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2011 Innovative Research Grant 6-Month Progress Reports

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Targeting MLL in Acute Myeloid Leukemia

Yali Dou, Ph.D., University of Michigan

To inhibit MLL activity, Dr. Dou’s laboratory has:

  • Collaborated with Dr. Shaomeng Wang’s laboratory at the University of Michigan to optimize a compound that disrupts the MLL protein complex.
  • The compound binds to WDR5 (WD-repeat protein-5), which is a component of the MLL protein complex.
  • Previous WDR5 inhibitors had low cell permeability; optimized compounds have higher cell permeability and are therefore more potent.
  • The compounds have been tested in a leukemia cell line and in myeloblasts.
  • Employed an NMR approach using a fragment library to investigate protein-protein interactions within the MLL protein complex.
  • 1000 fragments have been screened for interactions with the MLL protein complex.
  • In ongoing studies, Dr. Dou’s laboratory will work to identify the specific binding sites for the interactions.

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Targeting Genetic and Metabolic Networks in T-ALL

Adolfo A. Ferrando, M.D., Ph.D., Columbia University

To identify key genes that are essential for the growth and survival of T‐ALL cells, Dr. Ferrando’s laboratory has:

  • Analyzed and characterized a panel of human T-cell leukemia samples.
  • Based on genomic signatures, two subtypes of T-cell ALL have been identified.
  • Mutations in the ETV6 tumor suppressor gene are present in 25% of T-cell leukemias.
  • Utilized a systems biology approach to determine T-ALL “interactomes” or molecular interactions that occur specifically in T-ALL cells.
  • The tumor suppressor gene RUNX1 was found to contribute to the development of T-cell ALL.
  • Dr. Ferrando’s laboratory is beginning to employ metabolic profiling of tumors.

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Targeting Protein Quality Control for Cancer Therapy

Estela Jacinto, Ph.D., University of Medicine & Dentistry of New Jersey - Robert Wood Johnson Medical School

Dr. Jacinto’s laboratory is working to confirm the hypothesis that mTORC2 plays a role in translation and processing of ErbB1 and ErbB2 in cell models.

  • Models that genetically disrupt mTORC2:
  • Using murine embryonic fibroblasts (MEFs) that have genetically disrupted mTORC2, the lab has demonstrated that TORC2 is critical for synthesizing normal amounts of ErbB1.
  • Using another MEF cell line that inhibits the formation of the mTORC2 complex (SIN1 knockout cells), the lab also confirmed that mTORC2 is critical for ErbB expression and normal levels of glycosylation.
  • Wild-type MEFs and breast cancer cell lines treated with mTOR inhibitors:
  • ErbB2 expression (translation) is not altered in wild-type MEFs treated with an mTOR inhibitor (Torin 1).
  • ErbB1 and ErbB2 expression is not altered upon mTOR inhibition in the breast cancer cell lines tested. The lab is expanding to test other cell lines.
  • It is hypothesized that other signaling pathways might compensate for the mTOR inhibition in these models.

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Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment

Mei Kong, Ph.D., City of Hope

To determine the molecular basis of tumor cell survival under glutamine deprivation in order to develop novel drugs targeting this pathway, Dr. Kong’s Laboratory has:

  • Demonstrated that, among 16 different PP2A regulatory proteins, only the B55α subunit is induced upon glutamine deprivation.
  • This induction is specific to glutamine deprivation.
  • Initial results indicate that increased reactive oxygen species due to glutamine deprivation contribute to B55α induction.
  • Demonstrated that suppression of B55α expression impairs cancer cell viability in the presence of low glutamine.

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Chimeric RNAs Generated by Trans-Splicing and Their Implications in Cancer

Hui Li, Ph.D, University of Virginia

To better characterize the trans-splicing process, and translate our knowledge into better diagnostic and therapeutic approaches, Dr. Li’s Laboratory has:

  • Detected a gene fusion product, PAX3-FKHR, which is characteristic for alveolar rhabdomyosarcoma, which is produced transiently during the muscle differentiation by using an adult stem cell differentiation system to induce cells into to many distinguishable lineages at many time points.
  • Found that the expression of the newly identified fusion, SLC45A3-ELK4, correlates with prostate cancer progression and it plays important roles in prostate cancer cell growth.
  • Generated a specific antibody to JAZF1-JJAZ1 fusion that only recognizes the fusion product.
  • Using this method, Dr. Li found that the fusion protein is localized to a specific compartment inside the cellular nucleus called PML nuclear body that is known to suppress tumor growth by inducing cell death.

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Exome sequencing of melanomas with acquired resistance to BRAF inhibitors

Roger Lo, M.D., Ph.D., Santa Monica-UCLA Medical Center and Orthopaedic Hospital

To discover genetic alterations that cause disease progression of initially B-RAF inhibitor- sensitive human metastatic melanomas, Dr. Lo’s Laboratory has:

  • Made the unexpected observation that MEK1 mutations, proposed previously as a mechanism of acquired B-RAF inhibitor (B-RAFi) resistance, cannot account for acquired resistance since these mutations are found prior to B-RAFi therapy. This discovery of B-RAF/MEK1 double mutant melanomas and its implications for B-RAF targeted therapy has been submitted for publication.
  • Published work describing splicing isoforms of BRAF (V600E) that dimerize in a RAS independent manner, and showing that these may be mediating acquired resistance to RAF inhibitors.
  • Discovered, using a new type of analysis called ExomCNV, a gene amplification that mediates acquired resistance in melanoma. This discovery has also been submitted for publication.
  • Completed 20 whole exome sequences from six patients (each set consists of a normal tissue, a baseline pretreatment tumor, and a disease progression (DP), on- therapy tumor or tumors in some patients), with one patient contributing 3 DP tumors.

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Identification and Targeting of Novel Rearrangements in High-Risk ALL

Charles G. Mullighan, MBBS(Hons), MSc, MD., St. Jude Children’s Research Hospital

Dr. Mullighan is using genomic profiling to identify novel targets of rearrangement in high- risk ALL, and to determine the frequency and spectrum of these alterations.

  • They have used a variety of complementary approaches to screen over 500 cases of ALL and have identified the genetic bases of approximately 70% of childhood cases of BCR-ABL1-like ALL.
  • They are continuing to identify the genetic basis of additional BCR-ABL1-like ALL cases using advanced (next-generation) sequencing technology, including transcriptome sequencing and exome sequencing.

Dr. Mullighan is also developing experimental models of B-progenitor ALL that recapitulate the genetic alterations identified above and enable testing of targeted therapeutic agents.

  • Using laboratory cell lines, Dr. Mullighan’s laboratory has shown that several of these alterations accelerate cell growth and activate downstream signaling pathways. In addition, alterations such as EBF1-PDGFRB induce leukemia when expressed in mouse bone marrow cells.
  • They have also developed xenograft models in which human leukemia cells are grown in immunodeficient mice. Importantly, growth of these cell lines is inhibited by several TKIs including include imatinib (Gleevec), dasatinib (Sprycel) and ruxolitinib (Jakafi).

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A Systems Approach to Understanding Tumor Specific Drug Response

Dana Pe’er, Ph.D., Columbia University Medical Center

The first 6 months of the project was primarily focused on collecting the first phase of necessary data described in the proposal. Dr. Pe’er’s laboratory has:

  • Characterized the transcriptional and phenotypic response following pathway inhibition of MAPK, AKT and their combination in 12 melanoma cell lines of different genetic backgrounds.
  • Built two mathematical models that both consists of four different cell cycle states, between which cells can transition. Dr. Pe’er and her group are modeling how the drugs influence these transition rates, which allows them to compute how many cells are undergoing apoptosis, senescence and proliferation after treatment.
  • Collected proteomic data from three different melanoma cell lines at multiple time points following treatment with a B-RAF inhibitor (PLX4032/vemurafenib) in order to determine the relevant time points for further studies.

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Targeting Sleeping Cancer Cells

Sridhar Ramaswamy, M.D., Harvard Medical School

The goals of Dr. Ramaswamy’s project are to identify the dormant cancer cell epigenomic and signaling networks, and to validate candidate transcriptional and signaling targets: During this initial project period, Dr. Ramaswamy’s laboratory has:

  • Found that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating progeny that resemble dormant cells.
  • Found that this population of “quasi dormant” cells is enriched following chemotherapy in breast cancer patients.
  • Determined that asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during division.

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Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells

E. Alejandro Sweet-Cordero, M.D., Stanford University School of Medicine

The approach that Dr. Sweet-Cordero has chosen to identify novel regulators of chemoresistance in lung cancer cells involves inhibiting a set of genes whose expression is altered in response to chemotherapy treatment in vivo in a mouse model of lung cancer. To date, Dr. Sweet-Cordero’s laboratory has:

  • Established the methods to effectively infect primary cells and induce silencing and functional knockdown with lentiviral shRNAs in the 3D culture system.
  • Established the sensitivity of primary spheres to cisplatin in the 3D culture system.
  • Optimized the conditions of the 3D culture model and tested alternatives to Matrigel to determine if another matrix could be more effective at producing sphere-forming cells and, therefore, more cost-effective. None of the alternatives have been capable of substituting for Matrigel.

Dr. Cordero has also continued collecting human NSCLC primary tumor samples with the goal of establishing a tumor sample bank of frozen single cells. His laboratory is currently obtaining 2-3 samples a month and these are being processed into single cell suspensions and frozen for later use.

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Developing New Therapeutic Strategies for Soft-Tissue Sarcoma

Amy Wagers, Ph.D., Harvard Medical School and Joslin Diabetes Center

The ultimate goal of these studies is to identify new, more effective anti-sarcoma therapies, based on a better understanding of how these cancers arise and grow in skeletal muscle. So far, Dr. Wagers’ laboratory has:

  • Confirmed that 104 out of 141 candidate sarcoma-relevant genes identified previously are indeed upregulated in their mouse model.
  • Identified the gene “Gremlin” as a high-priority candidate gene, because it is upregulated 1326-fold in their mouse model. They also have in vitro evidence for decreased cell growth in sarcoma lacking Gremlin.
  • Shown that their mouse model for rhabdomyosarcomas (RMS) metastasized to the lungs of tumor-bearing animals.
  • Established protocols to induce and phenotype human sarcoma xenografts in mouse skeletal muscle.
  • Found that the mTOR inhibitor prolongs survival both in their mouse model and in human HT1080 fibrosarcoma xenografts, thereby validating that their sarcoma platform in skeletal muscle can be used to identify targets that modulate the progression of sarcomas in vivo.

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Framing Therapeutic Opportunities in Tumor-Activated Gametogenic Programs

Angelique Whitehurst, Ph.D., University of North Carolina, School of Medicine

During this initial reporting period, Dr. Whitehurst’s laboratory has:

  • Focused on a set of 22 tumor cell lines from a range of cancers and evaluated the level of expression of the 120 gametogenic genes previously demonstrated to be present in tumors.
  • Identifying 12 cell lines that cover 90% of the original data set.
  • Initiated the screening phase of the project, which consists of the systematic inhibition the function of each of these gametogenic proteins in the 12 cell lines selected. From these experiments, they can determine which of these proteins are required for tumor cells to grow, divide and survive. They have completed roughly half of the cell lines.
  • Found one protein, FATE1, expressed in Ewing’s Sarcoma cells and essential for survival of those tumor cells.
  • This work has revealed that many, but not all, of these proteins are indeed required for tumor cells to survive and divide and is now the basis for their further research into how these proteins are being exploited by tumor cells.

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Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia

Catherine J. Wu, M.D., Dana-Farber Cancer Institute

To discover genetic alterations important in chronic lymphocytic leukemia formation, Dr. Wu’s Laboratory has:

  • Sequenced the DNA of 91 CCL samples. She detected approximately 2,000 mutations that changed protein sequences. Nine of these genes were mutated significantly more often than normal. Four of the nine genes have previously been described occurring in CLL, but five have not been implicated in CLL before. Dr. Wu’s laboratory has begun work on confirming these results through other methods.
  • Found strong associations between common mutations and key chromosomal deletions in CLL.
  • Defined the effects of mutations in the Wnt pathway, which is often mutated in cancer. Using innovative nanowire delivery, Dr. Wu decreased expression of Wnt pathway proteins and found this decrease increased cell death in cancer cells compared to normal B cells. This indicates that mutational profiling may be able to identify patients more susceptible to Wnt pathway inhibition.