Developmental Research Awards

2002

1. Characterization of LMP1 signaling and effects in EBV-associated human lymphoma
   Investigator: Gail Bishop, Ph.D., University of Iowa
2. Characterization and molecular profiling of murine T cell lymphomas from mice expressing Bax versus Bcl-2
   Investigator: Michael Knudson, M.D., Ph.D., University of Iowa
3. Correlative Studies to Predict Response in a Clinical Trial of CpG ODN for CLL
   Investigator: James Wooldridge, M.D. (formerly University of Iowa)

4. The Role of BLyS in Lymphoma Growth and Survival
   Investigator: Anne Novak, Ph.D., Mayo Clinic

   This Developmental Research project focused on the tumor necrosis factor (TNF) family member BLyS (B-Lymphocyte Stimulator) and its role in lymphoma cell survival. Novak found that tumor cells from the different NHL histologic subtypes expressed one or more of the three known receptors for BLyS (BCMA, TACI, and BAFF-R); however, the pattern of expression of these three receptors was variable. Dr. Novak provided evidence that serum BLyS levels are elevated in a subgroup of NHL patients. She also demonstrated the importance of BLyS in B-cell survival. In the second year, she worked with a number of collaborators to identify small molecule inhibitors. This developmental project serves as the foundation of Project #3 in the 2007 SPORE competitive renewal application. Dialog that centered around this Developmental Research Award also led to collaboration between Dr. Novak and Stephen Ansell, M.D., Ph.D., at Mayo Clinic; and Dr. Bishop.

5. Interrogation of B-cell Signaling in Primary CNS Lymphoma
   Investigator: Brian O'Neill, M.D.

   Compelling data suggest that primary CNL lymphoma has both an infectious disease and immunologic component. The purpose of this Developmental Research award was to explore the proposal that viral genome integration into a host CNS cell results in an overproduction of survival factors, especially those of NF_B-associated-pathways. Brain lymphoma specimens were obtained in collaboration with Mayo Clinic Cancer Center's Brain SPORE and demonstrated expression of BLyS in peri-vascular and permeative malignant lymphocytes in a cohort of diffuse large B-cell lymphomas of brain. SV40 Large T Antigen (SVLTA) was found in tumor specimens from 14 of 17 primary CNS lymphoma specimens but not glioma specimens, autopsy brain, or systemic lymphoma specimens. These studies provide the rationale to study samples for BLyS and SVLTA to learn if they are predictive or prognostic markers in this disease.

   This is one of a number of inter-SPORE collaborations at Mayo Clinic Cancer Center.

6. Biodistribution of Radio-labeled Interleukin-2 in Patients Undergoing Immunotherapy of Lymphoma
   Investigator: Greg Wiseman, M.D., Mayo Clinic

   Radio-labeled IL-2 binds to T-lymphocytes and monocytes in mononuclear cell mediated inflammatory processes characterized by over expression of the IL-2 receptor CD25. Several UI/MC SPORE investigators, both at the University of Iowa and at Mayo Clinic, have explored the importance of T-cells infiltrating B-cell lymphomas. Because it is difficult to re-biopsy lymph nodes in these patients after therapy has started, we have sought to develop novel imaging techniques that can provide information on how new treatments are impacting the immune response. In this study, procedures were developed to label IL-2 with I-123, and to quantitate the radio-labeled IL-2 biodistribution within the normal organs and tumors in patients before and after immunotherapy with quantitative gamma camera planar and SPECT tomographic imaging. The agent has been produced successfully, and support for clinical evaluation in patients before and after immune modulating therapy is being sought.

2003

1. Heterogeneity of treatment benefit by grade of follicular lymphoma
   Investigator: Elizabeth Chrischilles, Ph.D., University of Iowa
2. Immunotherapy with GammaDelta T Cells for B Lymphomas
   Investigator: Craig Morita, M.D., Ph.D., University of Iowa
3. Molecular Regulation of Migration in SLL/CLL
   Investigator: Irene Ghobrial, M.D. (formerly University of Iowa)

4. Fluorescence in situ Hybridization Detection of Cytogenetic Anomalies in Peripheral T-cell Lymphoma
   Investigator: Karen Grogg, M.D., Mayo Clinic

   Peripheral T-cell lymphomas (PTCL) continue to present a diagnostic and classification challenge. Dr. Grogg evaluated whether FISH detection of cytogenetic anomalies would be a more sensitive and specific test than PCR- based T-cell receptor gene arrangement studies in demonstrating clonality in PTCL. She also evaluated FISH on single cells obtained by laser capture microdissection to detect novel translocations that could better delineate prognosis and diagnosis in PTCL. She focused her studies on angioimmunoblastic T-cell lymphoma (AITL) because it has not been well characterized. Sixteen of 21 AITL specimens (76 percent) were clonally abnormal. +X and +5 were the most common clonal anomalies observed (nine cases each).

   Dr. Grogg also used her Developmental Research award to perform studies of chemokine receptors in PTCL. Paraffin sections of 29 AITL lymph nodes were studied, with cytoplasmic expression of CXCL13 observed in the tumor cells in 86 percent (25/29) of cases. This finding provides evidence linking the tumor cells to germinal center T-helper cells and may provide insight into development of targeted immunomodulatory treatment strategies for this disease.

   Dr. Grogg's work has led to a new biomarker (CXCL13) for AITL that has now become a routine part of the evaluation of PTCL in the hematopathology laboratory.

2004

1. Genetic Epidemiology of Lymphoma
   Investigator: Susan Slager, Ph.D., Mayo Clinic

   Non-Hodgkin lymphoma (NHL) is the fifth most frequently diagnosed cancer among both men and women in the United States. Although NHL is known to be influenced by immunosuppression and viral infections agents (established risk factors), the majority of NHL etiology cannot be explained. There is significant evidence that a genetic component exists, and that this genetic component extends across all NHL subtypes.

   The overall aim of this project is to investigate the genetic basis of NHL through the use of high-risk NHL families. In order to achieve this overall aim, Dr. Slager and other research colleagues pooled resources across six institutions to form a multi-center, multidisciplinary consortium, Genetic Epidemiology of NHL (GEN) Consortium. This consortium is funded by the National Cancer Institute (NCI) and includes investigators from Mayo Clinic, M.D. Anderson, NCI, City of Hope, the University of Iowa, and the University of Utah. This family-based research resource allows Dr. Slager and her team to develop a study population enriched for genetic exposures and will position the researchers to characterize the genetic risk of NHL.

2. The Role of Immunglobulin in T-cell Immune Reconstitution after Autologous Hematopoietic Stem Cell Transplantation
   Investigator: Luis Porrata, M.D., Mayo Clinic

   Immune reconstitution after high-dose chemotherapy is critical for the patient's ability to fight infection and tumor recurrence. Dr. Porrata's group has demonstrated in multiple publications that the absolute lymphocyte count (ALC) recovery by Day 15 after an autologous stem cell transplant (ASCT) is an independent prognostic factor for event free and overall survival of patients with lymphoid disease. Immunoglobulin has been shown to promote/regulate T-cell immunity driving T-cells development/maturation, activating peripheral responses to antigens and being fundamental to the diversification of the T-cell repertoire. The hypothesis of this Developmental Project is that high levels of polyclonal serum immunoglobulin will promote post-transplant T-cell recovery. Dr. Porrata is measuring levels of serum immunoglobulin, recent thymic emigrants, and determining the proportion of naive versus memory CD4+ and CD8+ T-cells and their T-cell receptor diversity in patients currently undergoing ASCT for NHL.

2005

1. Role of EYA-4 in non-Hodgkin's Lymphoma
   Investigator: Julian Molina, M.D., Ph.D., Mayo Clinic

   Dr. Molina has performed a comprehensive genome wide search for methylated genes in a pool of human cancers and found eight genes with aberrant methylation; among them the EYA-4 gene. The role of EYA-4 gene alternations in human cancers remains unexplored; and specifically, there is no data regarding these genes in lymphoma. Molina has now studied 72 lymphoma samples and found that 45 demonstrated methylation of EYA-4. When the types of lymphoma were evaluated 20 of 24 large cell lymphomas were positive compared to only eight of 24 diffuse small lymphocytic samples (p<0.001). Patients with silencing of EYA-4 had a poor prognosis. Methylation of this gene was found in only three of 24 benign nodes. Molina's studies are ongoing and he is performing methylation mapping of the EYA-4 promoter.

2. Complement Polymorphisms and Response to Rituximab
   Investigator: Emil Racila, M.D., University of Iowa
3. Functional Role of PIM1 Mutations in Lymphomagenesis
   Investigator: Masaki Kashiwada, Ph.D., University of Iowa
4. Degradable particles/Lymphoma immunoprotection
   Investigator: Aliasger Salem, Ph.D., University of Iowa

2006

1. Induction of apoptosis in B-CLL with TRAIL and HDAC inhibitors
   Investigator: Thomas Griffith, Ph.D.

2. Development of a model for studying the role of regulatory T-cells in the tumor microenvironment of B-cell non-Hodgkin's lymphoma
   Investigator: Stephen Ansell, M.D., Ph.D., Mayo Clinic

   Dr. Ansell has previously demonstrated that infiltration of T-lymphocytes into B-cell lymphomas correlates with the outcome of patients. The overall hypothesis of the current study is that tumor Treg cells regulate the proliferation in malignant lymphoma B-cells by suppressing other tumor infiltrating T-cells thereby inhibiting the anti-tumoral T-cell response to malignant B-cells. He further postulates that malignant B-cells play an active role in this process by selectively recruiting Treg cells to the areas of B-cell NHL. The preliminary data from the previous funding period as well as from the work done so far in this Developmental Research project has provided the data for Project #4 in this renewal and is outlined in detail in that project.

3. Evaluation of sorafenib (raf kinase/VEGFR inhibitor) combinations in non-Hodgkin lymphoma (NHL)
   Investigator: Shaji Kumar, M.D., Mayo Clinic

   Tumor angiogenesis is a striking feature of NHL and increased tumor angiogenesis has been shown to be a poor prognostic predictor for these patients. The vascular endothelial growth factor (VEGF) is a key driver of tumor angiogenesis in multiple tumors including NHL. The raf/MEK/ERK pathway has been shown to be important in the proliferation of a majority of cancers including NHL.

   Sorafenib is a dual raf kinase/VEGF receptor inhibitor that has shown clinical promise in several solid tumors as well as impressive preclinical activity in multiple myeloma. Dr. Kumar and his colleagues have demonstrated potent in vitro activity of this drug in the setting of lymphoma. In addition, they have identified potent anti-lymphoma activity of sorafenib when combined with proteasome inhibitors (bortezomib) or mTOR inhibitors (rapamycin or its analogs) in vitro.

   Preliminary studies have demonstrated synergy between sorafenib and the mTOR inhibitor rapamycin. This has led to a Phase I/II clinical trial in patients with relapsed lymphoma that is currently going on through the lymphoma SPORE. The researchers are in the process of completing pre-clinical studies examining the role of combining this drug with other signal transduction inhibitors. They will explore inhibitors of this pathway in lymphoma cell lines and patient samples to assess whether there is preclinical rationale for testing these agents in NHL patients. In addition, in vitro studies with different lymphoma cell lines will delineate the mechanisms of cytotoxicity or resistance observed. Finally, Dr. Kumar's team will test the most promising combinations in a severe combined immunodeficiency (SCID) mouse xenograft model of lymphoma to confirm in vivo the activity of these combinations.

4. Radiosensitizer in combination with radioimmunotherapy for non-Hodgkin's lymphoma
   Investigator: Apollina Goel, Ph.D., University of Iowa