metabolic vulnerability" can be used to circumvent chemotherapy resistance. The scientists demonstrated that chemotherapy effectively reprograms TNBC cells to ramp up production of the pyrimidine nucloetides, key building blocks of DNA. This heightens the cells' DNA repair abilities and ultimately results in greater resistance to chemotherapies that work by damaging the DNA of rapidly dividing cells. "This actually makes sense if you think about it, because if a tumor cell is going to repair DNA and therefore evade the death-inducing effects of chemotherapy, the only way they can really do that is by rebuilding DNA, and the only way to rebuild DNA is to make more nucleotides," Toker said. Toker and his team reasoned that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities and make them more susceptible to the DNA-damaging effects of chemotherapy. To test this hypothesis, the team exposed TNBC cells in the lab to a drug combination of doxorubicin, a commonly used chemotherapy agent, and leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a crucial enzyme in the biochemical reactions that generate pyrimidines. "One of the major reasons we chose leflunomide is because we wanted a rapid path to clinical impact, and leflunomide is already FDA-approved and widely used to treat autoimmune diseases such as rheumatoid arthritis," Toker said. Toker's group found that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, thus impairing their ability to repair the DNA damage dealt by doxorubicin, and resulting in increased cancer cell death. The scientists then repeated the experiment in mice that had been transplanted with human TNBC cells. "We found that treating the mice with doxorubicin or leflunomide alone only slowed tumor growth, but that a combination therapy involving both drugs resulted in significant tumor regression," Toker said. Importantly, the combination therapy in mice did not cause any weight loss or gain in the animals - an indication that the drug regimen might be reasonably well-tolerated in humans. "One of the things we would like to do is develop clinical trials in patients with this combination strategy, whether it be with leflunomide or some other drugs that are coming online that might have better pharmacological properties in patients," Toker said. In the meantime, Toker said his group is moving forward with plans to investigate the molecular basis of increased pyrimidine biosynthesis in TNBC cells. "There is something about this pathway in triple negative breast cancer that is especially important," Toker said. "We don't know what the genetic basis underlying it is, but it's something we would really like to find out." Funding and support for this research was provided by the Virginia and DK Ludwig Fund for Cancer Research. Alex Toker, an investigator at the Ludwig Center at Harvard, is also a professor in the Department of Pathology at the Beth Israel Deaconess Medical Center and Harvard Medical School and Chief of the Division of Signal Transduction in the Departments of Medicine, Pathology and Cancer Center. Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www. . For further information please contact Rachel Steinhardt, email@example.com or +1-212-450-1582.
News Article | October 28, 2016
iTeos Therapeutics S.A, together with ChemCom S.A., ImmunXperts S.A., the de Duve Institute and IRIBHM have been awarded 1,6 million euro grant through a BioWin project called IT-Targets. The aim of this collaboration is to identify innovative drug candidates and biomarkers for immunotherapy of various types of cancer, starting from patient tumor derived material. The IT-Targets project will focus on G protein-coupled receptors (GPCRs), which will be selected by profiling the most important immune cell types purified from clinical samples. Despite the fact that GPCRs are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. GPCRs and their downstream signaling are involved in cancer growth and development by controlling many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. The project associates the expertise of IRIBHM in GPCR discovery and validation, the unique technology on sensory GPCRs developed by ChemCom, the in-depth tumor immunology expertise of de Duve with the drug discovery capabilities of iTeos and the expertise of ImmunXperts with human primary cells in immuno-oncology. “We are honored and pleased to be a recipient of this Grant Award, an integral part of our Bedside to Bench translation medicine strategy and its application to the identification of innovative targets for the treatment of cancer” said Christophe Quéva, CSO, iTeos Therapeutics. “This collaboration will focus on the exploration of the well -characterized class of GPCR drug targets that has been so far underexploited for immune therapy of cancer. This strategy will allow a fast progression from targets to therapeutic applications. About iTeos Therapeutics S.A. (http://www.iteostherapeutics.com) Based in Gosselies, Belgium, iTeos, a spin-off of Ludwig Cancer Research (LICR) and de Duve Institute (UCL), expands the benefits of immunotherapy to cancer patients. The company develops a proprietary pipeline targeting A2A, immune checkpoints and non-immunogenic tumors, and has licensed its IDO1 program, now in Phase 1, to Pfizer. iTeos’ competitive edge is in the combination of expertise in drug discovery and translational tumor immunology. The company uses a unique platform to identify rationale combination of immunotherapies and novel targets. The company is supported in part by the Walloon Region of Belgium and the FEDER (European Fund for Economic and Regional Development). About ChemCom S.A. (http://www.chemcom.be) Based in Brussels in the Medical Campus of the ULB (Université Libre de Bruxelles), ChemCom is the leading discovery company for products and services related to chemical communications mediated by human sensory receptors (GPCRs). ChemCom, relying on its scientific excellence and its patented technological platform, expresses the whole repertoire of human olfactory receptors. This enables a large scale deorphanization and characterization of human sensory receptors and allows the discovery of new products acting through activation (agonism or positive allosterism) or blockade (antagonism) of those sensory GPCRs. ChemCom activities are focused on new products for consumer’s needs in the area of Flavors & Fragrances, but also, by the use of ectopic sensory receptors, to pharmaceutical applications. The company is supported in part by the Brussels Region of Belgium (Innoviris) About ImmunXperts S.A. (http://www.immunxperts.com) Founded in 2014, ImmunXperts provides immunogenicity and immune-oncology screening services, assessing all aspects of the immune responses in donors and patients, supporting its partners in the full development cycle of novel drugs, biotherapeutics and stem cell therapies. Through its ImmunAcademy, the company supports biopharma companies to set up and build out immunology screening tools. About the de Duve Institute at the Université catholique de Louvain (https://www.deduveinstitute.be). The de Duve Institute is a multidisciplinary biomedical research institute hosting several laboratories of the faculty of medicine of UCL, as well as the Brussels branch of the Ludwig Institute. Several research groups of the Institute focus on tumor immunology and cancer immunotherapy. The IT-Targets project provides a unique opportunity to explore the roles of G protein-coupled receptors in human tumor immunology. We will combine our expertise on anti-cancer T cell responses with those of IRIBHM and ChemCom on the physiology of GPCRs, of ImmunXperts on cell purification and of iTeos on the development of innovative immune modulators for cancer immunotherapy. About (IRIBHM) Institut de Recherche Interdisciplinaire en Biologie Humain et Moléculaire from the Université Libre de Bruxelles (https://www.iribhm.org). IRIBHM has a long standing expertise in the functional characterization of G protein-coupled receptors in physiological processes and diseases. Amongst other topics, the Institute has pioneered the description of olfactory receptors and their function in other organs than the olfactory mucosa and is presently studying the role of receptors expressed in leukocyte populations in mouse models of carcinogenesis. About BioWin (http://www.biowin.org). Created in 2006, BioWin, the Health Cluster of Wallonia (Belgium), is the reference player for all the stakeholders (companies, research centers and universities) involved in innovative R&D projects and/or skills development in the field of health biotechnology and medical technologies. The cluster carries out a variety of actions designed to promote Wallonia’s scientific and industrial excellence at the international level. More information is available at http://www.biowin.org and the blog page http://www.win-health.org.
News Article | November 10, 2016
A Ludwig Cancer Research study shows that an experimental drug currently in clinical trials can reverse the effects of troublesome cells that prevent the body's immune system from attacking tumors. The researchers also establish that it is these suppressive cells that interfere with the efficacy of immune checkpoint inhibitors. This class of immunotherapies lifts the brakes that the body imposes on the immune system's T cells to unleash an attack on cancer cells. "Though checkpoint inhibitors have durable effects when they work, not all patients respond to the treatment," says Taha Merghoub, an investigator at the Ludwig Memorial Sloan Kettering Collaborative Laboratory who led the study with Director Jedd Wolchok. "Part of the reason for this is that some tumors harbor tumor-associated myeloid cells, or TAMCs, that prevent T cells from attacking tumor cells." In a study published online in Nature, Merghoub and his team used mouse models of cancer to show that the effects of TAMCs can be reversed by an appropriately targeted therapy. To show that TAMCs were indeed involved in resistance to checkpoint blockade, the researchers used a specific growth stimulant to increase their number in melanoma tumors to create a suitable model for their studies. They found that this made the tumors less susceptible to checkpoint blockade. "We were able to make a tumor that was not rich in immune suppressing myeloid cells into one that was," says Merghoub. Having established a link between TAMCs and checkpoint inhibitor resistance, the researchers next set out to test the hypothesis that blocking immune suppressor cell activity would improve immunotherapy response. To do this, they used an experimental drug manufactured by Infinity Pharmaceuticals called IPI-549. The drug, which is available for clinical use, blocks a molecule in the suppressor cells called PI3 kinase-gamma. Blocking this molecule changes the balance of these immune suppressor cells in favor of more immune activation. "We effectively reprogrammed the TAMCs, turning them from bad guys into good guys," Merghoub said. IPI-549 dramatically improved responses to immune checkpoint blockade (ICB) therapy for tumors with high concentrations of TAMCs. When checkpoint inhibitors were administered to mice with suppressed tumors, only 20% of the animals underwent complete remission. When the same drugs were administered with IPI-549, that number jumped to 80%. IPI-549 provided no benefit to tumors lacking the suppressor cells. Merghoub and his team also showed that tumors that were initially sensitive to checkpoint inhibitors were rendered unresponsive when their TAMC concentrations were boosted with growth stimulants. Taken together, these results indicate that TAMCs promote resistance to checkpoint inhibitors and that IPI-549 can selectively block these cells, thereby overcoming their resistance. Merghoub said the findings help pave the way for a precision medicine approach to immunotherapy that will allow cancer treatments to be tailored to a patient's particular tumor profile. "We can now potentially identify patients whose tumors possess immune suppressor cells and add a drug to their treatment regimen to specifically disarm them," he added. IPI-549 is currently undergoing a Phase I trial in the United States to assess its safety when administered alone and in combination with the FDA-approved checkpoint inhibitor drug nivolumab (Opdivo®).
News Article | April 8, 2016
Researchers at Karolinska Institutet and the Ludwig Cancer Research in Stockholm, Sweden have conducted a detailed molecular analysis of the embryo's first week of development. Their results show that there are considerable differences in embryonic development between humans and mice, which is the most common organism of study in this field. The new study, which is published in the journal Cell, also shows that genes on the X chromosome are regulated differently. Early human embryonic development is difficult to study, and most of our knowledge comes from mice. During the first seven days of fertilization, the egg develops from a single cell to a blastocyst, a hollow cluster of some 200 to 300 cells. It is during this time that the first three cell types appear: the trophectoderm, which gives rise to the placenta, the hypoblast, which forms the embryonic endoderm, and the embryonic cells that go to make up the embryo itself. If the embryo is to adhere to the uterus wall and pregnancy commences, all these three cell types must mature properly. However, exactly when and in which order and how the cell types form in humans has not been known. By detecting gene expression in individual cells, from donated human embryos that were not used for IVF treatment, two research groups led by Rickard Sandberg and Fredrik Lanner have managed to identify which genes are used in the embryo's cells at different times during the first week of development. They found that the first three cell types form later and seem to mature more simultaneously in the human than in the mouse. "The fundamental knowledge generated by our research doesn't only help us understand embryonic development better, it also tells us more about how pluripotent cells are formed and regulated in its early stages," said Lanner at Karolinska Institutet's Department of Clinical Science, Intervention and Technology. "This is important for the use of embryonic stem cells in regenerative medicine." The researchers also found that the expression of genes situated on the X chromosome is subject to an unexpected expression pattern. The X chromosome has a particular gene regulation problem, since women's cells have two X chromosomes, while men only have a copy (XY). To avoid women having twice the level of expression of all genes on the X chromosome as men, women's cells must offset the gene expression. In mice, where this process is well-studied, one of the two X chromosomes is simply shut off during the first week. However, it has always been uncertain if this process even begins during the first week of human embryo development. "What we've been able to demonstrate is that dose balance is gradually attained during day 4 to 7, interestingly through a completely new manner in which the gene expression from both X chromosomes in the female embryo is suppressed," said Sandberg.
News Article | April 7, 2016
Researchers at Karolinska Institutet and the Ludwig Cancer Research in Stockholm, Sweden have conducted a detailed molecular analysis of the embryo's first week of development. Their results show that there are considerable differences in embryonic development between humans and mice, which is the most common organism of study in this field. The new study, which is published in the journal Cell, also shows that genes on the X chromosome are regulated differently.
News Article | November 1, 2016
When information in our genes is used, for example to build a protein, it is first translated to messenger-RNA which functions as a blueprint for the protein. Our cells also contain non-coding, short, RNA sequences that do not contribute to the formation of proteins and whose functions are partly unknown. The best known of these is micro RNA (miRNAs), which can interact with the messenger RNA, and thereby regulate genes and cell function. Researchers at Karolinska Institutet have now mapped the presence of short RNA-sequences in an individual cell. Previous research on short RNA molecules is based on analysis of many cells simultaneously, making it difficult to study the precise function. "Our knowledge of the function of short RNA molecules is quite general. We have a picture of the general mechanisms, but it is less clear what specific role these molecules play in different types of cells or diseases," says Rickard Sandberg, professor at the Department of Cell and Molecular Biology, who is also affiliated to the Stockholm center of Ludwig Cancer Research. The analysis was done using single-cell transcriptomics, a technique which makes it possible to measure the absolute numbers of short RNA molecules in a cell. Two types of embryonic stem cells were used, intended to mimic the early embryo, before and after it has attached to the uterine lining. The researchers could detect large numbers of small RNAs in both cell states, including miRNA as well as shorter RNA fragments (tRNA and snoRNA) whose function is largely unknown. The researchers also found that large numbers of miRNAs are expressed differently in the two cell states. "This is basic research and a demonstration that the method works, giving suggestions for further research. To map the levels of short RNA molecules in a cell is a first step in identifying the specific function of these molecules," says Omid Faridani, one of the lead authors of the study. In the long run, Rickard Sandberg can imagine clinical applications of the method. "We are, for example, interested in the role short RNA molecules play during embryonic development. We hope that, with more knowledge, this method could be used to identify which embryos have the best chance to develop, which would then be used to improve current IVF treatments," he says. Explore further: New insights into early human embryo development More information: Omid R Faridani et al, Single-cell sequencing of the small-RNA transcriptome, Nature Biotechnology (2016). DOI: 10.1038/nbt.3701
News Article | December 7, 2016
MAASTRICHT, The Netherlands and GOSSELIES, Belgium, Dec. 07, 2016 (GLOBE NEWSWIRE) -- Cristal Therapeutics, a Dutch privately-held life sciences company developing novel nanomedicines against cancer and other diseases and iTeos Therapeutics SA, a Belgian privately-held biotechnology company applying its expertise in translational tumor immunology to the development of novel cancer immunotherapies, today announced a strategic partnership for the discovery, development and commercialization of optimized immuno anti-cancer drug candidates, using Cristal Therapeutics' medicinal nanotechnology CriPec® platform. The initial goal of this partnership is to determine the therapeutic efficacy of targeted drugs using Cristal's CriPec® application in iTeos' preclinical models which have been proven to be predictive in combinations of several immune activators - such as IDO1 and TDO2 - with checkpoint inhibitors. iTeos has an option to license Cristal's proprietary nanotechnology platform to support the development and commercialization of up to three of its immune tumor-targeting programs. CriPec®, a proprietary nanotechnology platform, consists of tuneable polymers and biodegradable drug linkers that allow for the rational design and straightforward manufacturing of custom-made nanomedicines. Applying the CriPec® platform - drugs entrapped in CriPec® nanoparticles - results in immuno nanomedicines with a superior product profile as compared to the native drug molecule. CriPec® nanoparticles improve the disposition of thousands of drug molecules per particle and allow the controlled release of these molecules specifically at the target site. This results in an improved therapeutic efficacy and tolerability. "This partnership with iTeos allows us to assess and demonstrate the application of our CriPec® nanoparticles, specifically in the area of novel immuno-oncology therapies. We are focused on applying our nanomedicine platform to several promising oncology indications, some of which will be evaluated for the iTeos' development pipeline." "We are very pleased to enter into this partnership with an emerging clinical-stage nanomedicine platform company. Cristal has a strong and experienced management team, and has demonstrated the capability to quickly develop valuable therapeutic programs. We look forward to applying their platform to some of our drug candidates. We believe it has particular potential in the evolving area of causing so-called "cold tumors" - which are less responsive to checkpoint inhibitors - to become susceptible to various immuno-oncology therapies." About Cristal Therapeutics Maastricht, The Netherlands based Cristal Therapeutics, is a privately-held life sciences company developing novel nanomedicines against cancer and other diseases, by using its patented CriPec® platform. CriPec® transforms drugs into polymeric nanoparticles via an innovative process. These nanoparticles provide improved distribution throughout the body. The substantial improvement of the efficacy and safety of the drugs entrapped in CriPec® nanoparticles has been demonstrated in several preclinical disease models. Cristal Therapeutics' products in development are primarily aimed at treating patients suffering from cancer but offer also opportunities for the treatment of chronic inflammatory diseases. CriPec® docetaxel is the most advanced product candidate, and is under clinical evaluation for the treatment of solid tumors. For more information please visit www.cristaltherapeutics.com. About iTeos Therapeutics S.A. Based in Gosselies, Belgium, iTeos, a spin-off of Ludwig Cancer Research (LICR) and de Duve Institute (UCL), is focused on expanding the benefits of immunotherapy for cancer patients. The company is developing a proprietary pipeline targeting A2A, immune checkpoints and non-immunogenic tumors. It has licensed its IDO1 program, now in Phase 1 development, to Pfizer. iTeos' competitive edge is in the combination of expertise in drug discovery and translational tumor immunology. The company uses a unique platform to identify rational combinations of immunotherapies and novel targets. The company is supported in part by the Walloon Region of Belgium and the FEDER (European Fund for Economic and Regional Development). For more information please visit www.iteostherapeutics.com.
News Article | November 1, 2016
Researchers at Karolinska Institutet have measured the absolute numbers of short, non-coding, RNA sequences in individual embryonic stem cells. The new method could improve the understanding of how our genes are regulated and different cell types develop. When information in our genes is used, for example to build a protein, it is first translated to messenger-RNA which functions as a blueprint for the protein. Our cells also contain non-coding, short, RNA sequences that do not contribute to the formation of proteins and whose functions are partly unknown. The best known of these is micro RNA (miRNAs), which can interact with the messenger RNA, and thereby regulate genes and cell function. Researchers at Karolinska Institutet have now mapped the presence of short RNA-sequences in an individual cell. Previous research on short RNA molecules is based on analysis of many cells simultaneously, making it difficult to study the precise function. "Our knowledge of the function of short RNA molecules is quite general. We have a picture of the general mechanisms, but it is less clear what specific role these molecules play in different types of cells or diseases," says Rickard Sandberg, professor at the Department of Cell and Molecular Biology, who is also affiliated to the Stockholm center of Ludwig Cancer Research. The analysis was done using single-cell transcriptomics, a technique which makes it possible to measure the absolute numbers of short RNA molecules in a cell. Two types of embryonic stem cells were used, intended to mimic the early embryo, before and after it has attached to the uterine lining. The researchers could detect large numbers of small RNAs in both cell states, including miRNA as well as shorter RNA fragments (tRNA and snoRNA) whose function is largely unknown. The researchers also found that large numbers of miRNAs are expressed differently in the two cell states. "This is basic research and a demonstration that the method works, giving suggestions for further research. To map the levels of short RNA molecules in a cell is a first step in identifying the specific function of these molecules," says Omid Faridani, one of the lead authors of the study. In the long run, Rickard Sandberg can imagine clinical applications of the method. "We are, for example, interested in the role short RNA molecules play during embryonic development. We hope that, with more knowledge, this method could be used to identify which embryos have the best chance to develop, which would then be used to improve current IVF treatments," he says. "Single-cell sequencing of the small-RNA transcriptome" Omid R. Faridani, Ilgar Abdullayev, Michael Hagemann-Jensen, John P. Schell, Fredrik Lanner and Rickard Sandberg Nature Biotechnology, online 31 October 2016. DOI: 10.1038/nbt.3701
News Article | October 26, 2016
Tumor cells collected during the removal of a cancerous bladder and - in some cases - transplanted into mice with weakened immune systems, could help physicians rapidly identify high-risk cancers, determine prognosis and refine the use of biomarkers to personalize care for patients with this common cancer, according to a study published online on Oct. 24, 2016, in Scientific Reports (one of the Nature journals). The researchers, based at the Ludwig Center at the University of Chicago, found that detection of poorly differentiated basal tumor cells in early stage cancers; overexpression in those cells of a gene known as cell division cycle 25C, which plays a key role in the regulation of cell division; or the ability of tumor fragments to grow when transplanted into a mouse, all predicted an increased risk of death. "If confirmed in larger studies, our findings could help physicians get a better handle on how a patient's bladder cancer is likely to progress and allow them to personalize treatment based on that knowledge," said study author Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology and Chair of the Department of Radiation and Cellular Oncology at the University. Bladder cancer is the fourth most common cause of cancer-related death among men in the United States. More than 75,000 new cases will be diagnosed this year and more than 16,000 people will die from this disease. Weichselbaum and colleagues obtained tumor samples from 71 bladder cancer patients treated at the University and used flow cytometry to isolate and count specific subtypes of tumor cells in each sample. They showed that an excess of one relatively rare subtype in early-stage cancers - the basal tumor cell (BTC) - was associated with a 3-fold increase in risk of death. Analyzing the global expression of genes in BTCs, the researchers also identified a potentially prognostic biomarker for bladder cancer: cell division cycle 25C (CDC25C), a protein that drives cell division. An expanded analysis, including 400 bladder cancer patients, found that the expression of this protein is associated with an increased risk of death even after the removal of the cancerous bladder. This association disappeared in patients who had previously received chemotherapy. A test for CDC25C could, the authors suggest, help determine whether a bladder cancer patient is likely to benefit from drug treatment. In more invasive tumors, the presence and number of BTCs had less prognostic value. When the researchers injected bladder-cancer tissue fragments from 69 patients with more advanced cancers into the flanks of immune-deficient mice, however, about 60 percent of these tumor fragments were able to take hold and grow in this setting. This was associated with a 6-fold increase in risk of death, compared to tumor fragments that did not survive and grow after transplantation. "Prognostic knowledge can change a lot about how you choose to treat a cancer," said Weichselbaum. "We may be able to avoid aggressive measures if we find a tumor has relatively few basal cells," he said. "We could treat an early-stage bladder cancer with less aggressive therapy, avoiding debilitating interventions like radical cystectomy. But if a bladder tumor has a lot of basal cells, we may need to take the entire bladder out and follow that with chemotherapy. Before this can happen, he added, the accuracy of his team's new prognostic model and biomarker "will need to be confirmed in larger studies." The study was supported by Ludwig Cancer Research, Rosalind and Burton Spellman Family Cancer Fund, The Foglia Foundation and Mr. and Ms. Vincent Foglia. Additional authors were K. B. Skowron, S. P. Pitroda, J. P. Namm, O. Balogun, M. A. Beckett, M. L. Zenner, O. Fayanju, X. Huang, C. Fernandez, W. Zheng, G. Qiao, R. Chin, S. J. Kron, N. N. Khodarev, M. C. Posner and G. D. Steinberg.