Albert Einstein Cancer Center Overview of Programs_ Shared

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					     Albert Einstein Cancer Center


Overview of Programs, Shared Resources,
       Strategic Plans and Needs



           October 18, 2006
AECC - Overview of Programs, Shared Resources, Strategic Plans and Needs                   10/18/06



1.0     INTRODUCTION

The Albert Einstein Cancer Center (AECC) was among the first biomedical research institutions
in the United States to be designated and funded by the National Cancer Institute in 1972. Since
then, AECC has successfully recompeted its core support grant. The most recent competitive
renewal application was submitted October 1, 2006. AECC is organized around seven
programs, “established” by peer-review, each consisting of investigators from diverse disciplines
who collaborate on studies directed to a specific theme or disease. NCI requires that each
program has a cancer focus to which its members contribute. The extent of NCI funding by
AECC members is considered an important indication of “cancer focus” and the number of joint
authored publications is considered to be an indication of the extent of collaboration by
members within and among programs. There are thirteen “established” shared resources along
with three that support clinical investigation. The current renewal application includes a request
for support for three new shared resources, Bioinformatics, Epidemiology Informatics, Genome
Imaging (FISH/SKY). There are currently 121 AECC members of whom 43 were appointed
since 2001. Total current NCI funding is $21.84M direct and $32.51M indirect. Intrinsic to the
renewal process is a statement of plans for the future of the Center now articulated in this report
within the context of the strategic planning process at the College.


2.0     A BRIEF DESCRIPTION OF AECC PROGRAMS AND REPRESENTATIVE RECENT
        IMPORTANT SCIENTIFIC CONTRIBUTIONS

2.1     Immuno-Oncology Program

The Immuno-oncology Program has traditionally represented a major focus of basic scientific
strength at AECC. Over the past five years this program has greatly increased its cancer focus
through changes in membership, the evolution of research of existing members and the
recruitment of new faculty, several of whom are physician-scientists, to the College and this
Program. The goals of the Immuno-oncology program are: 1) To determine how defects in the
targeting of the genomic instability of immunoglobulin genes required for the generation of
antibody diversity lead to the mutations and translocations that cause B cell lymphomas and to
search for ways to prevent such errors. One objective is to develop therapeutics targeted
specifically to molecularly distinct B-cell lymphoma variants. 2) To better understand how
antigen is presented to T cells and how to manipulate that process to increase the
immunogenicity of tumors and cancer vaccines. 3) To develop and apply new immune
therapies with a focus on radio-immunotherapy and vaccines to viral-induced tumors.
Translational accomplishments include the development of an anti-melanin-mAb-radionuclide
therapeutic, which emerged from studies on fungal melanin, that will enter clinical trials in 2007.
Studies focused on the role of Bcl6 in the pathogenesis of diffuse large B cell lymphoma have
identified a peptide inhibitor of the interaction between this protein and its corepressor. This
peptide is active pre-clinically, and is being further developed in preparation for transition to a
pharmaceutical company for clinical studies. The recruitment of two secondary members to this
program (Mark Einstein and Chandan Guha) has linked clinical and basic investigators who
study vaccines within the context of clinical trials focused on the treatment of cervical neoplasia
and other solid tumors. There are currently 16 program members from 11 departments, of
whom 11 are primary members, supported by 6 NCI ($1.45M Direct) and 7 other NIH grants.
Since 2001, there have been 176 cancer-relevant research papers by members of this program
of which 7% represent intraprogrammatic, and 19% represent interprogrammatic collaborations.

Recent Important Scientific Contributions


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•     N-terminal domain of the Rag1 gene has the structural characteristics and enzymatic
       characteristics of a E3 ubiquitin ligase suggesting that the non-core region of the Rag
       genes contribute to their regulation - Sadofsky (Genes Dev. 17:581, 2003)
•     A technology was developed to determine the origin and direction of replication of the IgH
       gene and showed that it changes during B cell differentiation in primary B cells and in
       malignant B cells that reflect those different stages of differentiation - Schildkraut (Science
       294:2361, 2001, Norio P, et al, Mol Cell 20:575, 2005)
•     Activation-induced cytidine deaminase (AID) activates somatic V region hypermutation in Ig
       genes in Hybridoma cells suggesting that AID is sufficient to turn on somatic mutation at
       any stage in B cell development and that it could be used to class switch and somatically
       mutate monoclonal antibodies – Scharff (Nature 415:802, 2002)
•     Malignant cells of good prognosis B-CLL patients with mutated V region, and patients with
       unmutated V regions with poor prognosis, make autoantibodies that appear to be based
       on V region usage and antigen binding – Chiorazzi (J Clin Invest 115:1636, 2005)
•     BCL6 negatively regulates its own transcription; this is blocked by mutations in its promoter
       that inactivate the BCL6 binding sites. This explains why BCL6 is constitutively expressed,
       and suppresses the expression of many downstream genes, in the thirty to forty percent of
       diffuse large B cell lymphomas that have not activated BCL6 expression through
       chromosomal translocations – Ye (Proc. Natl. Acad. Sci. USA 99:15018, 2002)
•     The co-crystal structure of PD-1 with its ligands was determined and compared to the
       structure of CTLA-4 to show that these factors use different strategies to negatively
       regulate T cell activation and therefore could be targeted by different small molecules –
       Nathenson and Almo (Immunity 20:337, 2004)
•     NKT cells can be activated by different synthetic lipid ligands to carry out different functions
       in both mouse and humans – Porcelli (Proc Natl Acad Sci USA 102:3383, 2005)

2.2      Tumor Microenvironment & Metastasis Program

The objective of the Tumor Microenvironment and Metastasis Program is to understand the
molecular mechanisms involved in the regulation of the survival, differentiation and function of
cells in tumors, the microenvironments responsible for invasion and metastasis, and signaling
pathways employed. The program is supported by a Program Project grant focused on defining
how signaling pathways in macrophages and carcinoma cells contribute to the motility and
chemotactic behaviors that generate the invasive phenotype. The major disease site studied is
breast but other cancers are also included. The program has three major goals: (1) Dissection
of the role the microenvironment plays in tumor progression and metastasis: There is an
emphasis on the interaction between tumor cells and tumor-associated macrophages, cells that
promote tumor progression and metastasis. These studies utilize mouse models as well as
human tumors explanted into immunocompromised mice. Six distinct functions have been
identified for macrophages in promoting malignancy. 2) The molecular mechanisms of growth
factor and hormone action in regulating cell motility and proliferation. Investigators study the
intrinsic mechanisms that feed downstream from receptors in regulating cell motility,
chemotaxis, invasion as well as cell proliferation. There is a particular emphasis on signaling
from the colony stimulating factor receptor in macrophages and the ErbB family of receptors in
tumor cells and the studies utilize a combination of systems, including cell lines in culture and as
xenografts, as well as mouse models of breast cancer. 3) Imaging and animal models. This is
directed to the development of innovative optical technologies using multiphoton microscopy to
image cells and their interactions within the tumor microenvironment in vivo coupled with
innovative mouse genetics to label lineages and perturb signaling pathways. There are currently



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21 program members from 10 departments, of whom 16 are primary members, supported by 17
NCI ($2.9M Direct) and 10 other NIH grants. Since 2001, there have been 246 cancer-relevant
research papers by members of this program of which 20% represent intraprogrammatic, and
21% represent interprogrammatic collaborations.

Recent Important Scientific Contributions

•     Tumor-associated macrophages regulate tumor progression and metastasis in a mouse
       model of breast cancer. This is due, at least in part, to regulation of angiogenesis.
       Macrophages were shown to control the angiogenic switch and accelerate the transition of
       benign tumors to malignancy - Pollard (J Exp Med 193:727, 2001; Cancer Research, In
       Press, 2006).
•     Macrophages and tumor cells are in an obligate paracrine loop with reciprocal EGF and
       CSF-1 signaling that is required for tumor cell motility and invasion - Condeelis, Cox,
       Pollard, R. Stanley and Segall (Cancer Res 64:7022, 2004; Cancer Res. 65:5278, 2005)
•     Anti-CSF-1 therapeutics in vivo inhibit tumor growth in xenograft models of human breast
       and colon cancer, in part through the inhibition of angiogenesis – R. Stanley (Cancer Res
       64:5378, 2004; Cancer Res 66:4349, 2006)
•     An “Invasion Signature” of gene expression specific to invading tumor cells was identified
       characterized by up-regulation of transcripts involved in motility and anti-apoptotic and
       down regulation of those regulating cell cycle and polarity - Condeelis (BMC Biotechnol
       3:13, 2003; Cancer Res 64:8585, 2004 )
•     Estrogens activate cell proliferation in uterine epithelial cells through the regulation of pre-
       replication licensing of DNA synthesis. Progesterone completely blocks estrogen induced
       DNA synthesis by inhibiting this activity – Pollard (Proc Natl Acad Sci USA 103:14021,
       2006)
•     Uncaging of proteins showed that cofilin polymerizes actin, generates protrusions, and
       determines the direction of cell migration. Cofilin is therefore the steering wheel of the cell
       – Condeelis and Lawrence (Science 304:743, 2004)
•     WASP activity is required for invadopodia formation in tumor cells which enhance tumor cell
       migration and invasion - Condeelis, Symons, Segall (J Cell Biol 168:441, 2005; Curr Biol
       14:697, 2004)

2.3      Cell Growth and Differentiation Control Program

Research by members of the Cell Growth and Differentiation Control Program is focused on
identifying and understanding the mechanisms of action of the cellular factors that control
proliferation, differentiation and cell death, how the programs controlling these processes are
coordinated and how they interact. The major scientific goals are: (1) to identify, characterize
and study the mechanisms of action of gene products controlling cell proliferation, lineage
commitment and cell differentiation, and cell death; (2) to understand how misregulation of
these gene products and processes contribute to oncogenesis; (3) to use this knowledge to
develop new approaches to cancer prevention and treatment. A major scientific focus of the
program is the control of gene expression during the cell cycle, differentiation and apoptosis and
the key role played by transcription factors in regulating these processes. Many members of the
program are also studying the role of epigenetic mechanisms in cancer, including changes in
the patterns of histone modifications and DNA methylation in cancer cells. A new method for
genome-wide methylation analyses has been developed by a program member for these
studies and, along with a highly versatile array platform, is being used to study gene expression
and epigenetic changes during normal cell growth and differentiation in a variety of



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malignancies and premalignant conditions. Within the program there are particular strengths in
studying the properties of stem cells, both adult stem cells and human embryonic stem cells, as
well as in three organ systems: the hematopoietic system, the liver and neuronal cells. The
program has benefited from members whose research programs utilize nonmammalian model
organisms including yeast, drosophila, and zebrafish. The program’s research is also
strengthened by investigators with expertise in the most advanced approaches for studying
control of gene expression in eukaryotic cells. There are currently 26 program members from
10 departments, of whom 25 are primary members, supported by 9 NCI ($1.8M Direct) and 33
other NIH grants.     Since 2001, there have been 439 cancer-relevant research papers by
members of this program of which 8% represent intraprogrammatic, and 20% represent
interprogrammatic collaborations.

Recent Important Scientific Contributions

•   A role for EGF and Notch signaling, Rb and the CDK inhibitor Dacapo was identified in the
      regulation of cell number in the Drosophila retina showing that differentiation can be
      uncoupled form cell cycle exit - Baker (Dev. Cell 8: 541, 2005; Dev. Cell 7:632, 2004;
      Dev. Cell 4:359, 2003)
•   Relapse of disease in APL patients after treatment with all-trans retinoic acid (ATRA) is
      associated with the rapid emergence of APL subclones with mutations in PML-RARα -
      Gallagher (Leukemia 20:556, 2006; Blood 101:2521, 2003)
•   B and T cells can be reprogrammed in vivo into macrophages by ectopic expression of
      C/EBPα providing evidence for the extensive plasticity in the hematopoietic system - Graf
      (Cell 117:663, 2004)
•   INI1/SNF5, a tumor suppressor gene mutated in rhabdoid tumors, represses cyclin D1
      transcription, establishing that Cyclin D1 is required for rhabdoid tumor formation in mice;
      inhibition of cyclin D1 suppresses rhabdoid tumor cell growth - Kalpana (Oncogene
      25:722, 2006; PNAS 102:12129, 2005; Mol. Cell. Biol. 22:5975, 2002)
•   ARC functions as a central regulator of apoptosis by inhibiting both the extrinsic and intrinsic
      cell death pathways and may be involved in the pathogenesis of breast cancer - Kitsis
      (Molecular Cell 15:901, 2004; Cell Death and Differentiation 12:682, 2005)
•   A lung cancer mouse model was developed by inactivation of the Nkx2.8 gene encoding a
      homeobox protein - Locker (Mol. Cell Biol. 22:6122, 2002; Cancer Research, in press).
•   The spliceosome and the mechanism of RNA splicing have important similarities with the
      ribosome and the mechanism of translation - Query (Mol. Cell 21:543, 2006; Mol. Cell
      14:343, 2004)
•    mRNA metabolism from transcription to degradation has been visualized in the nucleus of
      single living cells by powerful techniques - Singer (Nature Methods 2:663, 2005; Nature
      438:512, 2005; Cell 116:683, 2004; Science 304:1797, 2004; Cancer Res 64:8585,
      2004)
•   H1 linker histones are involved in regulating DNA methylation of imprinted genes and in
      signaling apoptosis in response to DNA damaging agents – Skoultchi (Cell 123:1199,
      2005; Cell 114:673, 2003)
•   A new Rb-dependent pathway of cell cycle arrest was identified: Rb binds Skp2, preventing
      Skp2 interaction with p27, and p27 polyubiquitination and degradation. A peptide inhibitor
      of Skp2 protein was developed that induces apoptosis in tumor cells - Zhu (J. Biol. Chem.
      281: 24058, 2006; Molecular Cell 16:47, 2004)




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2.4      Molecular Membrane Biology Program

The Molecular Membrane Biology (MMB) Program provides a long-standing forum for AECC
investigators with a primary interest in determining roles in cancer for molecules that function at
the cell surface or in the secretory pathway. The goals are to determine structure/function
relationships of molecules that reside in cell membranes or enveloped viruses, and to exploit
their properties in cancer diagnosis, prognosis or treatment. In the past 5 years program
members have identified new mechanisms of tumorigenesis, tumor progression, angiogenesis
and metastasis and mechanisms of resistance to chemotherapeutic drugs. About a third of the
MMB group investigates membrane transporters, including the Na+/I- symporter (NIS), glucose
transporters (GLUT4 and GLUT8), folate transporters, the F1/F0 ATP synthase, a multi-drug
resistance transporter, prostaglandin transporters and the Na+/monocarboxylate transporter
(SMCT). Several members investigate mechanisms of membrane trafficking and secretion
including two virologists investigating mechanisms of virus assembly and membrane fusion in
viruses that either cause cancer, or belong to a family of viruses that cause cancer. Another
focus is on cell surface interactions mediated by N-glycans, Notch receptors, cadherins, and
galectins. Future goals for the MMB program are to catalyze discoveries of new roles for
membrane molecules in cancer diagnosis, prognosis and treatment to clinical applications, to
expand the program to include scientists investigating integrins and selectins in cancer through
new recruitment, and to enhance interactions with the Tumor Microenvironment and Metastasis
program in order to expand the scope of cancer research in cell-cell interactions and
membrane-related phenomena. The group now comprises 18 members from 11 departments.
MMB members are supported by 10 NCI grants ($2.4M direct), a Susan Komen award, and an
additional 15 NIH grants. The group published 189 cancer relevant papers since 2001; 12%
represented intraprogrammatic, and 29% interprogrammatic, collaborations.

Recent Important Scientific Contributions

•     SMCT, a protein highly homologous to NIS but which transports small chain fatty acids, is a
       tumor suppressor whose increased expression in colon cancer correlates with longer
       disease-free survival - Carrasco, Augenlicht, Mariadson (Proc Natl Acad Sci USA.
       103:7270, 2006)
•     A novel proton-coupled, electrogenic, folate transporter ubiquitously expressed in human
       cancers was identified and shown to be required for intestinal folate absorption; mutations
       in this gene were shown to be the basis for Hereditary Folate Malabsorption - Goldman
       (Cell, in press)
•     Adipokines secreted from adipocytes in mammary gland stimulate mammary tumor growth.
       A C-terminal fragment of collagen VI was shown to be a key factor and to be generated in
       human breast cancer – Scherer, Pollard, Kitsis (J Clin Invest 115:1163, 2005)
•     A novel mouse model was developed allowing conditional deletion of adipocytes in vivo at
       any stage of postnatal development. This mouse allows stromal adipocytes to be removed
       to assess their effects on tumorigenesis and progression – Scherer, Kitsis (Nat Med.
       11:797, 2005)
•     Protein O-fucosyltransferase 1 was shown to be an essential component of Notch signaling
       pathways in mammals. This enzyme adds fucose to the extracellular domain of Notch
       receptors and a conditional mutant allows Notch signaling to be inhibited in any cell type
       was developed– P. Stanley (Proc Natl Acad Sci USA 100:5234, 2003)
•     The crystal structure of an alphavirus fusion protein in its "postfusion" conformation was
       determined. This information led to the development of a dominant-negative inhibitor of the
       alphavirus and flavivirus fusion reactions. This is highly relevant to understanding the



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       mechanism by which HCV enters cells and approaches to inhibit entry - Kielian (Cell
       114:573, 2003; Nature 427:320, 2004; J Cell Biol. 171:111, 2005)

2.5      Experimental Therapeutics Program

The goal of the Experimental Therapeutics program is to develop new cancer therapeutic
modalities, to better understand the mechanisms and determinants of the activities of existing
therapies, and to bring together laboratory and clinical scientists to focus on the treatment of
specific malignant diseases. This program is a resource for drug and radio-pharmaceutical
development to potential targets identified in basic studies in this and other AECC programs.
There is a broad spectrum of research. (1) Drug development emphasizes structural analyses
for the design of pM transition-state inhibitors. Fodosine, targeted to purine nucleoside
phosphorylase, is in advanced Phase IIb trials for the treatment of T-cell leukemia and
lymphoma. Agents targeted to methylthioadenosine phosphorylase (MTAP) to inhibit polyamine
synthesis and purine salvage, are being evaluated preclinically. There are other studies on the
development of antisense agents. (2) Another focus is on the biochemical and molecular
pharmacology of antineoplastics encompassing new-generation microtubule inhibitors and a
new-generation antifolate, pemetrexed. (3) A new element is studies on the mechanism of
action and toxicity of EGF inhibitors. (4) This program provides radiochemistry support for the
development of targeted pharmaceuticals, in particular, a melanin mAb-188Rheniun for the
treatment of malignant melanoma scheduled to enter clinical trials in the coming year. There are
disease-specific translational, multidisciplinary, activities in the areas of lung, head and neck,
and breast cancer and osteosarcoma. Intrinsic to these activities are studies that are exploring
gene expression, epigenetic, and proteomic patterns that are predictive of the natural history of
these diseases and their response to treatment. AECC participates in ECOG, GOG, COG and
the AIDS Malignancy Consortium. There is an active Phase I drug development effort and
members of this program lead and participate in the NCI-funded NY Phase II Consortium - a
focal point for the conduct of innovative investigator-initiated clinical studies. There are currently
29 members (27 primary) from 15 departments, supported by 24 NCI grants ($4.4M Direct) and
9 other NIH grants. Since 2001, there have been 315 cancer-relevant research papers by
members of this program of which 16% represent intraprogrammatic, and 25% represent
interprogrammatic publications.

Recent Important Scientific Contributions

•     FodosineTM, (Immucillin-H), conceived, and developed at AECC is in a registration trial for
        the treatment of T-cell leukemia and lymphoma – Schramm (Proc Natl Acad Sci USA
        98:4593, 2001)
•     A mAb to melanin linked to 188Rhenium conceived and developed at AECC will enter clinical
        trials for the treatment of malignant melanoma in 2007 – Casadevall and Dadachova (Proc
        Natl Acad Sci USA 101:14865, 2004)
•     A peptide inhibitor has been developed that blocks the interaction between BCL6 and SMRT
        that has marked anti-B cell lymphoma activity in vitro and in vivo – Melnick (Nat Med
        10:1329, 2004)
•     Positrons delivered with high-dose 18Fluoro-deoxyglucose is effective in the treatment of
        breast cancer in the polyoma middle T mouse model – Dadachova, Charron, Pollard
        (Breast Cancer Research 6: 199, 2003: Cancer Res. 65:698, 2005)
•     Hydrogen-deuterium exchange coupled to liquid chromatography-electrospray ionization MS
        can be effectively used to study conformational effects induced by small ligand binding to




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       microtubules providing insights into the mechanism of microtubule stabilization by Taxol -
       Horwitz, Angeletti, and Orr - (Proc Natl Acad Sci USA 103:10166, 2006)
•     Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock
       protein 90 degradation - the first account of a drug that reduces Hsp90 function by
       enhancing its proteasomal degradation and a previously undescribed action of Taxotere
       that may contribute to its antiangiogenic activity – Schwartz (Cancer Res. 66, 8192, 2006)
•     The pharmacologic target of G3139, the Bcl2 antisense inhibitor, may be the voltage-
       dependent, ion-selective (VDAC) in the mitochondrial outer membrane - Stein (Proc. Natl.
       Acad. Sci. USA 103:7494, 2006)
•     The farnesyl transferase inhibitor, tipifarnib can be safely combined with dose-dense AC
       using a dose and schedule that significantly inhibits FTase enzyme activity in human
       breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative
       dose-dense AC - Sparano (J Clin Oncol. 24:2981, 2006)
•     A phase II study of erlotinib in patients with HER1/EGFR-expressing non-small-cell lung
       cancer previously treated with platinum-based chemotherapy demonstrated that this agent
       was active, well tolerated, and that a cutaneous rash may be a surrogate marker of clinical
       benefit – Perez-Soler (J Clin Oncol. 22:3238, 2004)

2.6      Cancer Epidemiology Program

The major goal of the Cancer Epidemiology Program (CEP) is to understand the pathogenesis
of human cancers at the molecular level through the use of observational and interventional
studies in human       populations. This effort includes a number of large prospective cohort
investigations, case-control studies, population-based cross-sectional studies, and hospital-
based projects, to identify etiologic risk factors and cancer biomarkers related to the multiple
stages of tumorigenesis. Study populations derive from the Bronx/NYC AECC catchment area
and regional/national and international inter-institutional collaborations. The scope of research
has increased with faculty recruitment and expanded studies by senior CEP investigators.
Substantial progress has been made in several molecular epidemiologic research areas. This
includes (i) viral causes of cancer- human papillomavirus, simian virus 40, and hepatitis C virus;
(ii) the epidemiology of breast cancer and its precursors; (iii) the role of host immunity including
studies on immune compromised patients, immune genes (HLA and KIR), and specific immune
responses to viral oncoproteins. New research initiatives include (iv) inflammation and
cytokines in the development of colorectal cancer and polyps; (v) risk factors for head/neck
cancer; (vi) endocrine-based cancer risk factors such as hyperinsulinemia and insulin-like
growth factors (IGF), energy consumption, diabetes and obesity, sex hormones, and (vii)
genetic epidemiology - studies of gene polymorphisms (e.g., in the insulin and IGF signaling
pathways), variations in gene expression (involving use of mRNA arrays), and epigenetic
changes (e.g., DNA methylation). Studies on HPV are being translated into therapeutic
(vaccine) and screening approaches for cervical cancer. A Biostatistics Shared Resource was
established with several members based in the CEP, with ongoing methodological research.
There has been increased research in cancer-related behaviors - substance abuse (e.g.,
cigarettes/alcohol), energy consumption/obesity, and exercise, with funded intervention efforts.
There are currently 16 program members from 7 academic departments supported by 12 NCI
($2.6M Direct) and 4 other NIH grants. Since 2001, there have been 218 cancer-relevant
research papers by program members of which 19% represent intraprogrammatic, and 7%
interprogrammatic collaborative publications.




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Recent Important Scientific Contributions

•     SV40-contamination of early poliovirus vaccines in the United States (1955-1963) has had
       no effects on risk of pleural mesothelioma after forty years - Strickler (J Natl Cancer Inst
       95:38, 2003)
•     Smoking of very long duration and high intensity may be associated with increased risk of
       breast cancer – Rohan (Int J Cancer 100:723, 2002)
•     Polymorphisms of the insulin gene are associated with increased prostate cancer risk – Ho
       (Br J Cancer 88:263,2003)
•     A sustained humoral immune response to human papilloma virus type 16 is associated with
       a reduced risk for subsequent infection with this and genetically-related virus types – Ho
       and Burk (J Infect Dis 186:737, 2002)
•     The prevalent and incident detection of HPV16 is more weakly associated with immune
       status in HIV-seropositive women than with other HPV types, suggesting that HPV16 may
       be most effective at avoiding the effects of immune surveillance – Strickler and Burk (J
       Natl Cancer Inst. 95:106271, 2003)
•     HIV+ women who are cytologically normal and negative for oncogenic HPV can likely be
       followed safely without Pap smear for 3 years, as recommended for HIV-negatives – Burk
       and Strickler (JAMA 293:1471, 2005)

2.7      Biology of Colon Cancer Program

The Biology of Colon Cancer program remains focused on (i) fundamental cellular and
molecular mechanisms of intestinal cell maturation and lineage specific differentiation, and how
this establishes and maintains homeostasis of the intestinal mucosa; (ii) genetic and
environmental factors, and their interactions, that perturb these processes and alter probability
of tumor formation and progression; and (iii) approaches to prevent tumorigenesis and treat
intestinal cancer. Members utilize novel cell systems in culture, mouse genetic models, and
human tissues and subjects in their investigations. All of the members are independently
funded by grants that are highly cancer focused, and most participate in large multidisciplinary
programs that are jointly funded. During the past five years, this included an NCI U01 Director’s
Challenge grant on molecular markers of relative drug sensitivity in colon cancer and,
subsequently, an NCI U54 Center grant on nutritional-genetic interactions in intestinal cancer.
This joint funding, and a large number of joint publications, reflects the extensive interactions
and collaborations among members of the Program. Members of the Program also collaborate
widely across the AECC and have made unique resources available to other Center members.
The Program has continued to grow during the last 5 years, both by promotion from within and
recruitment, made possible by support from the AECC and a pilot project program funded by the
U54 Center grant. There are currently 12 program members from 8 departments, of whom 11
are primary members, supported by 15 NCI ($3.7M Direct) and 2 other NIH grants. Since 2001,
there have been 105 cancer-relevant research papers by members of this program of which
34% represent intraprogrammatic, and 33% represent interprogrammatic publications.

Recent Important Scientific Contributions

•     Targeting p27Kip1 resulted in intestinal tumor formation and a unique pathology of
       intussusception that was diet-dependent – Yang, Augenlicht (Cancer Res. 63:4990, 2003;
       Cancer Res. 65, 9363, 2005)
•     Targeting the mouse Muc2 gene resulted in tumor formation in intestines and rectum by a
       mechanism not involving beta-catenin/Tcf activation - Velcich (Science 295:1726, 2002)



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•     Increased mutation rates associated with the loss of DNA repair are sufficient to drive
        tumorigenesis in MMR-defective tumors - Edelmann (Cancer Cell 6:139, 2004)
•     Inactivation of Mbd4 is implicated in repair of methylated DNA sites, alters the mutation
        spectrum in cancer cells, and modifies APC initiated tumor formation – Edelmann (Proc
        Natl Acad Sci USA 99:14937, 2002)
•     Tumor cells with stable elevations in mitochondrial membrane potential exhibit greater
        invasive and metastatic potential, and resistance to growth factors and drugs, than those
        with lower mitochondrial membrane potential, and may pose the greatest threat to the host
        – Heerdt (Cancer Res. 63:6311, 2003; Cancer Res. 65:9861, 2005; Cancer Res. 66:1591,
        2006)
•     Colon tumor cells with an activated ras pathway down-regulate IFN signaling through
        repression of HDAC activity, suggesting that butyrate negatively regulates mucosal
        inflammation by inhibiting IFNγ/STAT1 signaling - Klampfer (Mol. Cancer Res. 1:855,
        2003; J. Biol Chem. 278:46278, 2003; J Biol Chem. 279:30358, 2004)
•     Gene expression profiles of intestinal epithelial cell differentiation along the absorptive and
        secretory cell lineages and during migration along the crypt-villus axis were characterized -
        Mariadason, Augenlicht (Cancer Res. 62:4791, 2002; Gastroenterology 128:1081, 2005;
        Exp Cell Res. 304:28, 2005).
•     Expression profiling with novel statistical analysis has greater predictive value in drug
        sensitivity than other markers – Mariadason (Cancer Res. 63:8791, 2003)


3.0      AECC LABORATORY FACILITIES

3.1      Analytical Imaging

The Analytical Imaging Facility (AIF) is a comprehensive microscopy shared resource that
makes routine and complex imaging technologies available to the entire AECC community.
These include macro-imaging with a stereoscope, classical microscopy including brightfield,
darkfield, phase contrast, Nomarski differential interference contrast and epifluorescence,
through live cell imaging and cell manipulation with light, through standard transmission and
scanning electron microscopy, up to cryoEM of macromolecules and whole mount cells. The
wide range of magnifications allows studying animal models. Cells labeled with fluorescent
reporter genes may be imaged at the whole animal or whole organ level down to single cells or
cell compartments. The facility offers customized full service sample preparation for electron
microscopy ranging from chemical fixation, embedding in resin and ultrathin sectioning, negative
staining, immunogold labeling, critical point drying and metal shadowing. In addition, the facility
offers a full range of low temperature techniques for electron microscopy including quick
freezing in the millisecond range by plunge, metal mirror or high pressure freezing.
Subsequently frozen samples can be freeze-substituted and embedded at low temperatures,
deep etched and rotary shadowed, freeze fractured or ultrathin cryosectioned. The facility has
traditionally emphasized teaching new users, on an individual basis, the imaging techniques
they require for successful execution of their experiments. Staff assists users in experimental
design, data collection, quantitative analysis and presentation. Novice users are trained in the
specific imaging technology appropriate to address the specific research objective.
Experienced users may customize any imaging station utilizing the large inventory of optics and
accessories that are available. The AIF provides support for the microscopy requirements of the
Genome Imaging and Histopathology Shared Resources. An important resource for the AIF is
the newly established Innovation Laboratory within the College’s Biophotonics Center that is




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focused on the development of new technologies that are subsequently made available to
AECC investigators through this shared resource.

3.2     Animal Barrier

The Animal Barrier Shared Resource (ABSR) provides an environment in which the highest
quality of animal research can be conducted while maintaining the highest standards of animal
care and welfare. A major objective of the ABSR is to maintain the health quality of barrier
housed specific pathogen-free (SPF) mice, keeping them free of adventitious murine infectious
agents that could disrupt breeding or confound research results. Barrier housing is provided for
SPF mice while permitting supervised access for investigators. AECC investigators maintain
breeding colonies either to expand novel strains bearing transgene or targeted mutations from
genetically-manipulated founder animals, or to recombine several specific alleles from different
genetic loci into a limited set of genotypes on a single strain background. Frequent convenient
access is crucial for investigators so that they may set up matings, collect tissue biopsies from
successive litters for genotype determination, and observe animals for physical and behavioral
characteristics (phenotype), specifically, their propensity to develop neoplasia. In addition,
many AECC investigators use SPF rodents that either have a genetic predisposition to develop
spontaneous neoplasia or are immunodeficient and tolerate tumor xenografts as models to
study specific processes such as angiogenesis and metastasis and for testing anti-neoplastic
therapies. These investigators must have frequent access to their animals to implant tumor
tissues, monitor tumor growth, administer various treatments, and collect tissue biopsies.
Animal husbandry services, veterinary care, and comprehensive rodent quality assurance and
quarantine programs are provided to the AECC by the Institute of Animal Studies (IAS). The
IAS consists of three faculty Laboratory Animal Veterinarians (including the Director), three
Veterinary Technicians, a staff of approximately 40 Animal Caretakers, a Facilities Manager,
two Husbandry Supervisors, as well as office administrative staff. In addition to providing
veterinary care, the IAS veterinarians also provide oversight of the animal care and use
program, monitor regulatory compliance, and conduct small-group and individual training
sessions for investigators. Pathology diagnostic services are provided by a Veterinary
Pathologist who also directs the Histopathology Shared Resource.

3.3     Bioinformatics

The Bioinformatics Shared Resource (BISR) was established in 2004 with a focus on
developing relational database resources for the AECC research community as the essential
foundation for the management of data from high-throughput technologies (especially
microarrays), and for the integration of data from different sources. Since then, the BISR has
established web-based clinical study databases and has adapted to the management of data
from evolving microarray platforms and applications; in particular, the NimbleGen custom
microarray system. The BISR has also been integrated into the cancer biomedical informatics
grid (caBIG) project and currently has three contracts from NCI for its contributions to this
program. The BISR is closely linked with the Biostatistics Shared Resource and is designed to
focus on data management and mining, leaving the responsibility for data analysis with the latter
facility. However, the expertise of both groups has been used to develop AECC’s high-
throughput analytical capabilities along with software programs to analyze microarray data that
work within the database environment and generate not only the final output but also
intermediate analyses that are informative about data quality. These analytical approaches are
developed and supervised by AECC biostatisticians, but implemented by the BISR staff,
leveraging the strengths of both groups to meet the evolving major challenge of processing and
analyzing high-throughput genomic, epigenomic and proteomic data from basic and


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translational applications as they emerge and expand at this Center. The BISR has developed
a pilot clinical study database for the AECC Head and Neck Cancer Affinity Group that allows
the integration of laboratory and clinical data from multiple sources and maintains HIPAA-
compliance through the use of metadata repositories that can be extrapolated to other disease
sites. A second component to the bioinformatics infrastructure is being developed to support
pre-existing applications such as TransFac, microarray analysis software, batched Blat and
Entrez analyses, and biological pathway analysis tools such as GenMAPP and PathwayAssist.
The facility is currently staffed by 5.25 FTE consisting of three bioinformaticists who provide
consultative support to AECC members along with two programmers, and a part-time staff
member who serves as a systems administrator and database administrator.

3.4     Biostatistics

The Biostatistics Shared Resource (BSR) of the Albert Einstein Cancer Center (AECC) provides
statistical expertise and collaboration to investigators on all phases of basic science,
translational, observational and clinical research. This includes guidance on study design, study
conduct, data analysis, and the interpretation and publication of results. The BSR was initiated
in 2000 and the resource has undergone considerable expansion since then to meet the
increasing and diverse biostatistical needs of the AECC. The BSR currently includes 6 doctoral
level and 2 master’s level biostatisticians who have a wide range of methodologic expertise to
ensure that appropriate statistical support is available for each project. The specific objectives
of the BSR are: (i) To assist and collaborate with AECC investigators on the design, analysis,
interpretation and reporting of basic science, translational, clinical, epidemiological and
prevention studies. (ii) To collaborate on new research initiatives and the development of
applications for peer-reviewed funding. (iii) To provide statistical expertise on the development
and scientific review of clinical trial protocols. (iv) To provide statistical support for short-term
research projects, including pilot studies. (iv) To develop new statistical methods as needed to
meet specific study needs. (v) To provide guidance on the design and management of study
databases. (vi) To educate and train AECC members in the statistical principles of biomedical
research.

3.5     Epidemiology Informatics

The Epidemiology Informatics Shared Resource (EISR) provides database management
expertise and services to AECC investigators engaged in epidemiological research. This
includes guidance on study operations, quality control systems, data collection instrument
design, descriptive analysis, and the publication of results. The EISR was established in 2000
and has undergone considerable expansion since then in terms of personnel and equipment to
meet the increasing and diverse needs of AECC investigators. The EISR has extensive
experience in creating and implementing data management systems, quality control procedures,
network and systems infrastructure, security protocols and backup procedures to ensure data
integrity and reliability. The Unit sets up and maintains study databases and is responsible for
form design, data collection procedures, data entry and supervision. These procedures include
tracking of all data forms, laboratory results and medication information, as well as producing
regular reports to monitor missing data, out-of-range values, inconsistent answers etc. The Unit
creates data dictionaries for all studies, creates and maintains study websites, and assists
senior biostatisticians in the production of statistical analyses and reports. The EISR works with
PIs on developing data collection instruments for each project where necessary, assists
investigators in the design of the database system, this includes the development of database
structures, schema, and data input systems; establishes and administers security measures for
all database systems to ensure that HIPAA standards are met and that all data systems are


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backed up securely; develops data management Manuals of Operations and procedures and a
Data Dictionary for each study which details all data management procedures, designs quality
control and data tracking procedures; supervises the implementation of these procedures by
research staff, collates study data including clinical data, microarray data, epidemiological data
etc., retrieves genomic, epigenomic and proteomic datasets from the Bioinformatics Shared
Resource and prepares files for biostatistical analysis by the Biostatistics Shared Resource. The
EISR employs 5 FTEs that include the director, a data manager, a network manager, an
assistant data manager, a SAS programmer and data entry personnel. The Unit currently
supports twenty-four research projects for thirteen faculty members at Einstein. Thirteen of
these research projects are directed by AECC members and have a primary cancer focus.

3.6     Flow Cytometry

The Flow Cytometry Shared Resource provides AECC investigators with convenient and
affordable access to a broad spectrum of important technologies in flow cytometry, and supports
numerous research studies that rely on high speed fluorescence activated cell sorting (FACS)
and advanced multiparameter fluorescence analysis. In addition to providing advanced flow
cytometry equipment, the facility provides technical expertise and training to guide AECC
investigators and their staff in the application of basic and advanced flow cytometry techniques.
The facility also organizes and supports a program of seminars on new technologies that inform
AECC investigators about newly emerging applications of FACS that can enhance their
research. The major usage of this shared resource is for multiparameter analysis and high
speed sorting of cell populations based on labeling with fluorochrome-conjugated antibodies or
other fluorescent protein or chemical dye reagents. Training of many investigators in the use of
the facility’s analytical instruments has led to a very large and well-trained user base. During
2005-2006, the facility provided services to more than 275 registered users, consisting of
faculty, postdoctoral fellows, students and technicians from 78 different laboratories. AECC
members were principal investigators of 45 of these laboratories, and two thirds of total hours of
usage of all facility services in 2005-2006 was attributable to the laboratories of AECC
investigators. These investigators have access around the clock and seven days per week to
the facility's analyzers, which include Becton-Dickinson FACScan (one laser, 3-color),
FACSCalibur (two laser, 4-color), and LSR-II (4 laser, 12 color) instruments. Standard
fluorescent microscopes and computer work stations with an extensive software library for
processing of FACS data are also routinely available. High-speed cell sorting with the facility's
3-laser, 8-color Dako-Cytomation MoFlo sorter is performed exclusively by the trained facility
staff during regularly scheduled weekday hours.

3.7     Gene Targeting

The Gene Targeting Facility was established in 1992 to assist AECC researchers in the
generation of animal models for human cancer. The goals of the facility are to provide services
that allow researchers to modify the mouse genome through the methods of gene targeting in
embryonic stem (ES) cells and to introduce these changes into the mouse germline. The facility
provides: (1) Advice in the theoretical and practical aspects of gene targeting vector design
including design of conventional knockout targeting vectors, knock-in targeting vectors as well
as targeting vectors for temporal and spatial ablation of genes. The facility also advises on the
methodologies required for targeting vector construction, including the use of gridded BAC 129
strain genomic libraries for the rapid isolation of genomic fragments, subcloning strategies and
also the use of recombination-based cloning. The facility maintains and makes available a
panel of vectors and resistance cassettes that facilitate targeting vector construction. In addition,
the facility established recombination-based cloning technology (“recombineering”) using the


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RecET technology that allows the modification of BAC clones and also permits the more rapid
generation of more complex targeting vectors. (2) The facility provides comprehensive ES cell
culture service and maintains stocks of mouse embryonic fibroblasts (MEF) for feeder cell
generation and ES cell lines with high germline transmission capacity. The facility offers
complete ES cell culture service encompassing all the required techniques but will train and
provide advice to investigators who wish to participate in parts of this process. The facility
provides services for chimera production. This includes ES cell microinjection into blastocysts,
blastocyst transfer and chimera production. To support these activities, stocks of ES cell lines
from different sources and of different genetic backgrounds (129J/Sv, 129/B6 and B6) are
maintained along with core mouse colonies sufficient to generate enough blastocysts for
injection, as well as pseudopregnant recipient mice for the blastocyst transfers and
vasectomized males to mate with these females. The facility is intimately involved in the
implementation of new technologies and the training of new investigators in the technical and
theoretical aspects of these procedures.

3.8     Genome Imaging

The Genome Imaging Shared Resource (GISR) is a new shared resource developed since the
last CCSG review. The facility provides tools for cytogenetic analysis of the entire genome as
well as specific probes targeted to regions of interest. These include fluorescent in situ
hybridization (FISH) with locus specific probes (LSP) generated “in house”, specifically designed
and labeled based upon the experimental requirements. Spectral Karyotyping (SKY) and whole
chromosome painting for human and mouse samples are also part of the service. This facility
was initiated in late 2004 with the recruitment of Cristina Montagna from Thomas Ried’s
laboratory from the NCI. The GISR is not a high-volume facility and, because it was inaugurated
only recently, the scope of usage is smaller than for most AECC shared resources. However,
this facility provides a very important technology and service to AECC investigators and will play
a critical role in the growing genomics and, in particular, epigenetics research activities at the
Center.

3.9     Genomics

The AECC DNA Sequencing Shared Resource was established in 1992 and has evolved
considerably since then and, in particular, since 2001, to meet the evolving scientific needs of
AECC members and programs. The new name of this facility, Genomics Shared Resource,
reflects this expansion of services and technologies. The facility now offers, in addition to DNA
sequencing, fragment analysis, dHPLC for SNP/mutation discovery, Pyrosequencing SNP
typing, pyrosequencing quantitative CpG methylation, and Taqman SNP typing. Real-time PCR
is now provided as well. At the time of the last CCSG review, this Facility provided Affymetrix
services, and there was a separate cDNA printing facility. With the further development of
microarray technologies, there has been a shift of emphasis to commercially available
microarrays. To meet the needs for epigenetic studies, services were contracted with
NimbleGen Direct to perform, on their site, gene expression, CGH, chromatin
immunoprecipitation on microarrays (ChIP-chip), and a novel genome-wide cytosine methylation
assay developed at AECC. NimbleGen services are managed by this facility. Within the context
of this application all of the microarray services (Affymetrix, NimbleGen and in-house printing)
have now been consolidated in this shared resource to provide a single source of intellectual
guidance to users and enhance cost-effectiveness. The facility provides access to three
computer workstations with design and analysis software to support a number of the services.
Over the past five years the capacity of the facility has been increased so that turnaround time
has been substantially decreased and fees to users have been decreased.


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3.10    Histopathology

The Histopathology Shared Resource provides AECC investigators with a full range of
histotechnology and histopathology services with a major focus on mouse models of human
cancers. The facility also supports the veterinary services of the AECC Animal Barrier Shared
Resource where AECC investigators' mice are housed. The facility provides necropsy and
histopathology services for phenotypic analysis along with a full range of histological services
including tissue preparation, paraffin and frozen embedding, standard and specialized stains
and immunohistochemical analyses to meet the needs of AECC investigators. Several new
techniques have been added since the last CCSG review. These include: (1) Staining with the
new ‘polymer’ technology which negates the need for avidin/biotin based staining giving less
background staining and reducing protocol length. (2) Immunohistochemical characterization of
multiple proliferation markers in the mouse (BrdU, Ki67, PCNA, and pRb) that allows the
investigator to choose different proliferative windows, with or without special experimental
manipulation prior to sacrifice. (3) Immunohistochemical detection of LacZ protein, which is
more sensitive and specific than X-gal staining, and allows integration of this marker into
standard paraffin-section based histology. (4) Immunoalkaline phosphatase detection with a
new fuchsin substrate that allows xylene-based mounting and higher resolution than aqueous
mounting. (5) Double antibody detection combining immunoperoxidase with DAB-nickel
detection, and immunoalkaline phosphates with new fuchsin detection. (6) Immunofluorescence
protocols for conventional paraffin sections, utilizing fluors with spectra that do not overlap with
tissue autofluorescence, and blocking agents that quench autofluorescence. This allows
immunohistochemical and conventional light microscopic analyses to be carried out on
consecutive sections of routinely processed tissue specimens. A Chemicon Tissue Arrayer was
recently acquired for the production of custom tissue arrays. The facility provides consultative
support and training to members, their trainees, and their staff.

3.11    Proteomics

The Proteomics Shared Resource provides state-of-the-art protein technologies for cancer
research with a focus on application of mass spectrometry and analytical chemistry. Services
include: protein identification from samples in solution or in 1D or 2D gels; 2D gel
electrophoresis, 2D-DIGE, image analysis, spot picking, and spot digestion; mass spectrometry
analysis of protein complexes; membrane proteins; organellar proteomes and subproteomes;
quantitative analysis of protein expression in different experimental conditions; posttranslational
modifications; top-down analysis of proteins; development of biomarker and discovery projects;
small molecule analysis by LC-MS, and hydrogen-deuterium exchange studies for protein
dynamics. There is an adjacent computing area for offline mass spectrometry data analysis plus
web-based searches and data mining. Major developments since the last review include a
major renovation of the entire Proteomics facility and the installation of cooling equipment for
temperature stabilization of instruments. Four new mass spectrometers (TOFTOF, LTQ linear
trap, FT-ICR, QSTAR XL) were acquired along with a Typhoon fluorescence scanner. Several
new highly qualified staff members have also been recruited to provide expertise on FT-ICR
mass spectrometry, hydrogen-deuterium exchange mass spectrometry, and quantitative
proteomics. Peptide synthesis was discontinued at the end of 2005 based upon the availability
of high-quality peptides from companies in the commercial sector, allowing more effective
utilization of personnel to support other critical services of high priority to users. The facility has
played an important role in a variety of mass spectrometry applications that support high-priority
AECC initiatives. These include development of transition-state enzyme inhibitors, the study of
tubulin isoforms and microtubule-inhibitor binding sites, proteomic analyses as a predictor of


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breast cancer risk and for the prediction of response to treatment in squamous cell cancer of the
head and neck. The facility has been active in the development of new methodologies to meet
AECC investigator needs and in training AECC investigators so that they can use open-access
laboratory equipment.

3.12    Structural Biology

The Structural Biology Shared Resource provides the expertise needed to obtain high resolution
structures by NMR and X-ray diffraction. These structural approaches are complemented by
significant strengths in computational biology, cryo-electron microscopy, electron paramagnetic
resonance, a wide range of vibrational spectroscopies and the development of novel
macromolecular footprinting approaches at the College and AECC. The X-ray component has
access to ~50 days/year on the X9A bending magnet beamline at the National Synchrotron
Light Source (NSLS), Brookhaven National Laboratory. An additional one day/month is currently
available on the X29 insertion device at NSLS through the New York Structural Genomics
Research Consortium (NYSGRC), along with access to the X4 bending magnet beamlines
through Einstein's participation in the New York Structural Biology Center (NYSBC). The
NYSGRC also provides access to the SGX-CAT beamline at the Advanced Photon Source,
which offers FEDEX crystallographic service. These arrangements ensure that access to data
collection resources is never rate-limiting. There is also in-house Rigaku rotating anode/image
plate data collection capabilities essential for characterization and pre-screening of samples
prior to synchrotron analysis. The NMR component at AECC consists of 300 MHz and 600 MHz
NMR spectrometers, one with a cryoprobe. In addition, AECC investigators have full access to
the NYSBC which houses two new 900 MHz and three 800 MHz instruments both with
cryoprobes, and one 750 MHz solid state NMR spectrometer. The facility is now providing
dedicated protein expression and purification expertise initially on E. coli expression systems
due to the relative efficiency and throughput. It is anticipated that these efforts will be expanded
to include higher order expression systems (i.e., insect and mammalian cell systems) and cell
free expression systems. The enhancement of this service is considered to be the single most
direct route to increasing the utilization of the Structural Biology Shared Resource by AECC
members. The capability of the facility has been strengthened by the acquisition of a custom
designed TECAN crystallization robot that can support the rapid (minutes) generation of a 96-
well crystallization trial.

3.13    Transgenic

The transgenic shared resource was founded in 1988 to train and assist AECC investigators in
the production and characterization of transgenic mouse strains. This technology allows
analysis of gene function through the introduction of DNA sequences into the germline, usually,
although not exclusively, by pronuclear injection of fertilized oocytes. The shared resource
director consults with individual investigators and advises on transgene constructs, making
plasmids, sequence cassettes, as well as other reagents. This results in DNA constructs
suitable for expression in the mouse. Usually this is in the form of a plasmid but the injection of
BAC DNA is also offered. The facility prepares the DNA and introduces this DNA into oocytes
by micro-injection. In some cases the sequence of interest is introduced into the oocyte by
lentivirus infection. After the manipulation of the oocyte they are transferred to pseudo-pregnant
mothers and, following birth, the pups are cared for to weaning. At this point mice are returned
to the investigator for further analysis. The production of useful transgenics usually takes less
than seven weeks from submission of the DNA. At least three founders are guaranteed per
construct although generally more are generated. There has been an essentially 100% success
rate with little need for re-injection of constructs. Between18-25 investigators use this service


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per year with approximately 100 constructs injected. In addition, the core provides embryo and
sperm freezing for long-term storage of mouse lines and in vitro fertilization (IVF) and intra-
cytoplasmic sperm injections (ICSI) to rescue frozen samples or difficult-to-mate strains.
Blastomere fusion is also provided to generate tetraploid embryos for aggregation with ES cells
to determine whether the phenotypes of mutations are intrinsic to the embryo or are the result of
placental abnormalities.




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4.0     AECC CLINICAL RESEARCH SHARED RESOURCES

4.1     Central Protocol and Data Management Unit

The Central Protocol and Data Management Unit (CPDMU) is a shared AECC resource widely
used by members from the various oncologic disciplines to perform clinical and translational
trials. The CPDMU plays a central role that supports other components of the clinical trials
infrastructure including the Protocol Review and Monitoring System (PRMS), Protocol Specific
Research Support (PSRS), and Data and Safety Monitoring Committee (DSMC). The CPDMU
administrative office is located on the second floor of the Weiler Division of Montefiore Medical
Center (MMC), and is immediately adjacent to the administrative office of the CPDMU Director
and to the Chanin Cancer Research Institute. The CPDMU performs the following functions:
protocol submission, regulatory affairs, data management and development, facilitates
interactions with the Bioinformatics and Biostatistics Shared Resources, provides quality control,
and serves as a resource for AECC investigators who require assistance in the design of clinical
trials. Services provided include: cataloging, preparing and submitting all new clinical protocols,
informed consent documents, and HIPAA authorization documents to the PRMS and to the
AECOM CCI and/or MMC IRB. Additional services include preparing a Spanish version of
informed consent documents, conforming to CCI/IRB guidelines for a fully translated consent for
non-English speaking subjects, cataloging and submission of all amendments, collection,
processing and distribution of all internal and external adverse events including distributions to
IRB and governmental agencies, initiation of all new clinical protocols, submission of sequence
numbers to pharmacy (insuring that all patients enrolled in clinical trials are properly entered into
the clinical database), overseeing eligibility check, registration and enrollment of new patients,
overseeing proper collection of data, recording of toxicities, dose modifications, performance of
tests in a timely fashion, submission of forms in a timely fashion, and scheduling and
performance of follow-ups. There are approximately 25 FTE CPDMU staff. Clinical trials are
supported by a N01 Phase II Contract (CA CM-17103), ECOG U10 grant (CA14959), AIDS
Malignancy Consortium U01 core site subcontract, along with funding from investigator-initiated
NCI and pharmaceutical industry studies.

4.2     Protocol Review and Monitoring

Scientific review and oversight of clinical trials at the AECC is a function of the Protocol Review
and Monitoring System (PRMS). The primary objective of the PRMS is to assure that clinical
research performed at the AECC is of the highest quality. Specifically, the functions of the
PRMS are: a) To review all new protocol submissions and amendments to evaluate their
scientific merit and feasibility. (b) To monitor accrual to ongoing studies on a continuing basis, to
assure that protocols meet their accrual goals in a timely fashion, thus assuring that the
research goals are met. (c) To ensure that there are no competing studies with completely
overlapping eligibility, and that there is adequate justification and patient resources in
circumstances where it may be desirable to have more than one protocol for a specific
indication, (d) To provide recommendations as to whether AECC investigator-initiated studies
are of sufficient scientific merit to warrant allocation of Protocol Specific Research Support
(PSRS) and/or other resources required for conduct of the study. The PRMS functions are
carried out by the Protocol Review and Monitoring Committee (PRMC). Members of the PRMC
are selected both to assure broad representation from the oncology clinical research community
and to assure the highest quality of review. Members are chosen who represent the different
clinical disciplines (e.g., surgery, adult-, pediatric-, medical-, gynecological- and radiation-
oncology; pathology, radiology) and therapeutic modalities (i.e. cytotoxic therapy,
immunotherapy, radiation), as well as expertise in various stages of drug development (Phases


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I, II, III trials) and translational science. The committee also includes representatives from,
nursing, pharmacy, data management, and biostatistics, a member from the AECOM CCI not
associated with AECC, and an external member.

4.3     Protocol Specific Research Support

Protocol Specific Research Support (PSRS) supports the conduct of innovative, high-priority
phase I and phase I-II investigator-initiated trials. In order to be eligible for PSRS support, the
study must be led by an AECC investigator or resulted from previous clinical or preclinical
studies performed at AECC. A process has been established for designating PSRS, which
includes a screen by the CPDMU for eligibility, evaluating the scientific merit of the study (as
determined by the PRMC), and assigning priority relative to other AECC investigator-initiated
trials. Clinical trials supported by PSRS included protocols evaluating the clinical and immune
effects of an HspE7 vaccine in patients with CINIII, the clinical and biologic effects of combining
the farnesyltransferase inhibitor tipifarnib with standard chemotherapy in locally advanced
breast cancer, and defining the recommended phase II dose, pharmacokinetics, and
pharmacodynamics of the epothilone B analog ixabepilone. These studies have led to additional
CTEP-sponsored and industry-sponsored phase II and phase III trials evaluating the effects of
HspE7 in patients with CINIII, tipifarnib in locally advanced breast cancer, and ixabepilone in
patients with advanced breast cancer.




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5.0     AECC STRATEGIC PLANS AND NEEDS

5.1     Expansion of the Clinical Oncology Services with Associated Laboratory and
        Clinical Research Programs to Encompass All Major Cancer Disease Sites –
        These Include the Specialties of Medical, Surgical, and Radiation Oncology.

There are now disease-specific affinity groups with clinical and laboratory representation in lung
and head and neck cancers, along with extensive collaborative research on breast cancer, with
a variety of translational research activities that span laboratory to clinic and clinic to laboratory
in most AECC programs. AECC needs to expand the scope of diseases studied and strengthen
existing affinity groups. Whenever possible, recruitment of physician-laboratory scientists to
buttress basic research components would be desirable.

Osteosarcoma - With the recruitment of Richard Gorlick, an expert in osteosarcoma from the
clinical and laboratory perspectives, there is the opportunity to build on this expertise and
resource by recruitment of a basic scientist who works on this disease and will engage other
AECC basic investigators in this area.

Brain Tumors - With the recruitment of Adam Levy, a pediatric neuro-oncologist and Richard
Abbott, a neurosurgeon, along with several basic investigators already at Einstein (Kalpana,
Hebert, Mehler) who work on neural development, mouse models, and rhabdoid tumors there is
the opportunity to form a strong brain tumor affinity group. This group is already acquiring a
bank of brain tumors that will be available for correlative studies. Recruitment of a basic scientist
is needed whose major focus is on brain tumors.

Melanoma - With the development of a new agent for the treatment of melanoma along with
ongoing research in this area, it will be important to recruit a medical oncologist with expertise in
melanoma; a physician-scientist with a laboratory effort on melanoma would be of particular
value.

Hematological malignancies - There are strong laboratory and correlative studies focused on
hematological malignancies along with a drug development effort in this arena that
encompasses many programs. This is supported by a bone marrow transplantation program at
MMC. A clinical leader of this group is required with at least regional stature.

Colon Cancer - The Biology of Colon Cancer program is engaged in basic, translational, and
correlative research but requires the addition of a seasoned medical oncologist who will add
investigator-initiated clinical studies based upon laboratory discoveries.

Surgical Oncology - The search for the Chair of the Department of Surgery at the Montefiore
Medical Center is in progress. The lack of a surgical oncology leader is a critical deficiency at
AECC. Leadership, along with seasoned surgeons who work in the areas of breast and GI
cancer are needed.

5.2     Programmatic Needs

Immuno-oncology - Laboratory investigators are needed who work in the areas of:
   Cancer vaccine development
      X- axis: Infect/Imm, Women’s Health, Liver Diseases
      Y-axis: Imaging, chemisty, human genetics



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    Development of agents that augment the immune response at the level of the immune
       synapse
       X-axis: Infect/Imm, Liver Diseases, Metabolic Disorders, Women’s Health, Aging
       Y-axis: Chem Biol., Struct Biol., Imaging, Human Genetics, Cell-Cell, signaling

Tumor Microenvironment and Metastasis; Molecular Membrane Biology - Areas that are
critical to both these AECC programs include; angiogenesis, molecules that transmit signals
from matrix including integrins, proteoglycans and other matrix molecules, molecules that alter
the membrane lattice structure such as galectins, molecules involved in tumor cell extravasation
like the selectins, and cells in the microenvironment including immune cells, fibroblasts and
adipocytes.
         X axis: Liver Diseases, Aging, Infect/Imm, Vasc. Biol.
         Y axis: Imaging, Chem. Biol., Struct. Biol., Stem Cells, Cell-Cell, Signaling

Cell Growth and Differentiation Control - There is a strong interest in this program on stem
cells and lineage commitment; specifically, understanding the mechanisms required to (i)
recapitulate the embryonic to adult stem cell transition and to (ii) activate endogenous stem
cells, especially neural stem cells. Other areas encompass (i) the epigenomics of cancer stem
cells, especially in leukemia, (ii) understanding the mechanisms that control asymmetric
divisions of stem cells and (iii) applications of stem cells for cell and gene therapy. This
program encompasses members who work in the areas of liver diseases, neurosciences as well
as hematopoiesis/leukemia – hence are intrinsically related to several of the health-related
focus areas. On the Y-axis, this work is intrinsic to Stem Cells and Regenerative Medicine but
relates to many other themes: cell-cell, imaging, chemical biology, etc.

This program is also a focal point for the epigenetics and other high-thruput genomics activities
although this research encompasses members from many other programs. This effort is highly
dependent upon Computational Science and Systems Biology which is a very high priority for
the Cancer Center.

Experimental Therapeutics - This program is the focal point for drug development based upon
targets identified by laboratory investigators in all AECC programs. It is also the base for
disease-focused affinity groups. The latter needs were addressed in the first paragraph of this
section. This program requires enhanced expertise in, and is highly supportive of recruitment
and core development in, the areas of Chemical Genomics and Chemistry. These activities will
impact on many of the Health-related focus areas and the Science-Technology themes. Drug-
development efforts draw heavily on Imaging as the effects of agents are evaluated in animal
tumor systems. Structural Biology is required for characterization of target and target-inhibitor
structures. Since agents are likely to act at the level of cell-cell interactions and signaling, these
theme areas are relevant. The development of methodologies for prediction of drug responses
and natural history of diseases at different stages requires functional genomic, epigenomic, and
proteomic studies and depends heavily on Computational Science and Systems Biology.

Cancer Epidemiology / Population Sciences - AECC has developed a strong effort in cancer
epidemiology but additional depth is needed particularly in the areas of molecular and genetic
epidemiology. Two other areas of population sciences are required to meet NCI’s expectations
that this center will move towards comprehensive status and will increasingly address the needs
of the Bronx population this medical center serves. First, a robust Behavioral Sciences-Cancer
Prevention program is required building upon strengths focused on smoking prevention
(Bernstein/Wills) and nutrition (Wylie-Rosett). This will require recruitment of several new
faculties, including at least one who is funded, and should be part of a larger academic unit that


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encompasses many of the other Health-Related Focus Areas including Metabolic Disorders,
Infection/Immunity, Women’s Health, Vascular Biology, among others. This has been
designated as a “Theme Area”. The important point here is that there needs to be an academic
unit, with a senior leader, that brings together behavioral scientists that work in many different
areas, one of which is cancer prevention. This is in contrast to the current situation where
behavioral scientists are working in different departments with little or no contact with their
colleagues in other departments. The second important new area in population sciences is in
cancer genetics. There is essentially no research in this area at Einstein at this time.

Biology of Colon Cancer Program - This is a highly successful AECC program that draws
heavily on mouse models of human colorectal cancer. Maintenance of sufficient mouse cages to
accommodate growth of this program is critical. Studies in this program are now extending to
the role of inflammation in intestinal cancer and will benefit by the recruitment described above
for the Tumor Microenvironment and Metastasis Program. This work relates to several of the
other Health-Related Focus Areas as well as to the Imaging, Stem Cell, Computational Science
and Systems Biology, Cell-Cell, and Signaling Theme areas. An important component of
research in this program is directed to nutritional and genetics aspects of colorectal cancer
prevention and this will benefit from the expansion of a Behavioral Sciences academic unit with
a strong cancer prevention program.

5.3     High priority Core Laboratory Facilities

Tissue Acquisition - This has been a high-priority for AECC; a developing tissue acquisition
shared resource is now functioning under the leadership of Dr. Michael Prystowsky. This facility
now meets the needs of the Head and Neck Cancer Affinity group and has facilitated the
acquisition of fresh tissues for a number of other investigators and affinity groups, especially for
the use of xenografts for studies on lung, breast, ovarian, and head and neck cancers. This
facility should be expanded to a full-service unit that meets the needs of all AECC investigators
along with other Einstein faculty. All Health-Related Focus Areas would benefit by this type of
facility. The facility would coordinate tissue procurement, processing and distribution of fresh
human tissues. Other potential services might include isolation of macromolecules, retrieval of
archival paraffin embedded tissue, preparation of tissue microarrays, and maintenance of a
database of tissues that have been acquired and distributed. This facility would interact will
several of the Science/Technology Theme Areas in Imaging, Stem cells, Cell-Cell, Signaling.

Imaging - The Magnetic Resonance Imaging Research Center was established at Einstein
since 2001 but there has been minimal use of this facility by AECC members. It is essential that
the new director support and encourage cancer-relevant as well as other applications. The
Micro-Pet Imaging Facility became operational the summer of 2006; it is used by AECC
members. Space has been allocated for an imaging facility in the Price Center that can contain
MicroPet, ultrasound, and in vivo fluorescence technologies. This will permit repetitive
analyses of tumor and metabolic behavior without removing animals from the Animal Barrier
Shared Resource, thus reducing the number of animals required for analyses of phenotype and
response to therapies. At the present time MicroPet does not include CT and there is neither an
ultrasound nor in vivo fluorescence instruments for use behind the barrier. It is important that the
College provides all these technologies to Einstein investigators, as an intregrated unit, along
with ongoing administrative and infrastructure support. This facility would support several of the
Health-Related Focus Areas, in particular Metabolic Disorders, Liver Diseases, Neuro, and
Aging. This represents one element in the Imaging Science/Technology Theme Area.




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Chemical Biology – This facility would be an important addition to the drug development efforts
at AECC. Currently, AECC investigators collaborate with scientists at other institutions who
have screening and chemistry capabilities. Einstein lacks the ability to screen large libraries and
modify lead molecules. Hence, promising agents are licensed to pharmaceutical firms at a very
early stage, placing Einstein at a significant disadvantage. AECC is very supportive of
developing Chemical Biology/Chemistry capabilities at this institution.

Bioinformatics - The College has provided resources for the development of a Bioinformatics
Facility. Some AECC funding has also been directed to this effort. This facility supports
functional genomics, epigenomics, and proteomics research along with clinical therapeutic and
correlative studies. While some funding may become available through the Cancer Center
Support Grant, this facility will require substantial ongoing funding from the College. This facility
is, and will be, essential to many of the Health-Related Focus Areas and will support many of
the Science/Technology Theme Areas including Imaging, Chemical Biology, Computational
Sciences and Systems Biology, Human Genetics.




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