IMBIO

Manoj Bhasin PhD

Manuel Guerrero

Dimitrios Spentzos MD

Cancer & Hematologic

Immunology, Transplantation

Vascular Biology

Summary: Dr. Libermann is the director of the BIDMC Genomics Center and of the DF/HCC Cancer Proteomics Core, which provide core assistance to medical center investigators in the use of various proteomics, genomics and bioinformatics technologies.
The Libermann laboratory focuses on both basic science and translational research with a particular focus on genomics and proteomics Systems Biology approaches to human disease. The laboratory is applying various cutting edge technologies for proteomics, transcriptional profiling and genotyping in order to define and compare protein and gene profiles and genomic DNA in kidney, ovarian, prostate, liver and breast cancer tissues and bodily fluids, correlate protein and gene profiles and mutations with biological activities and disease, define disease mechanisms at a molecular level and predict clinical outcome and response to therapy. Additional interests of the lab are to dissect the molecular mechanisms of drug action in order to rationally design combination therapies for cancer, understanding escape from programmed cell death in cancer cells and the role of Ets transcription factors in cancer. New efforts to develop novel proteomics methods for biomarker discovery and validation are in progress.

Discovery and validation of biomarkers and therapeutic targets in renal cell cancer
Renal Cell Cancer (RCC) is the most lethal of the urological cancers.  Despite numerous recent advances in diagnostic imaging, surgical therapy and basic molecular understanding there is still a considerable number of patients suffering and dying from metastatic disease.
The recent development of novel targeted therapies based on the precise biological pathways deregulated in a particular patient has paved the way for individualized, targeted patient management. Nevertheless, to achieve this goal it is of utmost importance to delineate the molecular mechanisms underlying cancer development and progression. Genomics and proteomics approaches have revolutionized the field of cancer research and have led to rapid discovery of multiple, parallel disease hypotheses that ultimately have to be validated in large cohorts of patients and in downstream biological experiments for translation into clinical applications.
The variable course of RCC and paucity of therapeutic options in the event of metastasis have led to the search for diagnostic and prognostic markers. The Libermann laboratory is using microarrays and mass spectrometry to classify different subtypes of RCC and to identify subtype- and metastasis-specific gene and protein signatures and biomarkers predictive for outcome and response to therapy. The effort is also focusing on identifying and validating emerging biological pathways underlying RCC development and progression and novel drug targets for therapeutic intervention. The goal is to improve management of patients with RCC by identifying the precise disease mechanisms for each individual patient and to devise targeted therapies.

Systems biology of renal cell cancer
Delineation of the genome and proteome has become the new frontier in many research areas including cancer as the result of completion of the human genome sequencing. In depth understanding of the cancer genome and proteome promises to solve many biological and clinical questions and is, therefore, considered an enabling and critical approach in cancer research and clinical investigation. Furthermore, each of these approaches may generate thousands of data points that require sophisticated bioinformatics and biostatistics analysis. It is becoming apparent that only if we understand the complexities of interactions of the genome and proteome within cells and in the extracellular compartments, will we be able to model the complex biological pathways in cancer. In particular in the context of cancer, mutations, deletions and fusions of proteins play central roles in the development and progression as well as response to therapy of cancer. Furthermore, deregulations of kinases, phosphatases, proteases, glycosidases, acetylases as well as various other protein modifying enzymes lead to complex, cancer-specific protein modifications.
Genomics analyses of renal cell cancer (RCC) by the Libermann laboratory and others have revealed a variety of biological pathways and multiple specific gene sets that are deregulated in RCC, providing ample opportunities for validation and eventual targeted therapies against validated targets. However, in order to prioritize potential drug targets and to understand the biological and physiological consequences of disrupting the activity of a specific gene, it is necessary to carefully dissect the biological pathways of deregulated genes. The Libermann laboratory is applying a systems biology approach to systematically analyze the relevance of different genes and biological pathways and delineate the molecular mechanisms for RCC development and progression by combining genomic and proteomic approaches with gene knock-down and overexpression studies in cell culture and animal models as well as patient cohorts of RCC. A particular effort focuses on the role of tyrosine kinases in RCC.

Identification of early detection and prognostic biomarkers in ovarian cancer
Epithelial ovarian cancer (EOC) is a major cause of gynecologic cancer mortality. Most patients present with advanced disease that is managed with surgical cytoreduction, followed by postoperative chemotherapy. Standard chemotherapy with carboplatin in combination with a taxane results in an initial response rate of over 70%, although subsequent relapse frequently occurs and eventually becomes resistant to a wide variety of agents. Consequently, the long-term survival of patients with upper abdominal involvement (stage III) or those with disease beyond the abdomen (stage IV) ranges from 30% to less than 10%. Traditional clinical factors are reasonable but imperfect measures of outcome and response to therapy.  While individual molecular markers carry some predictive and prognostic value, they have not by themselves been proven to be accurate enough for clinical application, suggesting that no single factor can serve as a surrogate for the complex genetic changes associated with tumor growth and response to chemotherapy.
Similarly, the etiology of ovarian cancer is not yet well understood, despite the low 5-year survival of this disease.  Relatively few plasma biomarkers have been examined in relation to ovarian cancer risk, and discovery of new protein risk factors has evolved slowly.  However new genomic and proteomic technologies now permit the simultaneous evaluation of the whole genome or proteome.
The Libermann laboratory is collaborating with S. Cannistra and S. Hankinson (Harvard School of Public Health) on identification and validation of gene and protein biomarkers for outcome, response to chemotherapy and early detection of ovarian cancer using ovarian cancer tumor tissue and serum in microarray and mass spectrometry based experiments. Gene signatures for outcome and chemoresponse were identified and the clinical relevance of specific biomarkers and biological pathways will now be validated to gain insight into the genetic, genomic and proteomic changes that are involved in ovarian cancer development, progression and response to therapy.

Early detection biomarkers for liver cancer
Hepatitis C is the commonest cause of chronic hepatitis in the United States and approximately 20 � 30% of patients with HCV will progress to cirrhosis and advanced fibrosis. Once HCV cirrhosis has developed patients are at risk for liver decompensation and hepatocellular carcinoma (HCC) at a variable rate of 2 � 7% per year. The national incidence of HCC is rising in the US and current screening practices of ultrasonography and tumor markers such as alpha-fetoprotein (AFP) are less than optimal for the early detection of HCC. In collaboration with N. Afdhal the Libermann laboratory utilizes cutting edge proteomics approaches to identify novel serum biomarkers that may be used for the early diagnosis of HCC. The overall goal is to develop better serological screening algorithms for HCC in patients with HCV cirrhosis and chronic liver diseases of any etiology. Biomarkers identified by the proteomic approach will then be validated by multiplex proteomics approaches to determine their potential clinical utility for the early non-invasive diagnosis and screening of HCC in at risk populations.

Molecular mechanisms of anti-cancer drugs
An increasing number of studies have demonstrated that some non-steroidal anti-inflammatory drugs (NSAIDs), at clinically tolerable concentrations, are effective in the treatment of several types of cancer. NSAIDs have been shown to reduce cancer proliferation and induce cancer apoptosis in vitro and in vivo. Nevertheless, the mechanisms of apoptosis induction are poorly understood and more studies are needed to fully elucidate the molecular and biochemical pathways of NSAID-induced apoptosis. The Libermann laboratory has started to dissect the molecular mechanisms involved in the apoptosis induction by various NSAIDs using genomics approaches to identify the biological pathways and genes that mediate the pro-apoptotic effect. The pro-apoptotic cytokine IL-24 and the GADD45 family were identified as critical mediators of NSAID-induced apoptosis in various types of cancer and further studies are elucidating the IL-24 pathway of apoptosis in detail. Understanding the molecular mechanisms involved in apoptosis induction by a panel of NSAIDs will be the first step in a systematic survey of NSAIDs with regard to their abilities to inhibit cancer growth and their particular mechanism of action and will provide opportunities for a rational design of new combination treatment modalities in cancer.

Ets transcription factor translocations and deregulations in prostate cancer and other cancers
The Libermann laboratory has focused for many years on the Ets family of transcription factors and has identified and characterized a set of new, epithelial-specific Ets factors whose roles in prostate cancer and other cancers is being explored.
A major breakthrough for prostate cancer (PCa) was the identification of recurrent fusions between an androgen regulated gene (TMPRSS2) and at least three Ets transcription factors (ERG, ETV4 and ETV1) in up to 80% of primary and metastatic PCa patients, which placed the Ets factors under androgen stimulated regulation of TMPRSS2. Nevertheless, the functional consequences of these translocations for PCa are unknown, necessitating not only the search for drugs that inhibit their activities, but also a systematic approach to define their functions in PCa development and/or progression. The hypothesis is that Ets factor translocations play an essential role in PCa development and progression and a systematic analysis of the biological functions and molecular mechanisms of these Ets factors in PCa will provide new opportunities to target these factors or their affected biological pathways. The Libermann laboratory is trying to understand the role and biological relevance of Ets factor translocations in PCa. The laboratory uses various state-of-the-art technologies including RNA interference, genomics, proteomics, cell based assays and animal models to elucidate the pathophysiological consequences of Ets protein dysregulation in prostate cancer.

Innovative proteomics methods for biomarker discovery and validation
Proteomics approaches for biomarker discovery are notoriously unreliable due to low inter- and intra-experimental reproducibility. Furthermore, the broad dynamic range of protein expression in serum and other bodily fluids or tissues is another major challenge to identify low abundant biomarkers. The Libermann laboratory has initiated a novel multiplexed quantitative proteomics approach to identify and validate biomarkers in plasma and other bodily fluids that combines multidimensional protein and peptide fractionation, immunoaffinity enrichment, isobaric labeling for protein quantitation and mass spectrometry. The goal is to develop a new platform that is able to quantitate multiple biomarkers in multiple samples with high throughput, high sensitivity and high reproducibility.

As director of the BIDMC Genomics Center and director of the Dana Farber/Harvard Cancer Center Proteomics Core we have established major collaborative studies with investigators at all major Harvard associated institutions including among others Lew Cantley, Brad Lowell, Olivier Kocher, Glen Rosen, William Aird, Frank Sellke,Ananth Karumanchi, Aria Olumi, Nezam Afdhal, Peter Oettgen, Alan Rigby, Mary Goldring, Steven Cannistra, Andrew Keates, Alex Toker, Vikas Sukhatme, Terry Strom, Bing Lim, Harold Dvorak, Jeffrey Flier, Jinrong Zhou,and Barbara Kahn at the BIDMC, with Charles Stiles, Jerry Ritz, Ken Anderson and Constantine Mitsiades at DFCI, with Isaac Kohane, Judah Folkman, Asher Schachter and Peter Hauschka at Childrens Hospital, with Susan Hankinson at the Channing LAboratory, and with Alice Brown, Ravi Thadhani, and Michael Detmar at the MGH. As a director of the DF/HCC Cancer Proteomics Core DF/HCC investigators from all major Harvard institutions are performing their cancer proteomics studies at the BIDMC Genomics Center.