Cancer Chemical Biology and Metabolism Training Program – Mentors

Dr. Agar’s lab applies state-of-the-art mass spectrometry and optical imaging technologies for examining drug uptake and metabolism in tumors with unprecedented resolution.

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Dr. Agudo has core research interests in identifying factors that control immune evasion of stem cells and cancer stem cells, and translating these insights into improved immunotherapy.

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Dr. Arthanari has been developing advanced nuclear magnetic resonance (NMR) spectroscopy and other biophysical methods to characterize critical interactions between transcription factors and the general transcriptional machinery known to be dysregulated in cancer.

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Dr. Blacklow’s investigates the structure-function relationships in proteins of the LDL receptor family and in human homologues of Drosophila Notch. He and his trainees have contributed key structural and mechanistic insights into the molecular logic of ligand binding and release by the LDL receptor. They have also used structural, biochemical and cell-based approaches to elucidate how Notch receptors are maintained in a resting conformation prior to ligand activation, and how Notch transcription complexes assemble on cognate DNA. Future trainees will carry out studies designed to uncover how Notch receptors recognize their ligands, to determine how ligand engagement leads to receptor activation, to elucidate how leukemia-associated mutations bypass the normal restraints on activation.

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Dr. Brown and his trainees are interested in the molecular understanding of the action of steroid hormone receptors and their role in human cancer. They were the first to identify the p160 class of steroid receptor coactivators and to show that coregulators play an important role in the tissue and promoter selective action of steroid hormone receptors and their ligands. This work has important implications for understanding the mechanism of action of selective steroid receptor modulators such as SERMs. They were the first to define steroid receptor binding sites on a genome-wide scale using a combination of chromatin immunoprecipitation and tiled microarrays, ChIP-chip. They are currently using ChIP-chip and ChIP-seq to define the epigenomic and cistromic changes that underlie the development of hormone independent cancer.

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Sara Burhlage’s lab is developing chemical biology strategies to study and target deubiquitinating enzymes (DUBs), including selective inhibitors of USP7 and USP1016,17. Dr. Buhrlage has ongoing collaborations with Dr. Jänne on chemical targeting of DUBs that stabilize mutant of EGFR; with Dr. Segal on novel therapeutic strategies in pediatric gliomas; with Dr. Stegmaier on USP7 inhibition as a novel treatment strategy for Ewing Sarcoma; and with Dr. Kaelin on targeting DUBs that stabilize cancer initiating transcription factors.

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Dr. Chouchani’s research interests center on identifying molecular targets of metabolic redox signaling especially in the context of mitochondrial control of physiologic processing, and using this information to develop targeted therapeutic strategies.

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Nika Danial’s lab studies the molecular mechanisms and functional consequences of metabolic fuel choice in cell fate and function. This line of investigation has led to the discovery of biochemical links between glucose metabolism and cell survival pathways, as well as metabolic control of normal and tumorigenic growth. More recently, the lab has begun to characterize the molecular determinants of mitochondrial specializations, nutrient preferences, and metabolic heterogeneity in B-cell receptor (BCR)-dependent vs independent subtypes of Diffuse Large B-Cell Lymphoma (DLBCL). This research has revealed that BCR-DLBCLs have Warburg-type metabolic characteristics and rely on glycolysis, while OxPhos-DLBCLs rely on mitochondrial fatty acid oxidation for survival independent of BCR signaling. Importantly, these metabolic distinctions are associated with DLBCL subtype-selective targetable vulnerabilities. Additional efforts are focused on understanding the relevance of OxPhos-type metabolic pathways as a resistance mechanism to small molecule inhibitors of BCR signaling. Dr. Danial has long-standing collaborations with Drs. Shipp and Walensky.

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Dr. Dougan’s lab focuses on mouse models of immunotherapy in pancreatic cancer.

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Benjamin Ebert’s lab studies the molecular basis and treatment of hematologic malignancies, with a particular focus on myelodysplastic syndromes (MDS). The Ebert lab elucidated the mechanism of action of lenalidomide and related drugs, showing that they exert their effects by modulating the function of an E3 ubiquitin ligase, inducing drug-dependent degradation of specific substrates that are essential for the survival of multiple myeloma and MDS cells. This represents the first class of drugs that bind and modulate the function of an E3 ubiquitin ligase. Dr. Ebert has ongoing collaborations with Drs. Fischer, Qi and Steamier.

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Dr. Eck and his trainees define molecular interactions that regulate intracellular signaling and rearrangement of the actin cytoskeleton. They use biochemical and structural methods (primarily X-ray crystallography) to understand how complex multi-domain proteins are inhibited and activated by their networks of interactions within the cell. They are especially interested in determining the structure of aberrant signaling proteins and complexes that underlie cancer, and in using structural approaches to facilitate development of anti-cancer drugs. Trainees in the group learn to apply biophysical and biochemical methods to problems of central importance in cancer biology.

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Eric Fischer’s lab focuses on the role of ubiquitination in development and cancer, with special focus on developing novel pharmacologic strategies to target the ubiquitin machinery. The lab combines structural biology, cell biology, proteomics and chemical biology to address the molecular workings of ubiquitin E3 ligase complexes such as CRL4CRBN, and has developed novel mass spectrometry approaches for proteome-wide E3 ligase screens to enable rapid development of degrader molecules (PROTACs). Dr. Fischer collaborates closely with Drs. Gray, Buhrlage, Ebert, Jänne, Kaelin, Livingston, Stegmaier, Qi, Chouchani and Kim. Drs. Chouchani is a co-mentor on this training grant application.

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Dr. Gray and his trainees are interested in developing small molecule inhibitors with selectivity towards a desired wild-type or drug-resistant kinase. They use these kinase inhibitors to dissect the molecular wiring of signaling pathways and to identify the biological targets for small molecules of unknown mechanism. They rely on synthetic organic chemistry to make combinatorial gene-family targeted libraries. They also perform medicinal chemistry to improve the potency, cellular activity, specificity, stability and pharmacological properties of their initial “lead” compounds. Dr. Gray’s research team has produced many ‘first-in-class’ chemical probes that have made freely available and are widely used by the research community including inhibitors of mTor (Torins), ALK (TAE684), JNK (JNK-IN-8) and CDK7 (THZ1). In addition, Dr. Gray’s research team has contributed to one FDA approved drug, ceritinib, an inhibitor of EML4-ALK for the treatment of non-small cell lung cancer.

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Dr. Haigis’ lab has a long-standing interest in understanding the mechanisms underlying distinct and context-specific functions of mutant K-Ras alleles and allele-specific therapeutic targeting mechanisms.

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Pasi Jänne’s lab has identified oncogenic alterations in lung cancer, including EGFR mutations, and uncovered the mechanism of acquired resistance to EGFR inhibitors44. These findings have been translated into clinical trials and approved therapies. Other studies in ALK-rearranged NSCLC have resulted in clinical trials of ALK inhibitors, as well as investigation of acquired resistance mechanisms. Dr. Jänne has ongoing collaborations with Drs. Eck, Gray, Meyerson, Fischer, Buhrlage and Walensky.

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Cigall Kadoch’s lab focuses on dissecting the mechanism and structures of ATP-dependent chromatin remodeling complexes in general and the mammalian SWI/SNF (BAF) ATP-dependent complex in particular. BAF complexes can both suppress or promote tumorigenic growth, and the Kadoch lab is employing a range of genetic, molecular, structural and chemical biology strategies to dissect these functions, with special focus on synovial sarcoma and malignant rhabdoid tumors.

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Dr. Kaelin’s trainees study the functions of human tumor suppressor proteins, including the von Hippel-Lindau protein (pVHL), the retinoblastoma protein (pRB), and p53. Their work on pVHL has provided new insights into the pathogenesis of kidney cancer as well as insights into the molecular basis for oxygen sensing in mammals. Trainees in the Kaelin laboratory are exposed to a variety of molecular and cell biologic approaches to studying tumor suppressor function with emphasis on integrating both biochemical and genetic data, including genetic data emanating from high throughput RNA interference screens in mammalian cells.

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Dr. Kim is developing new proximity-based labeling methodologies and high throughput mass spectrometry-based platforms for the discovery of small molecule modulators of protein-protein interactions in cancer.

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Dr. Livingston and his trainees investigate how the products of the BRCA1 and 2 genes elicit a state of mammary and ovarian tumor suppression. Both genes promote, at least in part, the maintenance of genome integrity through error-free repair of double strand DNA breaks. In addition, BRCA1 controls the development of functioning mitotic spindle poles and of normal procentrioles. They have recently made an unexpected finding, that BRCA1 is engaged in another form of genome integrity maintenance, i.e. the repair of bulky adduct-driven genome damage, of which estrogen metabolite-driven damage is an example. Estrogen metabolite-driven DNA damage is largely experienced in female somatic cells, and they are exploring the possibility that a failure of its repair contributes to the fact that, in BRCA1 mutation-bearing families, only women develop BRCA1 mutation-driven cancer.

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Dr. Losman employs a wide range of techniques, including mouse models and high-throughput CRISPR-Cas9 screening to gain mechanistic insights into how leukemia cell metabolism contributes to leukemogenesis.

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Dr. Marto’s lab develops and applies highly quantitative mass spectrometry approaches to understand the functional proteome in cancer, including post-translational modifications, and to study protein targets of small molecule chemical probes.

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Dr. Meyerson’s trainees work on fundamental problems of DNA structure that underlie human cancers. They apply genome-scale approaches to discover chromosomal alterations and cancer-causing mutations. They developed the use of single-nucleotide polymorphism (SNP) arrays to analyze loss-of-heterozygosity (LOH) in human cancer samples and are now systematically surveying the patterns of LOH and copy number change in human lung carcinomas. Together with the Broad Institute, the Meyerson group is re-sequencing the human genome to identify oncogenic mutations in cancer, as part of The Cancer Genome Atlas and other large-scale projects. They have identified frequent mutations in the EGFR receptor tyrosine kinase gene in lung adenocarcinomas. Notably, the EGFR mutations are tightly associated with clinical response to gefitinib, an EGFR kinase inhibitor.

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Research in the Polyak lab is dedicated to the molecular analysis of human breast cancer. Their goal is to identify differences between normal and cancerous breast tissue, determine the consequences of these differences, and use this information to improve the clinical management of breast cancer patients. They have devoted much effort to develop new technologies that allow for the comprehensive molecular profiling of cells isolated from primary human tissue samples. Their main interests are to understand the role of microenvironmental changes in breast tumor progression and mechanisms that underlie intra-tumor heterogeneity including genetic, epigenetic, and nonhereditary changes.

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Dr. Puigserver and his trainees are interested in the molecular mechanisms by which mammalian cells sense, communicate and respond to nutrients, in particular, how cancer cells use mitochondrial-based metabolic pathways to maintain cell survival and division. Dr. Puigserver investigates the genetic factors and metabolic components necessary for tumor progression, and has shown recently melanoma cells overexpress the transcriptional cofactor PGC-1α, exhibit increased mitochondrial energy metabolism and reactive oxygen species. These metabolic capacities allow this subset of tumors to increase their rate of survival under oxidative stress.

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Jun Qi’s lab is combining synthetic chemistry with cellular biology to develop small molecule tool compounds targeting epigenetics and gene transcription. The lab has developed a series of inhibitors and tool compound for epigenetic readers (bromodomains; JQ1), writers (methyltransferases; JQEZ5), and erasers (deacetylases; WT161). Notably one of these inhibitors, a derivative of JQ1, is being investigated in the clinic. Dr. Qi has active collaborations with Dr. Fischer, Zhao, and Roberts, and has joint grants with Drs. Ebert, and Stegmaier.

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The first definitive studies on phosphoinositide 3 kinase (PI3K) were done by the Roberts lab in collaboration with Lewis Cantley. Due to the importance of PI3K in human cancer, the lab has gone on to study it in detail, generating conditional knockout mice for the commonly expressed catalytic subunits of PI3K. While the end goal of these studies is to determine which isoforms to target in specific cancers, a new understanding of a surprising functional specialization in the two enzymes (termed p110a and p110b) has emerged: p110a plays the major role in receptor tyrosine kinase and ras signaling, while p110b plays the major part in GPCR signaling and in tumors arising from PTEN loss. Their research on PI3K has helped facilitate the development of PI3K inhibitors currently being tested in the clinic.

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Dr. Segal’s trainees study cell proliferation and death signals in the developing nervous system, and in brain tumors. We have focused on survival pathways that are activated by Trk receptor tyrosine kinases, including PI3 kinase/Akt and regulation of bcl2 family members. A second focus has been on the Sonic Hedgehog pathway in proliferation. Understanding and targeting these neural survival and proliferative pathways provide new approaches to targeted therapy of brain tumors.

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William Shih’s lab has been at the forefront of structural DNA nanotechnology as one of the most promising strategies for self-assembly-based nanofabrication. His lab has developed nanodevices made of DNA that self-assemble and can be programmed to move and change shape on demand. In contrast to existing nanotechnologies, these programmable nanodevices are highly suitable for medical applications because DNA is both biocompatible and biodegradable. The potential for these structures to serve as carriers of cancer drugs deep in the body is being actively investigated. Dr. Shih is currently collaborating with Dr. Gaudet to study dynamics of TNF receptor multimerization as a driver of downstream signaling.

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Margaret Shipp’s lab is focused on molecular signatures of aggressive B-cell malignancies and associated rational therapeutic targets. This research has led to the identification of genetic bases for immune evasion in classical Hodgkin lymphoma involving PD-L1/L2 amplification. These findings have important implications for predicting and managing sensitivity and resistance to PD-1 blockade therapy. In other work, the Shipp lab has carried out comprehensive genetic analyses that led to molecular classification of DLBCL. These discoveries identified BCR-independent OxPhos-DLBCLs, which formed the basis of subsequent collaboration with Dr. Danial on comprehensive characterization of functional metabolic signatures and metabolic heterogeneity in DLBCL subtypes, as well as the metabolic basis of resistance to B-cell receptor inhibition. Dr. Shipp has also been involved in multi-PI grants with Drs. Danial and Walensky.

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Dr. Sicinski’s research goal is to understand the role of cell cycle machinery in development and in cancer. He and his trainees address this issue by generating knockout or ‘knockin’ mouse strains lacking particular cell cycle genes, in particular, cyclins. They use these mice and cells derived from them for analyses at the organismal, cellular and molecular levels. They are currently analyzing cell cycle machinery in stem cells, and are also developing novel strains of mice that allow proteomic approaches to study the in vivo functions of cyclins in various tissues of the living animal.

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Dr. Spiegelman’s lab is focused on the control of energy homeostasis as it relates to metabolic disease and to cancer. It has been appreciated for 50 years that tumors are more dependent on glycolytic metabolism than normal tissues. They have identified several of the molecules that control the switch between oxidative metabolism and glycolysis, including PGC-1α and PRDM16. PGC-1α controls both mitochondrial biogenesis and angiogenesis in a novel, non-HIF dependent pathway. They are currently interested in finding molecules, both small molecules and polypeptides that control these pathways. Such agents will then be tested for their ability to control obesity, diabetes and the initiation and growth of cancers.

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Kimberley Stegmaier’s lab focuses on the identification of new cancer targets and small-molecule therapeutic leads in pediatric oncology using a multi-disciplinary approach based on genomics, chemical biology, and epigenetics. Specific targets that are being currently pursued are EWS-FLI1, CDK4/CCND1 and FAK in Ewing sarcoma and MYCN in neuroblastoma. More recently, the lab has investigated metabolic vulnerabilities in acute myeloid leukemia with specific focus on creatine kinase and mitochondrial one-carbon metabolism. Dr. Stegmaier has active collaborations with Drs. Gray, Walensky, Fischer, Ebert, Qi, Blacklow, and Buhrlage.

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Dr. Walensky and his trainees focus on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Utilizing hydrocarbon stapling, his group synthesized a panel of pro-apoptotic peptides, these peptides had improved pharmacological properties, and were able to kill leukemia cells. In ongoing studies, Dr. Walensky applies new peptide-stapling strategies to produce many cancer biology discovery tools to deactivate aberrant signaling pathways in a variety of human tumors.

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Dr. Wu’s lab has done pioneering work in cancer immunology that has clearly highlighted neoantigens as a novel class of cancer targets for immunotherapy.

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Dr. Zhao’s research program is focused on the area of how kinases, particularly the PI3K family control malignant transformation. Integrating molecular biology, tissue engineering and novel mouse models of cancer, Dr. Zhao and her trainees study oncogenic alterations in PI3K, and have shown there are distinct roles to the two isoforms of PI3K, with PI3Kβ driving tumor formation in PTE-null prostate tumors. This works provided the foundation for a new field of targeting PI3K isoforms in cancer.

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