Dr. Dina Lev, from the Cancer Biology and the Sarcoma Research Center at the University of Texas M. D. Anderson has published a new study on Alveolar Soft Part Sarcoma. Her study appeared in the Journal of Histopathology. The aim of this study was to evaluate the expression of potential gene therapeutic targets in a cohort of ASPS tumor samples. Dr. Lev analyzed 26 primary and metastatic ASPS tumor samples. Her study confirmes that activation of c-Met and its downstream effectors are prominent in ASPS. She also identified limited EGFR (Epidermal Growth Factor Receptor) expression in few tumors as well. VEGF (Vascular endothelial growth factor), was expressed in all the tumors to varying degrees. Dr. Lev concluded that there is a crucial need for better anti-ASPS therapies. Her study demonstrated that combination therapies against few activated pathways in ASPS could be the right concept for the treatment of Alveolar Soft Part Sarcoma.

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

A poster presented last month at the 2009 American Association for Cancer Research (AACR) Annual Meeting in Denver, CO, announced a breakthrough in research that aims to find a cure for ASPS.

For the first time, a team of researchers, among them Dr. David Vistica, reported their success in the establishment of a stable Alveolar Soft Part Sarcoma cell line for the first time. The origin of this cell line is from a lymph node metastasis which was donated by a female patient. Very importantly, the cell line was carefully tested and was found to maintain the characteristics of the original ASPS tumor for over three years.

This cell line will facilitate investigations into the biology of ASPS, and aid in the pre-clinical identification of new ASPS therapeutics. Here below is the abstract of the poster:

Establishment and characterization of ASPS-1, a novel cell line derived from metastatic alveolar soft part sarcoma

Investigation into the biology of Alveolar Soft Part Sarcoma (ASPS) and preclinical evaluation of potential ASPS therapeutics have been severely hampered by the lack of both in vitro and in vivo models of this soft tissue sarcoma. Recently we have described an in vivo xenograft model of ASPS in sex-matched NOD.SCID\NCr mice. This model, established from a lymph node metastasis from a female patient, has maintained characteristics consistent with those of the original ASPS tumor for over 3 years. Characteristics studied include: (1) tumor histology and staining with Periodic Acid Schiff/Diastase, (2) the presence of the ASPL-TFE3 type 1 fusion transcript, (3) nuclear staining with antibodies to the ASPL-TFE3 type 1 fusion protein, (4) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS, (5) stable expression of signature ASPS gene transcripts and finally, the development and maintenance of a functional vascular network, a hallmark of ASPS. Utilizing this ASPS xenografted tumor we have successfully developed the first cell line of this rare pediatric sarcoma. Organoid nests consisting of 15-25 ASPS cells were isolated from ASPS xenograft tumors by capture on 70 um filters and plated in vitro. Following attachment to the substratum, these nests deposited small aggregates of ASPS cells. Over a period of 1.5 years, these cells were expanded and monitored for the following: ASPL-TFE3 type 1 fusion transcript, the t(X;17)(p11;q25) translocation and expression of up regulated ASPS transcripts involved in angiogenesis (ANGPTL2, HIF1 alpha, MDK, MET,VEGF, TIMP-2) , cell proliferation (PRL, PCSK1, IGFBP1), metastasis (ADAM9) as well as the transcription factor BHLHB3 and the muscle specific transcripts TRIM63 and ITGB1BP3. This ASPS cell line forms colonies in soft agar and retains the ability to produce highly vascularized ASPS tumors in NOD.SCID\NCr mice. Immunohistochemistry of selected ASPS markers on these tumors indicated similarity to those of the original patient tumor as well as to xenografted ASPS tumors. This ASPS cell line will facilitate investigation into the biology of ASPS and aid in the pre-clinical identification of new ASPS therapeutics.

Authors:  Susan Kenney, David T. Vistica, Luke Stockwin, Sandra Burkett, Melinda Hollingshead, Suzanne Borgel, David Schrump, Robert Shoemaker. NCI-Frederick, Frederick, MD, National Cancer Institute, Bethesda, MD

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

Dr. David Vistica, and his collaborators from the National Cancer Institute (in Frederick, MD), published the results from their analysis of gene expression in donated ASPS tumors. It identified elevated expression of genes, related to cancer. These may have diagnostic and therapeutic potential. Few examples are:

1. Involved in angiogenesis: ANGPTL2, HIF-1 alpha, MDK, c-MET, VEGF, TIMP-2.
2. Involved in cell proliferation: PRL, IGFBP1, NTSR2, PCSK1
3. Involved in metastasis: ADAM9, ECM1, POSTN
4. Involved in steroid biosynthesis: CYP17A1, STS.

So far, the cell origin of ASPS was not clear. The study identifies the muscle-restricted gene expression as ITGB1, BP3/MIBP, MYF5, MYF6 and TRIM63. This strengthens the hypothesis that the primary ASPS tumor develops from muscle cell progenitor.

The full paper, including all genes found to be expressed in ASPS, is available here.
______________________________________________________

Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

In April 2008, iCureASPS started to support the research of Dr. Dina Lev, MD, on Alveolar Soft Part Sarcoma. Dr. Dina Lev is Assistant Professor at the Sarcoma Research Center, MD Anderson Cancer Center, Houston Texas. In November 2008, iCureASPS donated an additional $5,000 to her laboratory.

Dr. Lev published a study on angiogenesis-promoting genes in Alveolar Soft Part Sarcoma, in December 2007.  Dr. Lev is also co-author in a study on the activation of the insulin growth factor receptor 1R (IGFR1) in ASPS, which was recently reported at the 2008 meeting of the American Association for Cancer Research (AACR).

The contact person from iCureASPS for this collaboration is Dr. Nancy Landfish, who serves as the iCureASPS Medical Affairs Director.

Here is a summary of Dr. Lev’s research goals on Alveolar Soft Part Sarcoma:

The sarcoma research laboratory at MD Anderson Cancer Center is focused on the comprehensive multidisciplinary study of soft tissue sarcomas. One major area of interest is alveolar soft part sarcoma (ASPS). The rarity of these tumors and the lack of bioresources such as human tissues, cell lines, and animal models impedes intensive research in this field and thus enhanced molecular understanding as it relates to tumor inception and progression. Our major goals are to assemble and develop these needed bio-resources. Utilizing the MD Anderson Cancer Center tissue bank we were able to assemble an ASPS specific tissue microarray (TMA), which will potentially aid us in identifying the expression of genes and proteins of interest.  ASPS are highly metastatic; their metastatic propensity is possibly secondary to their enhanced angiogenicity and vascularity. We have recently utilized the ASPS TMA to evaluate the expression of multiple angiogenic factors and other molecular targets; data stemming from these studies will hopefully be submitted for publication in recent months. 

Our Research Aims:
1)  To expand our annotated paraffin and frozen tissue bank for ASPS
2)  To collaborate with other scientists with an interest in ASPS research
3)  To study the expression and function of angiogenic factors in ASPS and evaluate their potential as therapeutic targets 
4)  To evaluate the effect of the TFE3 fusion gene on the expression of the studied angiogenic factors

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

Cure Alveolar Soft Part Sarcoma International is very proud to announce the publication of a study that was supported by donations through our organization. The new study appears in the scientific journal ”Neoplasia”. It focuses on genes which are expressed in alveolar soft part sarcoma and in the normal cells surrounding the tumor. Those cells express essential genes for tumor proliferation and can be inhibited by Halofuginone.

Halofuginone belongs to the family of drugs called quinazolinone alkaloids. It is one of the analogues of the molecule febrifugine, which is the active component in the extract from the roots of a plant that was used in China to treat malarial fever and in the poultry industry to treat Coccidiosis in chickens. In the context of cancer, Halofuginone is studied for its ability to slow the growth of connective tissue and prevent the growth of new blood vessels to a solid tumor.

Dr. Mark Pines, the author of the study discovered the therapeutic effects of Halofuginone. In the first part of the study, Dr. Pines measures the expression of Halofuginone gene targets in ASPS tumors and in the second part of that study he tests Halofuginone’s effects on renal tumor that carries the ASPS translocation: ASPL-TFE3. Drug treatment inhibits tumor growth in mice and reduces the expression of tumor promoting genes.

We are proud to support Dr. Mark Pines’ research, and hope to continue these studies in order to find out if ASPS may eventually be cured by Halofuginone.

To read Dr. Pines study please see: Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: A novel target for treatment?

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

iCureASPS is looking for active members of the ASPS community to help maintaining viable collaborations with scientists who perform ASPS research in medical centers. If you wish to be part of an active search for Alveolar Soft Part Sarcoma Cure, please contact us!

Such a new collaboration was recently established with Dr. Dina Lev at the Department of Cancer Biology at the MD Anderson Cancer Center in Houston, Texas. The contact person from iCureASPS for this collaboration is Dr. Nancy Landfish, who serves as the iCureASPS Medical Affairs Director.

Recently, a member in the iCureASPS community donated the first $5,000 to support Dr. Dina Lev’s research, who recently published a scientific paper: “Angiogenesis-promoting gene patterns in Alveolar Soft Part Sarcoma”. Dr. Dina Lev conducts research on the highly vascular (angiogenic) nature of ASPS because she believes that this is an important factor driving ASPS metastasis. Her laboratory evaluates gene expression of ASPS frozen samples to identify candidate genes, possibly contributing to ASPS angiogenesis. Next, she would like to study the importance of these genes and gene products in ASPS metastasis, and their possible regulation by the ASPL-TFE3 fusion gene. Lev’s studies may potentially result in better understanding of ASPS progression, and would lead to identification of targets for the development of novel therapeutics.

The specific aims of Dr. Dina Lev are to:

1. Create an annotated paraffin and frozen tissue bank for ASPS.
2. Collaborate with other scientists with an interest in ASPS research, with the aim of expanding the available bioresources.
3. Study the expression and function of potential angiogenic factors in ASPS.
4. Investigate the effect of the ASPL-TFE3 fusion gene on the expression of the studied angiogenic factors.

If you are interested in supporting Dr. Lev’s research, please write to Dr. Nancy Landfish at Nancy.Landfish@HCAhealthcare.com.

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

iCureASPS has recently sent funds to sponsor an original research, which is carried out in the laboratory of Dr. Mark Pines at the Volcani Center, Bet Dagan, Israel. Halofuginone is an analog of the molecule febrifugine. Febrifugine is the active component in the extract from the roots of the Chinese herb chang shan (Dichroa febrifuga), which has been used as malaria therapy in Chinese traditional medicine for more than 2,000 years. In recent years, Halofuginone was used as a drug in the poultry industry to treat Coccidiosis (a parasitic disease) in chickens. Dr. Pines found that Halofuginone is a very efficient inhibitor of type I collagen synthesis. Then he found that Halofuginone is also a strong inhibitor of tumor progression.

While efforts are made in few medical centers to develop a convenient ASPS model system, there is currently no ASPS cell line or an animal model for studying mechanisms of drug therapy on ASPS. Therefore, for his initial research on ASPS, Dr. Mark Pines performed studies on: (1) tumor samples that were donated by ASPS patients and (2) on a renal (kidney) tumor cell line derived from a patient, which contains the same genetic translocation as ASPS (ASPL-TFE3).

iCureASPS is very proud to be a supporter of Dr. Mark Pines in his efforts to understand the oncogenic nature of ASPS and in his efforts to develop a novel therapy for this disease.

Additional resources on Halofuginone (click on the links to learn more):

Halofuginone - U.S. National Institutes of Health: 
1. Halofuginone Hydrobromide in treating patients with progressive advanced solid tumors
2. Topical Halofuginone Hydrobromide in treating patients with HIV-Related Kaposi’s Sarcoma

Halofuginone – other resources:

3. Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect
4. Halofuginone receives FDA orphan drug status for Scleroderma
5. Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

Two scientific publications on Alveolar Soft Part Sarcoma have been recently published: “Angiogenesis-promoting gene patterns in Alveolar Soft Part Sarcoma” by Lazar et al., 2007 (from M. D. Anderson Cancer Center) and “Immunohistochemical discrimination between the ASPL-TFE3 fusion proteins of Alveolar Soft Part Sarcoma” by Vistica et al., 2008 (from The National Cancer Center).

Lazar and colleagues analyze expression of genes, which are known to modulate angiogenesis. Angiogenesis is the process involving the growth of new blood vessels to supply blood to organs, and in the context of cancer, to malignant tumors. In his study Lazar finds that at least 18 of these genes are uniquely over expressed in ASPS. Lazar uses bioinformatics analyses to show that at least five of these genes contain regulatory elements that may directly be induced by the ASPL-TFE3 fusion protein, the translocation product of ASPS (ASPL-TFE3 fusion protein). The induction of these genes will then activate angiogenesis. Lazar’s study further suggests that the cure for ASPS may be achieved by therapies that inhibit angiogenesis. The material for this study comes from 33 ASPS tumor samples from patients who were treated at MD Anderson in 1986-2005. This last point indicates the importance of donating tumor samples to support ASPS research.

Vistica and colleagues describe the development of a new tool (antibody-based diagnostic detection) that easily discriminates between the two forms of Alveolar Soft Part Sarcoma: Type I and Type II. ASPS is characterized by a chromosomal translocation of two chromosomes: X and 17. This translocation forms the ASPL-TFE3 fusion transcript (see above). One of two different ASPL-TFE3 fusion transcripts is found in ASPS tumors, producing type 1 or type 2 fusion proteins. Currently, it is not known if the prognosis of ASPS patients with type 1 is different from those with type 2. This diagnostic tool by Vistica enables detection of the ASPL-TFE3 fusion proteins, and the discrimination between the two ASPS types.

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

Cure Alveolar Soft Part Sarcoma (iCureASPS) is currently supporting three initiatives that hopefully will bring us closer to the day when a cure for Alveolar Soft Part Sarcoma is a reality.

Here is a progress report on those projects.

1. The GVAX clinical trial – Opened on January 2006, the first cancer vaccine trial for ASPS is still open and continues to recruit more patients. This tumor vaccine is tailored for each patient based on his/her own tumor. The GVAX technology was developed by Glenn Dranoff, M.D., Director of the Human Gene Transfer Laboratory Core, Dana-Farber Cancer Institute, Co-Leader Cancer Vaccine Center, Department of Medical Oncology, Dana-Farber, Harvard Medical School. In the current trial, Dr. Dranoff incorporates experience that he accumulated over 10 years of cancer vaccine studies in patients with metastatic melanoma and lung cancer. This clinical trial is led by Dr. Glenn Dranoff, Dr. Steve Hodi, and Dr. John Goldberg.

2. The creation of an Alveolar Soft Part Sarcoma tumor transplant in mice (NEW PROJECT) – Many new cancer therapies are developed and tested in clinical trials. How could one predict the efficacy of a drug against ASPS? The goal of this project is to grow ASPS tumor fragments in mice. The resulting ASPS tumors can then be propagated in more mice and used as a preclinical model to test candidate drugs.
This project is led by Massimo Loda, M.D., Professor of Pathology, Harvard Medical School, Dana Farber Cancer Institute. In his lab, Dr. Ewa Sicinska, Dr. Carmen Priolo and Dr. Joseph Brito make up the team working on this project. We encourage ASPS patients who are operated at the Dana Farber to donate their fresh tumors to the Massimo lab. More material obtained means better chances for successful transplant lines.

3. Identification of Kinase Inhibitors that target ASPS (New PROJECT) – During the last few years, much progress on understanding the biology of ASPS was made through studies that were done in the laboratory of David Fisher MD, PhD, Director Melanoma Program in Medical Oncology & Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, in collaboration with John Goldberg, MD, Fellow in Pediatric Hematology/Oncology Dana-Farber Cancer Institute, Children’s Hospital Boston. In this study Dr. Fisher and Dr. Goldberg will try to identify “weak links” in ASPS that can be targeted by kinase inhibitors.

Following is a message from Dr. Fisher and Dr. Goldberg to the iCureASPS community:

“Dear iCureASPS and supporters,

We at the Dana-Farber Cancer Institute would like to express our gratitude for your support of our efforts to find a cure for alveolar soft part sarcoma, and we applaud your participation in the Pan Mass Challenge. We share your goal of bringing laboratory based findings into clinical trials as rapidly as possible for this insidious cancer. Over the coming year, our efforts will focus on targeting specific molecular switches that research has demonstrated to be potential weak points in ASPS. The first action will be to initiate a specific clinical trial with a biotechnology company to treat ASPS with a targeted kinase inhibitor. While there is no guarantee that any one targeted agent will help ASPS, we are working with many companies to insure that no stone goes unturned in our quest for a cure and that no weapon is left behind in this effort. These trials will involve both treating the patient and learning as much as possible from them to improve the future protocols. Both laboratory and clinical research are heavily resource dependent, but our patients need new therapies and science is pointing the way to many promising options. Of course, we will continue to monitor the progress of patients who received study vaccine on DFCI 05-115 (The GVAX clinical trial), which is an ongoing project here. We will also continue our efforts to find new targets in these cancers in the laboratory through the analysis of upregulated genes and activated proteins.

Best,

John M. Goldberg, MD
David E. Fisher, MD, PhD”

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com

Written by Folpe AL and Deyrup AT at the Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Minnesota, USA.

Alveolar soft-part sarcoma (ASPS) is a rare, distinctive sarcoma, typically occurring in young patients. Although it displays a relatively indolent clinical course, the ultimate prognosis is poor and is often characterised by late metastases. Recently, our understanding of the genetic events underlying the pathogenesis of ASPS has greatly increased. The historical, histopathological, ultrastructural, immunohistochemical and genetic aspects of ASPS are reviewed in this article.

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