Cancer Pharmacology Faculty
Irving J. Bigio, Ph.D.
Professor of Biomedical Engineering, Electrical & Computer Engineering, Physics.
Research Interests: The focus of Dr. Bigio’s research is the development of minimally-invasive diagnostics and therapeutics based on optical and photonic technologies. Ongoing projects include: 1) Development of fiber-optic probes to perform spectroscopic measurements on tissue in vivo and noninvasively to instantly detect early cancer and other pathologies in situ. 2) Fiber-optic probes to measure drug concentrations in tissue, local spatial profiles and local kinetics, noninvasively and in real time. 3) Sensors to monitor the response of tumors to specific treatments. 4) Optical methods for noninvasive imaging of neuronal activation and brain function.
Herbert T. Cohen, M.D.
Associate Professor of Medicine, Section of of Hematology and Medical Oncology, Pathology and Laboratory Medicine, and Pharmacology & Experimental Therapeutics.
Research Interests: Dr. Cohen’s laboratory is addressing the molecular basis of renal cancer, renal cystic disease and renal development and offers special expertise in gene expression mechanisms, signal transduction, protein-protein interactions, transcription factors, and renal epithelial cell biology. The laboratory has identified the first member of new protein family, the Jade family of proteins, on the basis of its interaction with the von Hippel-Lindau tumor suppressor pVHL. pVHL protein is a key component of the cellular oxygen-sensing system. VHL is also the major renal cancer gene in adults. Jade-1 is a novel, growth suppressive plant homeodomain transcription factor that is the first protein found to be stabilized by pVHL. Jade-1 is also a ubiquitin ligase and key component of histone acetylation complexes. Interestingly, Jade-1 is stabilized by VHL protein in a manner that correlates with risk of renal manifestations in von Hippel-Lindau disease, which includes a cystic renal disease phenotype. A wider role for Jade-1 in renal cyst formation was therefore sought. Jade-1 is regulated by the product of the major gene for autosomal dominant polycystic kidney disease (ADPKD), polycystin-1, in a manner that is also disease relevant and physiologic. Importantly, Jade-1 serves as a critical ubiquitin ligase for the oncoprotein beta-catenin, which also plays key roles in renal cancer, renal cyst formation and renal development. This work identifies the canonical Wnt signaling pathway and beta-catenin as potential pharmacologic targets in these disorders, and this possibility will be explored. By controlling gene transcription and beta-catenin ubiquitination, Jade-1 and related family members are likely to be particularly important in many contexts.
Geoffrey M. Cooper, Ph.D.
Professor of Biology, Associate Dean of the Faculty, Natural Sciences.
Research Interests: Dr. Cooper’s laboratory studies the roles of proto-oncogene proteins in the signal transduction pathways that control proliferation and survival of mammalian cells. Current research is focused on the mechanisms by which the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling pathway regulates cell proliferation and survival. The targets of PI 3-kinase/Akt signaling include the Bcl-2 family member Bad, a variety of transcription factors, and the protein kinase GSK-3. Substrates of GSK-3 also include a variety of transcription factors, as well as the translation initiation factor eIF2B. Their principal effort is focused on transcriptional regulation, using global gene expression profiling to identify genes that are regulated by PI 3-kinase/Akt/GSK-3 signaling. They have combined these results with computational prediction of transcription factor binding sites, chromatin immunoprecipitation, and RNA interference assays to identify transcription factors that are targeted by the PI 3-kinase/Akt/GSK3 pathway. These studies have identified a network of Myc superfamily transcription factors which function coordinately with Foxo to regulate PI 3-kinase-dependent genes that are critical to cell proliferation and survival. They are currently investigating the relationship of the p53 tumor suppressor to this transcriptional regulatory network and the role of this transcriptional regulation in cancer cells.
Rutao Cui, M.D., Ph.D. Associate Professor of Pharmacology and Dermatology, and Member, The Cancer Center; Director, The Laboratory of Skin Cancer Therapeutics (LSCT).
Research Interests: Our primary research interests include: understanding molecular mechanisms of melanoma development, defining the molecular effects of UVB radiation on melanocyte growth and differentiation, and developing murine genetic models for human melanoma.
Gerald Denis, Ph.D.
Associate Professor of Medicine and Pharmacology, Cancer Research Center.
Research Interests: Our laboratory is investigating transcriptional control of the cell cycle and how the cell cycle is perturbed in cancer. We are specifically interested in the double bromodomain protein Brd2, which is a transcriptional co-activator of the cyclin A gene. Levels of cyclin A correlate closely with DNA synthesis during the S phase of the cell cycle; S phase entry is often earlier in tumor cells. Brd2 binds to acetylated histones through its bromodomains, associates with the SWI/SNF chromatin remodeling complex, then recruits transcription factors and co-activators to cyclin A promoter chromatin to regulate transcription. In transgenic mice that constitutively express Brd2 in B cells, cyclin A is upregulated and the cell cycle is destabilized, leading to an aggressive non-Hodgkin’s lymphoma. Genome-wide transcriptional profiling of this malignancy revealed that its molecular signature most closely resembles the ‘activated B cell’ form of non-Hodgkin’s lymphoma in humans. Therefore, this mouse represents a new model for diffuse large B cell lymphoma; we now suspect that it recapitulates some aspects of Richter’s transformation of B cell chronic lymphocytic leukemia into a much more aggressive type of B cell lymphoma that is often fatal, and which is poorly understood in human cases. We are identifying new drug targets and developing original pharmacologic approaches for its treatment. We have recently reconstituted the murine immune system with hematopoietic stem cells transduced with lentiviruses for Brd2 overexpression or shRNA knockdown, and learned that Brd2 expression causes a dramatic expansion of the B cell compartment in vivo and B cell hypersensitivity to mitogenic stimulation in vitro, nicely recapitulating the transgenic model. On the other hand, Brd2 knockdown completely blocks lymphoid development, suggesting that this factor plays a crucial and fundamental role in normal immune biology and the processes of adaptive immunity.
Isabel Dominguez, Ph.D.
Research Assistant Professor, Hematology & Medical Oncology.
Research Interests: The canonical Wnt pathway is essential for embryonic development and it is dysregulated in cancers. Our long-term goal is to characterize the mechanism of Wnt signaling to understand the role of the Wnt pathway in development and cancer. We are focusing our studies on the function, regulation and mechanism of action of two components of the Wnt pathway: the serine-threonine kinases CK2 and GSK3beta. We are using Xenopus frog embryos and cell culture to understand the molecular mechanism of action of CK2 and GSK3beta in Wnt signaling. Understanding how the Wnt pathway is normally activated is a prerequisite to understand its dysregulation displayed in cancers. Utilizing Xenopus embryos, we have shown that CK2 is sufficient and necessary for canonical Wnt signaling. Ongoing studies focus in determining the mechanism of regulation of Wnt signaling by CK2, and in the development and testing of novel CK2 inhibitors in vivo in Xenopus and in vitro in breast and colon tumor cell lines.
Hui Feng, M.D., Ph.D.
Associate Professor of Pharmacology and Medicine, Section of Hematology and Medical Oncology
Research Interests: Dr. Feng is Director of the Laboratory of Zebrafish Genetics and Cancer Therapeutics. Dr. Feng’s research interests focus on identifying novel genes and pathways that are essential for MYC-related tumor transformation and progression, particularly for T-Lymphoblastic Lymphoma/Leukemia and Neuroblastoma. The research strategy of Dr. Feng’s research is to combine the analysis of human cancer genomic databases with the genetic and imaging capacities of the zebrafish system.
Current research areas in Dr. Feng’s laboratory include:
1) To determine the molecular mechanisms underlying tumor cell intravasation and tumor progression.
2) To test the identified genes’ therapeutic potential in treating MYC-related cancers and to characterize their molecular relevance to MYC.
3) To identify additional genes and pathways that, when mutated, delay the initiation and progression of MYC-related cancers.
The long-term goal of Dr. Feng’s research is to discover novel molecular therapies to target critical components of MYC-driven oncogenic pathways, thus providing treatment alternatives that are more specific and less toxic.
Rachel L. Flynn, Ph.D.
Assistant Professor of Pharmacology and Medicine, Section of Hematology and Medical Oncology
Research Interests:The focus of the Laboratory of Genomic stability and Cancer Therapeutics is to understand the mechanisms regulating mammalian telomere maintenance and to understand how defects in this process contribute to premature aging and cancer progression. The hope is that these studies will allow us to gain the mechanistic insight necessary to define novel targets and/or strategies in the treatment of human disease.
In my lab we use a combination of biochemical and cell biological approaches to study the function of mammalian telomeres. Telomeres cap the ends of linear chromosomes and provide a molecular barrier for the human genome. Following each cell division, progressive telomere shortening erodes that barrier and compromises the stability of the genome. Critically short, or dysfunctional telomeres induce replicative senescence and/or cell death and ultimately, lead to cellular aging. Cancer cells, however, overcome the replicative senescence associated with critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme telomerase or activation of the Alternative Lengthening of Telomeres (ALT) pathway accounts for cellular immortalization in the majority of all human cancers. Clinical trials are currently underway to test the efficacy of telomerase inhibitors in the treatment of telomerase-positive cancers; however, there are no known treatments for ALT-positive cancers. By gaining a better mechanistic understanding of how normal telomeres are maintained, and how dysfunctional telomeres bypass replicative senescence, we hope to identify novel therapeutic approaches in the treatment of both premature aging syndromes and cancer.
Neil J. Ganem, Ph.D.
Assistant Professor of Pharmacology and Medicine, Section of Hematology and Medical Oncology
Research Interests:Dr. Ganem’s laboratory uses a combination of high-resolution microscopy, genome-wide RNAi screening, cell biology, and bioinformatics to study the causes and consequences of genome instability in human cancer. Dr. Ganem’s lab seeks to define the tumor suppression mechanisms that limit the proliferation of highly abnormal aneuploid cells, as well as to identify the common genetic adaptations made by cancer cells to overcome these growth barriers.
Current projects in the lab are aimed at:
1) Identifying the cellular defects that trigger activation of the Hippo tumor suppressor pathway in aneuploid cells.
2) Examining the consequences of oncogenic signaling on mitotic fidelity and chromosome segregation.
3) Characterizing novel regulators of growth factor signaling and the Hippo pathway, as uncovered by a functional RNAi screen.
Thomas D. Gilmore, Ph.D.
Professor of Biology.
Research Interests: Research in the Gilmore laboratory is primarily directed at understanding the role of NF-kB transcription factors in human leukemia and lymphoma. In recent studies, we have been using a variety of cell-based systems to understand the genes and signaling pathways that are perturbed in different subtypes of human diffuse large B-cell lymphoma. In addition, we have an ongoing collaboration with Dr John Porco (Chemistry Department, Boston University) to identify and characterize natural product-based inhibitors of NF-kB signaling for biological and therapeutic use. Finally, we have also been characterizing the evolutionary origins of NF-kB signaling, using sea anemone and coral model systems, and seek to identify how environmental factors influence NF-kB signaling in these simple marine organisms.
Mark W. Grinstaff, Ph.D.
Professor of Biomedical Engineering, Chemistry and Ophthalmology.
Research Interests: The Grinstaff group pursues highly interdisciplinary research in the areas of biomedical engineering and macromolecular chemistry. In one current research project, his group is designing, synthesizing, and characterizing novel dendrimers, termed “biodendrimers,” for tissue engineering and biotechnological applications. These novel biomaterials are being evaluated for the repair of corneal lacerations, for the delivery of anti-cancer drugs, for the delivery of DNA, and as temporary biodegradable scaffolds for cartilage repair. In a second project, his group is creating novel polymeric coatings termed “interfacial biomaterials” that control biology on plastic, metal, and ceramic surfaces.
Adam Lerner, M.D.
Associate Professor of Medicine and Pathology.
Research Interests: Dr. Lerner studies the potential use of cyclic nucleotide phosphodiesterase inhibitors as novel therapeutic agents for the treatment of human lymphoid malignancies. He has found that PDE4 inhibitors not only induce apoptosis in primary human chronic lymphocytic leukemia (B-CLL) cells but also augment the ability of glucocorticoids to induce B-CLL apoptosis, and he is elucidating the mechanisms of these phenomena. He also studies AND-34, an SH2 domain-containing protein that he has shown binds to the focal adhesion protein p130Cas. His current work focuses on understanding the signaling pathway by which AND-34 over-expression induces anti-estrogen resistance in human breast cancer cells.
Maria V. Panchenko, Ph.D.
Assistant Professor, Pathology & Laboratory Medicine.
Research Interests: Multicellular organisms consist of various highly specialized cells that are known to express different sets of specific proteins and perform diverse functions. How do cells with identical genetic information feature a variety of phenotypes? An important mechanism accounting for such differences operates on an epigenetic level and utilizes chromatin structure. It has become clear that proper packaging of DNA strands is not the only function of chromatin. By virtue of dynamic post-translational modifications and protein-protein interactions, chromatin can regulate DNA metabolism and transcription. The proper functioning of this chromatin-mediated signal transduction network is required for DNA maintenance and integrity, whereas defects are known to result in inappropriate cell division, DNA damage and instability leading to various diseases. Our long-term goal is to determine mechanisms and roles of chromatin and factor modifications in regulation of DNA replication and transcription.
Anurag Singh, Ph.D.
Assistant Professor of Pharmacology and Medicine, Section of Hematology and Medical Oncology
Research Interests: Our lab studies global mechanisms underlying oncogene-driven cancer progression. We use state of the art technologies, including gene expression profiling and RNAi-based screening. Subsequently, through application of functional genomics and systems pharmacology we identify novel oncogenic signaling networks that can be exploited for therapeutic target identification and validation. Current research in the lab seeks to identify KRAS-regulated signaling networks and to use this information to provide detailed mechanistic insight into KRAS-driven tumor progression. We are also interested in contextual variability in these networks based on tissue lineage and genetic background. Through this approach, we have identified a number of attractive candidate therapeutic targets that can be antagonized to promote cancer cell death in a context-dependent manner, such as the kinase TAK1 in colon cancers. Since effective pharmacological targeting of the mutant KRAS protein has proven challenging, a key translational goal is to identify clinically efficacious small molecule inhibitors against critical nodes in oncogenic KRAS signaling networks to provide benefit for patients with highly aggressive KRAS-driven cancers.
Sam Thiagalingam, Ph.D.
Associate Professor of Medicine, Genetics & Genomics and Pathology & Laboratory Medicine.
Research Interests: Our major research focus is on the use cancer genomics, employing primarily breast, colon and lung cancers as model systems, to shed light on genomic instability, genetic and epigenetic aberrations and metastasis of cancer. Furthermore, we are also interested in unravelling the role of the epigenome in the pathogenesis of major psychiatric disorders such as schizophrenia and bipolar disorder. Our pioneering studies showed that SMAD4 is the major target tumor suppressor gene localized to the minimally lost region on chromosome 18q. Currently, we are testing the hypothesis that the direct/indirect inactivation of Smad4 is a major switch for benign to metastatic form of colon cancer. TGF-beta levels are increased in advanced breast cancers and believed to induce epithelial mesenchymal transition (EMT), a critical process during cancer progression. We exploited a model system and found that TGF-beta regulates promoter DNA methylation of genes during the acquisition of the EMT phenotype. We are extending these studies to examine other modes of epigenetic regulation and the molecular basis of these effects. We have also proposed a simplified scheme to explain the complexity in cancer progression as alternations that accrue in a series of a cascade of sub-network modules and elicited as events in a multi-modular molecular network (MMMN) of cancer progression.
David Waxman, Ph.D.
Professor of Biology and Medicine.
Research Interests: Humans, like other mammals, are exposed to a large number of toxic foreign chemicals, many of which are lipophilic and have a tendency to persist in fatty tissues. In response to this environmental challenge, mammals have evolved a large number of genes which encode cytochromes P450 and other enzymes that oxygenate lipophilic foreign compounds. Expression of these genes is controlled by a complex array of molecular regulatory circuits that respond to varying physiological conditions and changes in hormonal and environmental stimuli. In addition to metabolizing foreign chemicals, P450 enzymes hydroxylate physiological substrates, such as steroid hormones, arachidonic acid and cholesterol, which both compete with drug and other foreign chemical substrates and can regulate P450 metabolism through the modulation of P450 gene expression.