RESEARCH PROJECTS SUPPORTED BY THE LYMPHOMA FOUNDATION

THE LYMPHOMA FOUNDATION SUPPORTS WORK BY CLINICIAN/SCIENTISTS WHO ARE AT THE FOREFRONT OF INNOVATIVE RESEARCH

RESEARCH OF AGING AND CANCER

THROUGH the Lymphoma Foundation's Werner and Elaine Dannheisser Fund for Research on the Biology of Aging a grant has been distributed for A Pilot Study to Utilize Linkage Disequilibrium to Discover Genetic Polymorphisms That Are Protective Against Cancer in the Elderly by Kenneth Offit, M.D., M.P.H. Memorial Sloan-Kettering Cancer Center, New York, New York

In his grant proposal solicited by the Lymphoma Foundation Dr. Offit stated: “The demographic phenomenon of the aging and increasing size of the U.S. population will lead to a doubling of the current number of cancer cases by the year 2050. Cancer will become even more important as a threat to the health of the elderly, compared, for example to cardiovascular diseases. Increasing evidence demonstrates that a significant proportion of cancer is due to hereditary causes. Genetic mutations have been shown to cause familial cancers of the breast, prostate, colon, ovary, and other sites.

Less well studied, however is the hypothesis that genetic factors may also be protective against these cancers. This project will perform pilot studies that will set the stage to test this hypothesis in a genetically homogeneous and well-studied population: the Ashkenazim….. Identification of genes associated with decreased risk for cancer in the elderly will allow a better understanding of the biology of cancer-resistance. The proteins encoded by these cancer-protective genes may be involved in biologic processes that are amenable to modulation in the general population, thus decreasing the cancer burden.”

This genetic research and the study of the role of telomeres in the prevention of human aging relates to the causation of all forms of cancer.

ABOUT TELOMERES

“Recent research has shown that inserting a gene for the protein component of telomerase into senescent human cells reextends their telomeres to lengths typical of young cells, and the cells then display all the other identifiable characteristics of young, healthy cells. This advance not only suggests that telomeres are the central timing mechanism for cellular aging, but also demonstrates that such a mechanism can be reset, extending the replicative life span of such cells and resulting in markers of gene expression typical of "younger" (i.e., early passage) cells without the hallmarks of malignant transformation. It is now possible to explore the fundamental cellular mechanisms underlying human aging, clarifying the role played by replicative senescence. By implication, we may soon be able to determine the extent to which the major causes of death and disability in aging populations in developed countries-cancer, atherosclerosis, osteoarthritis, macular degeneration, and Alzheimer dementia--are attributable to such fundamental mechanisms. If they are amenable to prevention or treatment by alteration of cellular senescence, the clinical implications have few historic precedents.” Telomerase and the aging cell: implications for human health. Fossel M. JAMA. 1998 June 3;279(21):1732-5.

Because the role of the telomere in its effect on 'normal aging' as well as its role in cancer formation may be the source of promising new ways to treat all forms of cancer as well prolong life in general... through the Lymphoma Foundation's Werner and Elaine Dannheisser Fund for Research on the Biology of Aging a research grant was awarded to Dr. Christopher Counter, Ph.D. Department of Pharmacology and Cancer Biology, Duke University Medical Center, to help support his research efforts with regard to the telomere.

Exploring the role of the telomere with regard to his cancer research and the research of ageing Dr. Counter wrote: "...telomere shortening may limit the ability of human cells to regenerate tissues after years of use. Indeed, excessive telomere shortening in mice causes some aging phenotypes and in humans is thought to play a role in the disease dyskeratosis congenital, which is characterized by a decrease in the proliferative potential of certain tissues. Moreover, cells from patients with premature aging syndromes like Hutchinson-Gilford Progeria and Werner's Syndrome have shorter or abnormal telomeres compared to age-matched controls. Telomere shortening in vascular cells has also been implicated in atherosclerosis, a disease associated with aging. Understanding how telomeres length is controlled should provide important insight into the molecular clock that governs the replicative potential of cells and ultimately the ageing process itself."

THE MARIE PROJECT INITIATIVE of the LYMPHOMA FOUNDATION

Young women exposed to radiation therapy to the upper body for the treatment of Hodgkin’s or the non-Hodgkin’s lymphomas have a significant increased risk of developing breast cancer. The only currently known way to improve survival in this setting is to start mammographic screening early... at least ten years after radiation therapy and therefore in many instances well before the age of 40. It is hoped that all young women in this category will alert their physicians to this need and review it with them. They should speak with their family physicians or their oncologists and request that they monitor their mammographic follow-up studies.

NOTE: The traditional ‘mantle’ radiation field used to treat lymph nodes in the chest and neck unfortunately included the medial portion of both breasts as well as the ‘tail’ portion of both breasts that extends into the armpits. Other less inclusive radiation fields may still include significant portions of breast tissue.

It is crucial, therefore, to develop methods to prevent and as well as to treat the late complications of therapy especially Breast Cancer, Ovarian Cancer, Colon Cancer and Cardiac and Pulmonary immobilizing disabilities. For that reason Lymphoma Foundation research and Fellowship grants have been awarded to Dr. Joachim Yahalom and Dr. Elisa Wu to continue this development of Intensity Modulated Radiation Therapy Radiation (IMRT) and to support the education of radiation therapists in these improved techniques.

TODAY: Radiation oncologists in the United States have just begun to use Intensity Modulated Radiation Therapy (IMRT)
In a study (published online: June 5, 2003 in the journal Cancer, volume 98, issue 1 pp. 204-21) to assess the current level of intensity-modulated radiation therapy (IMRT) use in the United States the authors Loren K. Mell, M.D., John C. Roeske, Ph.D., and Arno J. Mundt, M.D. concluded: “Approximately one-third of radiation oncologists in the United States use IMRT. However, this number appears to be growing rapidly.”
The importance of preventing or limiting radiation exposure to the heart, lungs, GI tract and bones is clear... as some of the late occurring side-effects of the radiation can be prevented.

THE APPLICATION OF NEW FORMS OF CHEMOTHERAPY

PROTEOMICS A unique form of chemotherapy using a Proteasome Inhibitor was recently approved by the FDA for clinical use in patients with lymphoma and other cancers. A primary clinical research trial had been conducted with partial grant support from the Lymphoma Foundation over the past three years (to Drs. Soignet and O'Connor of the Developmental Chemotherapy Service of the Memorial Sloan Kettering Cancer Center) resulting in the following publication in the Journal of Clinical Oncology in November 2002.

Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies By Robert Z. Orlowski, Thomas E. Stinchcombe, Beverly S. Mitchell, Thomas C. Shea, Albert S. Baldwin, Stephanie Stahl, Julian Adams, Dixie-Lee Esseltine, Peter J. Elliott, Christine S. Pien, Roberto Guerciolini, Jessica K. Anderson, Natalie D. Depcik-Smith, Rita Bhagat, Mary Jo Lehman, Steven C. Novick, Owen A. O’Connor, Steven L. Soignet Journal of Clinical Oncology, Vol 20, Issue 22 (November), 2002: 4420-4427. This unique chemotherapeutic agent now is known as Velcade

NANOGENERATORS TARGETING A WIDE VARIETY OF CANCERS including leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer may be possible

Another unique form of chemotherapy supported in part by Lymphoma Foundation grants to Drs. Houghton and Scheinberg is just being presented to the FDA for approval to use this treatment in patient clinical trials... moving the results of many years of basic laboratory research into the realm of direct patient care.

The following abstract from the research paper published in SCIENCE Vol. 294 16 November 2001 pp. 1537-1540 by Dr. Scheinberg's research group supported in part by Lymphoma Foundation grants is a forerunner to their application to the FDA to apply this treatment method in humans: Tumor Therapy with Targeted Atomic Nanogenerators Michael R. McDevitt, Dangshe Ma, Lawrence T. Lai, Jim Simon, Paul Borchardt, R. Keith Frank, Karen Wu, Virginia Pellegrini, Michael J. Curcio, Matthias Miederer, Neil H. Bander, David A. Scheinberg1* A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.

BONE MARROW or STEM CELL TRANSPLANTATION THERAPY

With partial support from Lymphoma Foundation grants Dr. Craig Moskowitz and the Lymphoma Treatment Group at the Memorial Sloan Kettering Cancer Center have been at the forefront of successful high dose chemoradiotherapy for patients with relapsing Hodgkin's disease or aggressive non-Hodgkin's lymphoma.
High-dose chemoradiotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis Kewalramani, T., Zelenetz, A.D., Hedrick, E.E., Donnelly, G.B., Hunte, S., Priovolos, A.C., Qin, J., Lyons, N.C., Yahalom, J., Nimer, S.D., Moskowitz, C.H., Blood, Vol. 96 No. 7 October 1, 2000: 2399-2404

A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model Moskowitz, C.H., Nimer, S.D., Zelenetz, A.D., ... Straus, D., Portlock, C.S., Yahalom, J., et al; Blood 1 February 2001, Vol. 97, No. 3 616-623.

PRIMARY CELL RESEARCH
With the assistance of Lymphoma Foundation grants Dr. Gerald Spangrude and his research team continue to study basic cell structure and function

Characterization of Thymic Progenitors in Adult Mouse Bone Marrow S. Scott Perry, L. Jeanne Pierce, William B. Siayton, and Gerald J. Spangrude (Departments of Oncological Sciences and Hematology University of Utah).
Thymic cellularity is maintained throughout life by progenitor cells originating in the bone marrow. In this study, we describe adult mouse bone cells that exhibit several features characteristic of prothymocytes. These observations describe the phenotype of an adult mouse bone marrow population highly enriched for rapidly engrafting, long-term thymocyte progenitors. Furthermore, they note disparity in B and T cell expansion from this lymphoid progenitor population and suggest that it contains the progenitor responsible for seeding the thymus throughout life. The Journal of Immunology (2003 in press) supported in part by a grant from the Brian Rooney Fund of the Lymphoma Foundation.

Aspects of early lymphoid commitment Hongfang Wang, MM, and Gerald J. Spangrude, PhD
Departments of Pathology, Oncological Sciences, and Medicine, Division of Hematology, University of Utah, Salt Lake City, Utah, USA (in press) Current Opinion in Hematology 2003, 10:000-00 This work was supported by grants from the National Institutes of Health (DK57899) and the Brian Rooney Fund of the Lymphoma Foundation.

The analysis of the inherited genetic characteristics of the lymphomas
A body of scientific information regarding the genetic characteristics of the lymphomas and the relationship with other cancers (e.g. colon cancer, breast cancer) has been developed with support of Lymphoma Foundation grants to Dr. Kenneth Offit and his research team and also see additional research by Dr. Offit and colleagues in 2004.

Similar Patterns of Genomic Alterations Characterize Primary Mediastinal Large-B-Cell Lymphoma and Diffuse Large-B-Cell Lymphoma, Palanisamy, N., Abou-Elella, A., Chaganti, S.R., Houldsworth, J. Offit, K., Louie, D.C., Terayu-Feldstein, J., Cigudosa, J.C., Rao, P.H., Sanger, W.G., Weisenburger, D.D., Chaganti, R.S.K., Genes, Chromosomes & Cancer, 33:114-122 (2002).
Rare Variants of ATM and Risk for Hodgkin’s Disease and Radiation-associated Breast Cancers, K. Offit,, S. Gilad, S. Paglin, P. Kolachana, L.C. Roisman, K. Nafa, V. Yeugelewitz, M. Gonzales, M. Robson, D. McDermott, H.H. Pierce, N.D. Kauff, P. Einat, S. Jhanwar, J.M. Satagopan, C. Oddoux, N. Ellis, R. Skaliter, J. Yahalom, Clinical Cancer Research, Vol. 8, 3813-3819, December 2002
Analysis of Mismatch Repair Defects in the Familial Occurrence of Lymphoma and Colorectal Cancer, Teruya-Feldstein, J., Greene, J., Cohen, L., Popplewell, L., Ellis, N.A., Offit, K., Leukemia and Lymphoma, 2002 Vol. 43 (8), pp. 1619-1626.
BRCA1 and BRCA2 Germline Mutations in Lymphoma Patients, O. Yossepowitch, N. Olvera, J. M. Satagopan, H. Huang, S. Jhanwar, B. Rapaport, J. J. Boyd, K. Offit, Leukemia and Lymphoma, 2003 Vol. 44 (1), pp. 127-13

Monoclonal antibody therapy of non-Hodgkin’s lymphomas and Hodgkin's disease

Rituximab for aggressive non-Hodgkin's lymphomas relapsing after or refractory to autologous stem cell transplantation. Pan D, Moskowitz CH, Zelenetz AD, Straus D, Kewalramani T, Noy A, Qin J, Teruya Feldstein J, Portlock CS. Cancer J. 2002 Sep-Oct;8(5):371-6. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
This was a retrospective study (between January 1997 and February 2000) evaluating single agent rituximab as treatment for aggressive non-Hodgkin's lymphoma in patients relapsing after or refractory to high-dose chemotherapy and autologous stem cell transplantation. These patients have a poor prognosis with an anticipated median survival of 6 months prior to the introduction of rituximab. Seventeen patients were treated (thirteen with diffuse large B-cell lymphoma and four with mantle cell lymphoma) and although the number of patients achieving a complete response (four) or a partial response (five) was limited, the overall improved responses and extended survival indicated that Rituximab was effective. It was also well tolerated with no serious adverse events.

All of the individuals whose names are in italics have received or are receiving research grants from the Lymphoma Foundation or were recipients of Lacher Fellowship grants.

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The Lymphoma Foundation is a nationwide not for profit foundation dedicated to funding clinical and basic laboratory cancer research and applying the knowledge developed by the clinician scientists for the general welfare and education of all cancer patients.