Institute Without Walls
New Advances in Cancer Research Funded with SWCRF Support
Alterations of Gene Expression in Blood Malignancies
The physician/scientists in the Program of Altered Gene Regulation in Hematological Malignancies
receiving support are at Mount Sinai Medical Center, Albert Einstein College of Medicine, Northwestern
University, Shanghai Second Medical University, University of Maryland, Johns Hopkins University,
Brandeis University, University of California, San Francisco, Wistar Institute, Philadelphia, Leukemia
Research Foundation, UK, Tel Aviv University, Israel, McGill University in Montreal and Ontario
Research Institute, Ontario.
The members of this group have helped define the importance of aberrant gene shutdown as a root cause
of leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome (MDS). We are defining the
mechanisms and using this knowledge to develop therapeutics to reverse repression. This work
produced treatments saving thousands of lives worldwide. Recent highlights include:
1. Design of a specific compound which interferes with the action of the cause of B-cell lymphoma:
a designer treatment in the making which should selectively kill lymphoma cells in patients
(Nature Medicine 10: 2005).
2. Demonstration that treatment with arsenic trioxide is effective in certain forms of
myelodysplastic syndrome and acute leukemias (Cancer Research: 2006 in press).
3. Demonstration that combining all trans retinoic acid and arsenic trioxide increases survival and
cure of patients with acute promyelocytic leukemia (Proceedings of the National Academy of
Science USA 101: 2004).
4. Identification of a new human silencing enzyme which may be abnormal in certain forms of
lymphoma and multiple myeloma (Journal of Biological Chemistry 80: 2005).
5. Demonstration that oral forms of arsenic and Gleevac may be more effective in the treatment of
chronic myeloid leukemia (Blood 104: 2004 and 2006 in press).
Brain Cancer Program
The first grantee for the Brain Cancer Program was selected this year and is a physician/scientist at the
University of North Carolina. Already internationally known for developing the best animal models of
brain cancer, tumor tissues are used to define abnormal signals vital in the pathogenesis of this disease.
Already, two abnormal pathways are being evaluated for potential agents that might have therapeutic
effect. As other SWCRF programs, basic scientific research is being matched with translational science
and studies with the hope of developing therapeutic clinical trials. These animal models will be provided
to other SWCRF scientists as well as future grantees for an expanding program in brain cancer.
Breast Cancer Program
The Breast Cancer Program has grown in scope and accomplishments over the past 3 years with your
assistance. Basic scientific research is being matched with translational studies involving therapeutic
clinical trials. The grantees are physician-scientists at Mount Sinai Medical Center, University of North
Carolina, McGill University, Beth Israel/Harvard/Ontario Cancer Institute. Research highlights include:
1. Genetically engineered animal models which mimic possible causes of breast cancer in women
were developed. Breast cancer stem cells are obtained from the tumors and studied for gene
alterations. This will provide a blue print of how breast cancer stem cells are genetically
produced. Abnormal regulated genes are studied for gain or loss of function and appropriate
strategies will be developed to counteract these pathologic processes.
2. We have reported a link between silenced vitamin A genes and early stages of breast cancer. This
has great significance in the prevention of breast cancer.
3. A recent newsworthy report (Journal of National Cancer Institute, 2006) is our finding that cyclin
D1, overexpressed in many cases of breast cancer takes on a new function which can be
selectively inhibited by a drug called Velcade, used in the treatment of lymphoma. Clinical
studies are planned to determine if cyclin D1 can be used as a guide for when to use Velcade in
the treatment of breast cancer and other malignancies.
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Liver Cancer Program
The Liver Cancer Program has grown in scope and accomplishment during the past few years. The
grantees in the Liver Cancer Program are physician/scientists at Mount Sinai Medical Center, University
of Barcelona, Spain and Institute de Tumori, Milan, Italy. Basic scientific research is being matched with
translational studies involving therapeutic clinical trials. The major discoveries of this program include:
1. Complete gene profiling of human liver cancer due to hepatitis C from initial infection through
advanced cancer. This will lead to the identification of pathways required for the development of
liver cancer.
2. A recent report (Gastroenterology 2006) showed that 7 genes can be used to separate pre and
early liver cancer. This will result in a simple diagnostic test that will be helpful in the early
diagnosis and perhaps prevention of this form of liver cancer, one of the most rapidly developing
forms of cancer in the United States.
3. Clinical trials are in progress that target abnormal regulated genes based on recent work by the
SWCRF investigators.
Lung Cancer Program
The grantees in the Lung Cancer Program are physician/scientists at the Dartmouth University, MD
Anderson, Weizmann Institute, Rehovet, Israel and Mount Sinai Medical Center. Basic scientific
researchers are being matched with translational studies involving therapeutic clinical trials. The
members of this group have made significant progress and the highlights include:
1. The development of a mouse model for lung cancer based on the insertion of a gene vital for
vitamin A metabolism. This model is used to identify abnormal gene regulation in the tumor
found in these mice and map out a strategy for developing selective cancer treatments.
2. A collaborative clinical trial in the treatment of early and advanced lung cancer has been initiated
at Dartmouth University and Mount Sinai Medical Center. Two drugs (Targetin and Tarceva)
were shown to be highly active in combination in laboratory studies. Early clinical results
(Journal of Clinical Oncology 2006) show a significant improvement in survival using this
treatment as compared to conventional therapies presently available. A much larger study is in
progress.
3. Basic research has identified a new approach to recover the function of a gene called p53 that is
mutated in many forms of cancer and is an important cause for abnormal growth, differentiation
and cell death. Compounds are being devised to revitalize this gene’s function.
Melanoma
The Melanoma Program has grown in scope and accomplishments over the past three years. The grantees
in the Melanoma Program are physician/scientists at the University of California, Los Angeles, California
Institute of Technology, Columbia University, Mount Sinai Medical Center and Memorial Sloan-Kettering
Cancer Institute. Basic scientific research is being matched with translational research including
therapeutic clinical trial. The significant accomplishments include:
1. A better understanding of how the B-raf mutation, which is present in 80% of patients with
melanoma, contributes to the development of this disease and the design of new inhibitors to
block this abnormality. Clinical trials are in progress based on these discoveries.
2. The development of an individualized specific long lasting immune therapy which utilizes gene
insertion into normal bone marrow stem cells has just been funded. This program includes a
Nobel Laureate, a world famous scientist and a clinical research group all doing pioneering work
in immune therapy of melanoma. The basic research and preclinical studies are advancing
rapidly and it is expected that clinical trials will be initiated within the next 18 months.
3. Differentiation therapy of melanoma targeting recently discovered differentiation genes in
animal studies and early clinical trials.
Pancreatic Cancer Program
The Pancreatic Cancer Program has just been started. The first physician/scientist is from the
Massachusetts General Hospital. The initial work will be characterization of the pancreatic cancer stem
cell. Pancreatic cancer is uniquely resistant to present day medical treatment and the answer may reside
in the pancreatic stem cell since this is the root cause of this disease. Pancreatic cancer stem cells are
isolated and the deregulated genes profiled. These are the clues to identify the mechanisms required for
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developing pancreatic cancer and allow for the scientific development of therapies for this disease. The
SWCRF plans to fund additional scientists in the future to build a collaborative Pancreatic Cancer
Program.
Prostate Cancer - Molecular targeted therapy
The grantees in the Program on Molecular Targeted Therapy in Prostate Cancer are physician/scientists
at Memorial Sloan-Kettering Cancer Institute, University of California, Los Angeles and the Dana-Farber
Cancer Institute.
This recently initiated program was selected because these scientists are already in collaboration and are
at the cutting edge for developing new treatments in prostate cancer. Basic scientific research is being
matched with translational studies involving therapeutic clinical trials using analysis of specimens
obtained from patients before and after undergoing treatment. The members of this group are defining
the importance of abnormal gene expression, deranged pathways for growth differentiation and cell
death and are defining how to develop therapies to reverse these abnormalities. These scientists are at the
cutting edge of prostate cancer research and are leaders in all disciplines necessary to bring forth newly
discovered therapeutic approaches. The SWCRF plans to enlarge this program in the coming years.
Shanghai Institute of Hematology
Samuel Waxman Cancer Research Foundation
Co-PI Program
The grantees in the Shanghai Institute of Hematology (SIH)/SWCRF Co-PI Program are
physician/scientists of the SIH, Leukemia Research Institute, London, Mount Sinai Medical Center, MD
Anderson, McGill University, Brandeis University and Northwestern University.
The SIH/SWCRF program in Blood Malignancies has grown in scope and accomplishments over the
years. This program brings together Chinese and Western scientists to develop translational studies
leading to therapeutic clinical trials. This work is being done at the Shanghai Second Medical University
and seeks to define the importance of the aberrant gene shut down as a root cause of leukemia,
lymphoma, multiple myeloma and MDS. Recent discoveries include:
1.
2.
3.
The finding that combining all trans retinoic acid and arsenic trioxide is the most effective way to
induce clinical remission in acute promyelocytic leukemia. This approach may offer a cure
without the need for cytotoxic chemotherapy.
An oral form of arsenic has been combined with a western drug called Gleevac and may be
superior than Gleevac alone in the treatment of the accelerated and blastic phase of chronic
myelogenous leukemia. These treatments can be used world-wide since they are safe, given
orally and less expensive than standard therapy used in the Western world.
Additional discoveries include an understanding of new genes that are regulated during the
differentiation of acute leukemia and the finding of an exciting new differentiating agent for
another form of acute leukemia.
Tumor Dormancy Program
The Tumor Dormancy Program has grown in scope and accomplishments over the past few years with
your assistance. The grantees in the Tumor Dormancy Program include physician-scientists at the Mount
Sinai Medical Center, State University of New York at Albany, Albert Einstein College of Medicine, and
Finsen Laboratory, Denmark. Basic scientific research is being matched with translational studies
involving therapeutic clinical trials. The significant achievements of this program include:
1. The development of a human cancer model that has been used to identify a single protein on the
surface of cancer cells that can control aggressiveness and dormancy. This is part of a complex
scenario and the components have been carefully described during the past few years and
reported in prestigious scientific journals.
2. This has led to the development of specific structural inhibitors that have been designed to
maintain the cancer dormancy state. These inhibitors are being refined utilizing structural
biology methods. It is anticipated that preclinical development including collaboration with
pharmaceutical companies will result in drugs that will be tested in clinical trials to maintain the
dormant state of cancer cells. This could result in a revolutionary treatment for converting cancer
to a chronic inactive disease.
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