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
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.
“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
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
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
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.
Radiation oncologists in the United States have just begun to use
Intensity Modulated Radiation Therapy (IMRT)
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
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
NANOGENERATORS TARGETING A
WIDE VARIETY OF CANCERS
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
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,
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.
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
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
Analysis of Mismatch Repair Defects in the Familial Occurrence of Lymphoma and
Teruya-Feldstein, J., Greene, J., Cohen, L., Popplewell, L., Ellis, N.A.,
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.
Monoclonal antibody therapy of non-Hodgkin’s lymphomas and Hodgkin's
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
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.
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FOUNDATION All rights reserved