Alveolar Soft Part Sarcoma Tumor Metabolizes Lactate by Goodwin and Jin et al in “Cancer Cell” Journal

Cancer Cell 26, 851-862, December 8,2014

The research from the group of Dr. Kevin Jones from the university of Utah was published in December 2014. It gives very important information on the metabolism of ASPS. It demonstrates that lactate drives proliferation of ASPS.

The full paper is available here.

The researchers initiated the study by creating transgenic mice carrying the ASPS gene in all of their cells. In patients this gene (ASPSCR1-TFE3) is found only in tumor cells. As expected this gene induced the formation of rapidly growing tumors. Unexpectedly, the ASPS tumors formed only in the heads of these mice. Every transgenic mouse developed a tumor within the skull, but never in the extremities (legs or hands) where usually patient ASPS tumors form. Close analysis of the tumors showed that these tumors had the same histopathology of human ASPS.

Next, the researchers identified the 500 most abundant genes expressed in the mice tumors and found them to be similar to those that were reported in human ASPS. As expected some of the genes are in pathways as “cell division” and “cell cycle”. However some of these genes belong to the “carbohydrate metabolism” pathway. This was another unexpected finding.

The surprise did not ended here: In addition to the fact that the ASPS in mice developed only in their heads, the researches found these tumors within skeletal muscles, although it was clear that the tumor origin did nor arise from muscle.

Then the researchers made few important findings explaining the above-unexpected observations. They found that the normal cells in the microenvironment of the tumors drove the formation of the tumors in the mice heads. The researchers discovered that ASPS tumors need the metabolite lactate for growth. Both brain and muscle are producing lactate flux. ASPS tumor cells then absorb this lactate and use this metabolic substrate as their energy source. Helping the ASPS tumors to uptake lactate are the MCT1 transporters and their binding partner CD147 protein. Those transporters are highly expressed by ASPS cells.

Finally, the researchers found that when they inhibited the lactate transporters MCT1 with a specific drug inhibitor namely CHC they could inhibit lactate signaling effects.

The researchers concluded that their research opened the door for exploring possible metabolic treatments for ASPS patients that could reduce the ability of ASPS to benefit from lactate which is available in their microenvironment.

 
_____________________________________________________

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

Research on ASPS presented at the conference of the “American College of Medical Genetics”

Dr. Shamini Selvarajah presented a summary of her studies on Alveolar Soft Part Sarcoma at the 2011 ACMG Annual Clinical Genetics Meeting that took place at the Vancouver Convention Center, Vancouver, BC, Canada. Dr. Selvarajah is one of the dedicated scientists from the Dana Farber Cancer Institute in Boston. They study ASPS relentlessly, aiming to understand the biology of this tumor and develop novel therapies which are in such a need for ASPS patients.photo.jpg

The work presented at the ACMG meeting included the identification of 323 genes which are specifically expressed in Alveolar Soft Part Sarcoma tumors. 207 of these genes are mostly abundant in the primary, and 116 of them are mostly abundant in ASPS metastases of 12 patients whose tumors were analyzed in this study. The 323 genes represent 16 key biological processes, gene signatures, and pathways that can be targeted in future studies.

iCureASPS will continue to support this research at the Dana Farber Cancer Institute through efforts of our Team ASPS participating in the PMC bike ride, and through generous donations from friends and family members of the large ASPS community.

To see the presentation of this study, follow the link – Identification of neural stem cell gene expression signatures associated with disease progression in alveolar soft part sarcoma by integrated molecular profiling

ASPS_ACMG_2011_thumb.JPG

Shamini Selvarajah1,2, Pyne Saumyadipta2, Eleanor Chen1, G. Petur Nielsen3, Glenn Dranoff2, Edward Stack2, Massimo Loda1,2 and Richard Flavin1,2

[1]Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
[2]Center for Molecular Oncologic Pathology, Dana–Farber Cancer Institute, Boston, MA 02115;
[3]Massachusetts General Hospital, Boston, MA 02114

______________________________________________________

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

Tumor Expression Profile of Alveolar Soft Part Sarcoma May Pave the Way for New Treatments at The Dana Farber Cancer Institute

Scientists from the group of Dr. Massimo Loda reported the results of an extensive study that aims to identify potential therapeutic targets for ASPS last Friday.

The research team, comprised of Shamini Selvarajah (PhD), Eleanor Chen (MD, PhD), and Saumyadipta Pyne (PhD), used cDNA microarray technology (gene expression array) to examine the expression of 18,401 genes in primary, and metastatic ASPS tumors from 14 ASPS patients. The work was done in collaboration with Brigham and Women’s Hospital, and the Broad Institute, affiliated with the Massachusetts Institute of Technology, and Harvard University.

Significant gene expression changes were discovered in 1,063 genes. The team elected to focus on 323 of them, which were singled out for their dramatically increased (or decreased) expression from the time the ASPS tumor was a primary (original tumor) to the time it turned into a metastasis. In other words, this work identified genes (those genes turn into proteins in the tumor) that changed their expression, as the tumor increased in aggressiveness. Such genes are well suited to be targeted as a therapeutic modality. Initial analysis of those genes points to several known molecular pathways that contribute to tumor growth and angiogenesis (formation of new blood vessels) in other types of cancers. The next challenge will be to identify the most promising target genes, for which approved drugs already exist. As an initial next step, these drugs could then be tested in animal tumor models of ASPS, and in ASPS cell lines.

Dr. Glenn Dranoff is an active participant, and collaborator in this project. Dr. Dranoff developed the GVAX vaccine, and ran the first GVAX clinical trial for ASPS patients. He will continue to be involved in the efforts to find a cure for ASPS.

Dear ASPS patients, friends and family members! We need your help to continue supporting the science behind results like this one. Through cutting edge research, more groundbreaking findings will be made that will bring a cure for ASPS. You can help, and be part of these great efforts.

Please:

1.   Consider fund-raising and donations to support the efforts to find a cure for ASPS at the Dana-Farber Cancer Institute.

2.   Encourage patients who are planning surgeries to donate their tumors to the Dana Farber.

3.   Communicate with me in regards to both of the above to ensure that funds and tumor donations reach their destination.

We are thankful to Dr. Massimo Loda and the scientists who did this important work, Dr. Glenn Dranoff, Dr. Ewa Sicinska, and the administrative staff Marcia Izzi and Laurie Peterson.

iCureASPS will continue to support these studies through direct funding, and through Team ASPS with the Pan Mass Challenge, as we believe that this is the way to discover the much needed cure!

2010_asps_reseach_04.JPG2010_asps_reseach_01.jpg 2010_asps_reseach_02.jpg 2010_asps_reseach_03.JPG

______________________________________________________

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

Potential Therapeutic Targets in Alveolar Soft Part Sarcoma – by Dr. Dina Lev

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.

______________________________________________________

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

Establishment of the first Alveolar Soft Part Sarcoma cell line by Dr. Vistica and other researchers from the National Cancer Institute, Bethesda, MD

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

______________________________________________________

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

Gene Expression Profiling of Alveolar Soft-Part Sarcoma (ASPS)

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

iCureASPS Continues to Support ASPS Research in the Laboratory of Dr. Dina Lev at MD Anderson Cancer Center, TX

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

______________________________________________________

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

 

Research sponsored by iCureASPS published: Is ASPS a target for Halofuginone therapy?

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?

______________________________________________________

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

iCureASPS supports ASPS Research in the laboratory of Dr. Dina Lev at MD Anderson Cancer Center

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.

______________________________________________________

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

iCureASPS Sponsors Studies on Halofuginone, a Possible Therapy for Alveolar Soft Part Sarcoma

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
  3. Halofuginone – other resources:

  4. Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect
  5. Halofuginone receives FDA orphan drug status for Scleroderma
  6. 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