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THE LYMPHOMA FOUNDATION SUPPORTS RESEARCH OF THE LYMPHOMAS AND ALLIED DISEASES ON THE CUTTING EDGE OF NEW APPROACHES TO CANCER CURES The Lymphoma Foundation has awarded research grants to Marcel van den Brink, M.D., Ph.D. and his group of research scientists at the Memorial Sloan Kettering Cancer Center. (Dr. van den Brink is the Head, Division of Hematologic Oncology and the Immunology of Bone Marrow Transplantation Laboratory). His laboratory team is studying clinically important problems in allogeneic Human Stem Cell Tranplantation (HSCT)including graft-versus-host disease (GVHD), graft-versus-tumor (GVT) activity and post-transplant immune reconstitution. [Allogeneic stem cell transplants refer to stem cells that are taken from one person and given to another]. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for many hematopoietic malignancies including leukemias and lymphomas, but is associated with significant post-transplant T cell deficiency. This results in an increased susceptibility to viral and fungal infections and increased risks for graft failure and malignant relapse. In seeking ways to improve T cell immunity Dr. van den Brink and his colleagues have performed a series of preclinical studies focused on T cell recovery in recipients of an allogeneic T cell-depleted (TCD) HSCT and they have developed a strategy for adoptive immunotherapy with ex vivo generated T cell precursors [ex vivo refers to experimentation or measurements done in or on living tissue in an artificial environment outside the organism with the minimum alteration of the natural conditions]. T cell precursors were generated using a so-called “Notch-based” culture system and their administration resulted in an early ‘wave’ of T cell reconstitution from thymic and extrathymic sites, enhancing T cell immunity after allogeneic HSCT. The goal of this research is the perfection of these strategies extending them beyond the laboratory and into clinical practice that will enhance T cell recovery after Human Stem Cell Tranplantation (HSCT)... as this will improve the overall outcome for patients receiving this therapy. MORE BASIC RESEARCH At the Duke University Medical Center in Durham, NC… Dr. Christopher Counter, PhD is also receiving research grant support from the Lymphoma Foundation to fund a pilot project dealing with the oncogenic Ras protein. This will expand their studies of eNOS in relation to cancer development. Dr. Counter wrote to the Lymphoma Foundation: “Specifically, we propose to compare Ras-mediated lymphomagenesis or leukemogenesis in eNOS +/+ versus eNOS-/-mice. If genetic ablation of eNOS reduces cancer in these mice, we would next address whether the NOS small molecular inhibitor L-NAME inhibits such cancers in mouse genetic models. These studies dovetail nicely with our current work on NOS inhibitors in pancreatic cancer.”
ABOUT RAS and eNOS proteins:
1)
Signaling pathways are indispensable for cellular
communications that control proper development of multicellular
organisms. Cancer cells undergo active proliferation. The central
importance of the RAS signal transduction in promoting cell
proliferation, neoplastic transformation, and oncogenesis is well
established.
Oncogenic RAS proteins, which are hyperactived forms of RAS, are
among the most common genetic alterations detected in human cancer.
2)
The protein
eNOS mediates Ras oncogenesis in solid tumors. Small
molecular inhibitors against NOS proteins have been tested in phase
III clinical trials for septic and cardiac
shock, but not cancer. Dr. Counter will be studying the role of the
eNOS protein to control Ras-mediated cancers.
John
Leonard, M.D. and his colleagues at the Weill Cornell Lymphoma
Myeloma Cancer Center in New York City reported to the Lymphoma
Foundation their current research and future plans supported in part
by Lymphoma Foundation grants:
Studies
of radioimmunotherapy as part of initial therapy for lymphoma.
“We
have reported exciting data on fludarabine + I-131 tositumomab (JCO),
and are currently evaluating CVP and CHOP in sequential combination
with I-131 tositumomab as upfront treatment. Initial results
have been promising, with significant numbers of patients remaining
in continuous multi-year remissions. We have also analyzed outcomes
by prognostic group (identified by the follicular lymphoma
international prognostic index, or FLIPI), and are looking at this
approach to support the idea of a “risk-adapted” treatment approach
for follicular lymphoma based on reliable prognostic indicators. We
are participating in an ongoing SWOG/CALGB study to compare CHOP-R
versus CHOP-Bexxar as initial treatment in indolent lymphoma. While
this approach may fall into the “intensive” category, early results
suggest a potential survival benefit relative to a historical
comparison group.”
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LYMPHOMA FOUNDATION NEWSLETTER SEPTEMBER 2008 THE LYMPHOMA FOUNDATION GRANT SUPPORT FOR PATIENT ORIENTED RESEARCH HELPED RESULT IN A MAJOR CHANGE IN HODGKIN’S DISEASE TREATMENT SPEARHEADED BY THE RESEARCH “Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease” published in the journal Blood, 1 December 2004, Vol. 104, No. 12, pp. 3483-3489, a major change of treatment by many medical oncologists occurred. Chemotherapy alone is now used for the initial treatment of most patients with early stage non-bulky Hodgkin lymphoma… avoiding the use of radiation that has a high incidence of late serious side-effects. And Dr. David Straus the leader of this Memorial Sloan Kettering research project wrote to the Lymphoma Foundation: “I am very grateful for your [the Lymphoma Foundation] support of this study.”ANOTHER HODGKIN’S STUDY UPDATE: Dr. Straus reported that as of August 1, 2008 “We have also made progress in our long-term Hodgkin’s survivor study. Jennifer Ford, a clinical psychologist in the Department of Psychology and Behavioral Sciences, Kevin Oeffinger, a cancer survivor expert in the Department of Pediatrics, and Matt Matasar, one of our medical oncology fellows with an epidemiology back ground, are helping me with this project. Matt will be joining the staff of the Lymphoma Service. Our protocol, “A Global Assessment of Medical Morbidities and Quality of Life Among Survivors of Hodgkin Lymphoma” (IRB #05-041), is nearing completion of enrollment.” And once again, Dr. Straus noted: “The support of the Lymphoma Foundation has been invaluable in moving forward these efforts to improve the outcome for patients with Hodgkin lymphoma, and I am deeply grateful for your … support.”
UPDATE
REGARDING A VACCINE AGAINST LYMPHOMA
The
CD20 DNA vaccine
developed by the Sloan Kettering research team headed by Dr. Alan
Houghton and assisted by Dr. M. Lia Palomba and many other members
of the Houghton laboratory staff… after over ten years of support by
annual Lymphoma Foundation grants... is finally leaving the
laboratory phase and is entering a clinical patient oriented phase.
This clinical phase is proving to be more difficult than initially
anticipated as the need to protect the patients from any possible
untoward effect of the vaccine has led to extremely stringent and
narrow criteria for entry into the clinical trial and follow-up
care. In this regard… Dr. Palomba informed the Lymphoma Foundation
in August 2008 that “…The
FDA has requested that the first enrolled patient be followed until
completion of all vaccinations and his/her circulating B cells and
quantitative serum immunoglobulins be serially monitored before
enrolling patient
number 2. This will delay accrual of the second patient of about 3-4
months.” Patient
accrual for safety reasons, therefore, will be very slow and the
ultimate test of the value of the vaccine will not be known for many
months to come. “… we have fully characterized MPNST [Malignant Peripheral Nerve Sheath Tumor] cell lines derived from a patient with metastatic and recurrent disease with NF1 disorder, and also identified a gene associated with metastatic potential which is amenable to various therapeutic and chemo preventative approaches. These cell lines with extensive characterization of genetic abnormalities, therefore, are likely to provide important reagents for various biochemical, molecular, and pharmacological studies related to MPNST.” Molecular characterization of Permanent Cell Lines from Primary, Metastatic and Recurrent Malignant Peripheral Nerve Sheath Tumors (MPNST) with Underlying Neurofibromatosis-1 by Fang Yuqiang, Abul Elahi, Ryan Denley, Pulivarthi H. Rao, Murray F. Brennan, and Suresh C. Jhanwar And there is further Lymphoma Foundation grant support for ongoing research of Neurofibromatosis by Dr. Jhanwar and his associates: The expression profiling and array-based CGH data is currently being analyzed to identify specific genes altered in metastatic and recurrent cell lines. We have identified several recognized genes namely ITGA4, PDGFRB, PDGFA, CDK1C, and CDKN2D which are differentially regulated in these cell lines. The studies are in progress to validate this data both by RT-PCR and Western blotting. Future plans: Study of (1) Methylation inhibitor, 5-AZA CdR and Lycopene mediated re-expression of Nm23-H1 in metastatic cell line and its impact on motility and invasion, characteristic features of metastatic tumor and (2) Investigation of NF-1 interaction with the Ras and PI3K, pathways involved in deregulation of cell growth and tumorigenesis and modulation of the metastasis, following chemotherapeutic drugs as well as chemo-preventive agents. Such studies are expected to provide molecular mechanism of the metastasis, a major cause of mortality in these tumors, and also expected to provide information relating to targets of chemo-preventive strategies in patients with underlying NF-1. |
OLDER NEWSLETTERSLYMPHOMA FOUNDATION NEWSLETTER
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LYMPHOMA
FOUNDATION NEWSLETTER
LYMPHOMA FOUNDATION NEWSLETTERS
SEEKING SOLUTIONS TO SERIOUS LATE OCCURRING COMPLICATIONS OF RADIATION THERAPY
Use of the radiation therapy to a 'mantle field' was responsible for effectively limiting the chances of early relapses and helped introduce long survival in many patients with Hodgkin's disease. Now it is understood that this treatment has its own unique limitations.
THE
PROBLEM: In Hodgkin’s patients
treated with radiation therapy to the chest and neck areas a shortened life
expectancy is caused by an increased late occurring incidence of coronary heart
disease and stroke.
THE POSSIBLE SOLUTIONS:
Consider stopping the routine use of Radiation Therapy
for patients with Hodgkin’s disease and treat
primarily with chemotherapy [**Reference a research study supported in part with
Lymphoma Foundation grants by Dr. D. J. Straus, et al at Memorial Sloan
Kettering Cancer Center published in
Blood,
1 December 2004, Vol. 104, No. 12, pp. 3483-3489 with a supporting commentary by
Dr. D. L. Longo of the National Institute of Aging p. 3418:
”ABVD chemotherapy alone is as effective as ABVD plus radiation therapy in early-stage Hodgkin disease; thus, the majority of patients are curable without being exposed to the life-long, life-threatening risks of therapeutic radiation.”
¨ Because the use of Radiation therapy may not be stopped but only modified it will continue to be a significant risk factor for the development of coronary heart disease. Therefore cardiologists and oncologists should unite to consider and initiate a study of the value of adding long term use of a statin to the radiation treatment.
¨ Advise the American College of Cardiology (ACC) and the American Heart Association (AHA) that radiation therapy to the chest and neck in lymphoma patients should be added as a serious risk factor for the development of acute coronary syndromes and stroke and the already treated surviving patients post-radiation should consider starting statin medication and be sure to lower the LDL cholesterol levels to the lowest levels now expected to achieve the best results.
In this regard an Editorial appeared
in the Journal of the American Medical Association entitled
JAMA. November 16, 2005;Volume 294:page 2492
“… patients should know their cholesterol numbers, for both LDL-C and HDL-C, to enable them to see how much lowering is needed to reach targets of an LDL-C level of less than 100 mg/dL for patients with risk factors or less than 70 mg/dL for patients with heart disease … any drug treatment should be taken together with an appropriate diet and exercise program to lower cholesterol and overall vascular risk. … The amount of LDL-C lowering with diet is only in the range of 7% to 12%. Clearly, diet is a central part of the treatment, but to get the benefits of very low cholesterol levels, drug treatment is often necessary. ...Optimal use of diet and appropriate use of medications will dramatically reduce the risk of MI, stroke, and death from heart disease. These new data should help motivate any patients who have been hesitating about treating their cholesterol to talk with their physician to get the benefits of intensive cholesterol lowering”
And... in the August 2, 2005 issue of the Annals of Internal Medicine of the American College of Physicians Dr. John V.L. Sheffield and Dr. Eric B. Larson reviewed data regarding Cardiovascular Disease and Statin Use and they noted the following:
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“This year's trial results [2004] indicate a real change in our understanding of indications for the use of statins.
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ATTENTION ALL LYMPHOMA PATIENTS AND ALL PERSONS —- BE INFORMED AND INFORM YOUR PHYSICIANS AND YOUR FRIENDS ABOUT THE DATA REGARDING ‘STATIN’ ANTI-CHOLESTEROL MEDICATION and THE ROLE OF MAMMOGRAPHY TO ACHIEVE AN EARLY DIAGNOSIS OF BREAST CANCER —-
GO TO THE ‘HEART' AND ‘BREAST CANCER’ PAGES OF THE LYMPHOMA FOUNDATION WEBSITE TO REVIEW THIS INFORMATION
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UNIVERSITY OF UTAH — HEMATOLOGY DIVISION — SCHOOL OF MEDICINE—
SALT LAKE CITY, UTAH
Studies of the early
stages of lymphoid development, using a novel culture model that provides a
differentiation signal crucial to specification of the T lymphocyte lineage at
the stage of the lymphoid progenitor.
DUKE
UNIVERSITY MEDICAL CENTER — DURHAM, NORTH CAROLINA
Studies in aging
regarding the relationship of hPot1 and cellular senescence, a biomarker of
aging. The objective will be to determine which proteins hPot1 interacts with
to keep the telomere in a closed state, and hence protect telomeres from
eliciting a senescence signal.
YALE
UNIVERSITY CANCER CENTER — NEW HAVEN, CONNECTICUT
Clinical management of
patients with Hodgkin’s disease and the non-Hodgkin’s lymphomas
TUFTS MEDICAL CENTER ---
BOSTON, MASSACHUSETTS
Studies in new approaches to the
treatment of multiple myeloma and allied disorders
CORNELL NEW
YORK-PRESBYTERIAN HOSPITALS — NEW YORK, NEW YORK
▪ Further assessment of the anti-CD22
antibody epratuzumab and other monoclonal antibodies in B-cell malignancies.
▪ Evaluation of combination regimens with rituximab and biologic agents
(including IL-2, anti-CD80, revlimid and CpG immunostimulatory
oligonucleotides).
MEMORIAL SLOAN KETTERING CANCER CENTER —NEW YORK, NEW YORK
▪ Targeting the ubiquitin proteasome
pathway in indolent and mantle cell lymphoma.
▪ Alpha-particle immunotherapy by targeted Alpha-emitters or Alpha-emitting
isotope generators.
▪ Seeking genetic
modifiers that are protective against cancer in a subset of elderly
individuals.
▪ Analysis of cancer prevention data
in children of families affected by hereditary cancer syndromes.
▪ Intensity-modulated
radiotherapy for lymphoma involving the mediastinum.
▪ Methods to overcome platinum resistance, consolidation strategies in
patients with ovarian cancer and immune directed strategies directed towards
CA-125.
▪ New approaches to the treatment of multiple myeloma.
▪ Treatment of patients with low grade lymphoma and chronic lymphocytic
leukemia.
▪ Analysis of Schwann cell origin: the role of tumor environment of
Neurofibromas in NF1.
▪ High-dose chemotherapy and stem cell
transplantation for Large Cell Lymphoma and relapsed and refractory Hodgkin’s
disease.
▪ Continuing development of DNA vaccines against CD20 antigen expressed by
lymphoma cells.
SUMMARIES OF RESEARCH IN PROGRESS
Monoclonal antibody, Anti-sense BC-2 and Bortezomib therapy JOHN P. LEONARD, M.D., Joan and Sanford Weill Medical College of Cornell University “The assistance of the Lymphoma Foundation [will] be used to support the following efforts at our center in very meaningful ways…” “Novel initial therapies for aggressive lymphoma. We continue to explore ways to improve outcomes with chemotherapy, particularly combinations of CHOP chemotherapy and rituximab along with agents such as Bcl-2 antisense, idiotype vaccines, and bortezomib (Velcade). Trials with these are ongoing, and initial phase I results of the CHOP-R-Velcade study have been submitted to ASH. We are excited about these preliminary findings, and the support from the Lymphoma Foundation will help us to continue this trial as well as to conduct correlative studies on tumor tissue that will allow us to characterize tumors from the molecular standpoint in the patients on the study. We also plan additional future trials with other novel agents.” “Further assessment of the anti-CD22 antibody epratuzumab and other antibodies in B-cell malignancies. We continue to study this agent, with which we have demonstrated evidence of clinical activity and manageable toxicity. We are evaluating patients treated with single-agent epratuzumab, repeated courses (at relapse) as well as in combination with rituximab. Substantial numbers of these patients remain in remission years later (initial results from one study recently reported in the JCO). Our initial efforts are encouraging in this regard, and we are currently conducting a pilot study in lymphoplasmacytic lymphoma (which highly expresses CD22). We are also attempting to identify clinical, laboratory, and pathologic parameters, which may correlate with response and therefore allow us to better target appropriate patient populations. Further trials in combination with CHOP-R and with rituximab are being planned. Additionally, we are currently conducting phase I studies with anti-CD40 and anti-interleukin 6 monoclonal antibodies.”
Is there a genetic (inherited) component that protects against the development of cancer? KENNETH OFFIT, M.D., MPH, Memorial Sloan Kettering Cancer Center: As a result of the “genetic revolution” it is now possible to look for genetic variations between individuals and to learn if these are associated with disease. The goal of one aspect of our genetic research at the Memorial Sloan Kettering Cancer Center has been to use “whole genome” technologies to look for genetic markers that will predict resistance to disease in the elderly. Our initial research paper soon to be published demonstrated that it is possible to do “whole genome” analysis to “rediscover” known genes. As preliminary data we performed low density genomic scans and we have been able to resolve two significant regions: one on chromosome 12 and one on chromosome 22 that may be associated with the resistance to breast cancer in this elderly population. As we continue our research we hope to better map these regions and to discover other genetic regions that confer cancer resistance in the elderly.
How is
cell senescence (aging) controlled
CHRISTOPHER M. COUNTER, PhD, Duke University Medical School
Human cells can continue
to divide up to a time when they stop growing and enter a period termed
senescence. It is thought that this hard-wiring of cell lifespan may be related
to the process of aging. One of the 'clocks' that keeps track of how long a
cell can continue to divide is the end of the chromosomes, or telomeres.
Telomeres shorten every round of cell division, ticking off the number of
divisions a cell has left. When telomeres reach a short length associated with
senescence it is proposed that they signal the cell to stop dividing, perhaps
because the telomeres become recognized as damaged DNA. We have shown that
reducing the amount of the telomere-binding protein, hPot1, achieves the same
fate, namely that cells stop dividing and enter what appears to be senescence.
We are now very interested in determining how this occurs, and are currently
testing what functions of hPot1 can stop this senescence. Understanding how
loss of hPot1 function induces senescence may shed light on this process, and
aging.
THE DILEMMA POSED IN CHOOSING TREATMENT OF ‘LOW GRADE’ FOLLICULAR LYMPHOMAS
The ‘indolent’ follicular
lymphomas are not usually aggressive early in their course and may be ‘observed’
for many years without any treatment
as noted in
a
COMMENTARY by Craig H. Moskowitz, M.D. (in
BLOOD
February 15,
2005,
Vol.105,
Number 4)
“Follicular
lymphoma is a chronic disease with a variable course; many patients can be
monitored for
years without therapy yet others need to be treated aggressively at the onset.
Median survival in 2004 approaches 14 years…”
New
approaches to treatment are being studied in order to secure the much needed
improved longer-term survival.
1)
Human clinical trials are
underway with an ‘auto’ vaccine (a
vaccine developed from the patients’ own lymph node cells) added to primary
forms of chemotherapy with or without monoclonal antibody treatments. Uniquely different trials are outlined on the National Cancer Institute Clinical
Trials website. There are no conclusions yet and much time will have to pass
before it is determined whether or not this approach improves survival.
[GO TO HOME PAGE TO REVIEW HOW TO LOG ON
TO THE CLINICAL TRIALS SITE AND ACCESS THE LYMPHOMA VACCINE TRIALS]
2) Some of the latest clinical human research implies that the best current
approach to treatment for Follicular Lymphoma
is a combination of chemotherapy plus the monoclonal antibody rituximab in
sequence… and possibly with long term intermittent maintenance treatment with
rituximab
“Frontline
therapy with rituximab added to the combination of cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP) significantly improves the
outcome for patients with advanced-stage follicular lymphoma compared with
therapy with CHOP alone: results of a prospective randomized study of the German
Low-Grade Lymphoma Study Group”
Hindemann, et al in
BLOOD
December 1, 2005 Vol.106, Number 12, pp 3725-3732:
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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 to the general welfare and education of all cancer patients. Copyright 2006 The LymphomaFoundation All Rights Reserved. |
