DTRF Grant Awards

 

2013 Grant Awards

Raphael L. Pollock, MD, Ohio State Comprehensive Cancer Center


A rational search for novel anti-drug therapies

This is the final year of a study started by Dina Lev, MD, Phd at MD Anderson Cancer Center.



The goal is to investigate the molecular driving forces behind the development and progression of desmoid tumors. Dr. Pollock, et al, are trying to identify potential targets that modify beta-catenin transcriptional activity using an siRNA screen. Identifying genes and their cognate proteins whose alteration would inhibit beta-catenin activity might provide future targets for novel molecular therapies relevant to DT patients.

Aim 1: To validate previous findings of the prognostic power of beta-catenin 45F mutation in predicting the outcome of patients with primary desmoids.

Aim 2: To identify the molecular deregulations contributing to the sensitivity or resistance to the commonly used anti-desmoid therapies, mainly Tamoxifen, NSAIDS and Gleevec.

Aim 3: To identify potential novel anti-desmoid therapeutic targets using a rational siRNA screen. Potentially these targets harbor the capacity to modify the transcriptional effect of beta-catenin.

Note: Dr. Lev has previously identified significant associations between the presence of 45F mutations and an increased rate of of desmoid recurrence as well as shorter time intervals to recurrence. Analysis of a large primary desmoid subset showed that desmoids having a 45 F mutation had an estimated five year recurrence -free survival rate of only 47% and a median time to recurrence of 3.16 years. In sharp contrast, the estimated five year recurrence free survival rate for all other desmoid primary tumors was 83%; median time to recurrence not yet being reached.

Chiara Colombo, MD, Fondazione IRCCS Instituto Nazionale dei Tumori


High throughput genome study to identify predictors of aggressiveness in patients with sporadic desmoid tumor who undergo a wait and see approach


Desmoid tumors (DTs) are rare mesenchymal disease with a high tendency to recur despite an adequate surgical excision. An observational approach has been recently proposed in order to select patients who mostly benefit from medical therapy or surgical intervention because they have a painful or progressive disease or patients having an indolent or stable disease who can just be observed. There is not enough data or information at the beginning of the history that can help in predicting the behavior. Recently, specific β-catenin mutation (45F) has been correlated with a higher risk of recurrence after complete surgery. These results are based on retrospective data and they can be biased. In order to understand the natural history of this challenging disease, Fondazione IRCCS Instituto Nazionale dei Tumori proposed a prospective multicenter observational study for patients with measurable primary extra-abdominal disease who undergo W&S approach. This study has just been approved in Italy and the recruitment is ongoing. The aim of this translational project is to identify genome alterations that guide an aggressive behavior and to look for predictive factors in patients enrolled in the prospective clinical study using a high throughput genome approach. Dr. Colombo expects to observe different pattern of disease behavior that may reflect specific genome alterations. The data will be then validated in a larger cohort of patients surgically treated in the past and for whom FFPE materials are available. The assumption is that progression (in patients “observed”) and recurrence (in patients “operated”) represents different faces of biological aggressiveness. This could be helpful in the future to personalize treatments according to the predicted aggressiveness of the disease in each patient from the beginning.

Justin M. Cates, MD, PhD, Vanderbilt University


Genetic determinants of local recurrence in desmoid-type fibromatosis


This study will collaborate with the below study of Dr. van de Rijn at Stanford. In many patients with desmoid-type fibromatosis (DTF), the tumors recur after surgical excision. A major problem confronting clinicians who treat DTF is the lack of well-established criteria that predict which tumors will recur. Treating physicians do not know which patients are at high risk, and they are sometimes unsure about how aggressively to treat an individual patient. Recently, researchers have suggested that specific genetic mutations in the gene encoding β catenin predict a greater risk of tumor recurrence. While β catenin mutations seem to be useful prognostic markers, it is hypothesized that there are other so-called “driver mutations” that contribute to aggressive behavior in DTF. Therefore, Dr. Cates proposes to sequence the entire coding region of genomic DNA in DTF and adjacent normal tissues to identify additional DNA mutations in these tumors. To discover somatic mutations that predict tumor recurrence, he will also compare cases of DTF that recurred to similar cases that did not recur. Identification of mutations associated with an increased risk of local recurrence might assist doctors and patients faced with difficult management decisions and lead to discovery of potential drug targets.

Matt van de Rijn, MD, PhD , Stanford University


Next generation sequencing approach to desmoid tumors


Dr. van de Rijn has started to perform gene expression profiling (determining at which level each of >20,000 human genes is expressed) on archival tissue of desmoid tumors, scars from desmoid patients and a large number of fibroblastic lesions using an approach developed in his laboratory. The current proposal is a logical and necessary continuation of this project. This project will use cutting edge next generation sequencing to pursue two major clinical problems in desmoid tumors. First, it is well known that not all desmoid tumors behave in the same manner. Some are very aggressive, others have an indolent behavior. While attempts have been made to develop predictors for the behavior of desmoids, these rely only on clinical parameters such as tumor size, site and age of the patient and no molecular markers for recurrence risk have been identified. At this moment it is impossible to tell with certainty which tumors require aggressive treatment and which can be followed by “watchful waiting”. Through the ability to perform next generation sequencing on paraffin embedded tumor samples he can now perform a very broad search for changes in DNA that can help predict the behavior of desmoids. The data acquired under this proposal will complement the already existing dataset in his laboratory. Through collaboration with the oncology group at Stanford and at the Dana Farber Cancer Institute, there will be access to a more than sufficient number of cases for the study. In addition to identifying markers that can be used to predict the behavior of desmoid tumors, Dr. van de Rijn will also perform an in-depth search for markers that can be used by pathologists to distinguish scar from desmoid recurrence.

Nancy L. Cho, MD, Brigham and Women’s Hospital


Targeting Hyaluronic Acid in Desmoid Tumors


Desmoid tumors (DTs) are rare tumors that can be inherited or occur spontaneously. Although they do not metastasize, DTs can invade surrounding structures and cause pain, bowel obstruction, bleeding, and death. Recently, progress has been made in research efforts to understand DT biology. However, there is still no cure or reliable treatment for these tumors. Dr. Cho's laboratory is interested in understanding how DT cells “talk” to their surrounding environment to promote tumor survival, invasion, and growth. There is data to show that hyaluronic acid (HA) is a prominent component of the cellular matrix surrounding DTs. Dr. Cho believes that HA is critical in recruiting inflammatory cells that are necessary for DT formation and proliferation. This proposal will test the effects of anti-hyaluronic acid drugs in desmoid tumor cell lines obtained from human patients as well as animal models of this disease. It will also investigate whether HA promotes desmoid growth by recruiting specialized bone marrow progenitor cells that contribute to DT proliferation and invasion. This study will gain an understanding of how DTs manipulate their host environment to enhance tumorigenesis and may identify a novel target for therapy. The overall goal is to identify treatments for DT patients and improve survival and quality of life.

Benjamin Alman, MD, Duke University, with collaborators Robert Maki, MD, PhD, Mt. Sinai Medical Center; Alexander Lazar, MD Anderson Cancer Center; Alessandro Datti, PhD, Samuel Lunenefeld Research Institute


Collaboration for a Cure: Identifying new therapeutic targets for desmoid tumors


Desmoid tumors (DT) are locally invasive lesions that are difficult to treat using conventional therapies. While there is some success with chemotherapy in people who have recurrence of their tumors after surgery and/or radiation, much of the time the results from chemotherapy are temporary, and regrowth of tumor is seen. One approach to treatment is to develop a combination of medications that target different aspects of tumor growth, but have few side effects. Since desmoids are locally invasive but do not metastasize to other locations in the body, it is not necessary to wipe out every tumor cell, but just to get the tumor to shrink. Dr. Alman has assembled a consortium of researchers from different backgrounds, and with complementary skills, whose ultimate goal is to develop a treatment to therapeutically target tumor cells in desmoid patients without causing serious side effects.

To achieve this goal, the collaborators will:

1. Screen drugs in the laboratory on cells taken from desmoid tumor patients to see which drugs kill the tumor cells.

2. Test successful drugs using cell cultures from a variety of desmoid patients or cell lines.

3. Test drugs that are effective in cell lines in a mouse model that is engineered to develop desmoids.

4. The agents identified in the screen will then be analyzed for the ability to use them in combination, and these combinations will be tested in both desmoid cell cultures and in genetically modified mice.

Dr. Alman previously screened 1,000 agents in desmoids. There are libraries of over 100,000 compounds available for testing. The team of collaborators will use desmoid tumor primary cell cultures and normal fibroblasts to screen a large and comprehensive compound library using a robotic high throughput facility, to identify drugs that inhibit desmoid tumor cell growth but not normal fibroblast cells. The screening process will employ both commercially available drugs as well as otherwise untested agents.

Drugs that yield a positive result from the screen will be tested using a large collection of desmoid tumor cell cultures of different genetic etiologies, and in mice that develop desmoid tumors. Drugs that inhibit desmoids tumor growth in both cells and mice will then be studied in to using pharmacokinetic analysis, to identify drugs that work in an additive fashion when used in combination, but will still have an acceptable safety profile. They will then test the drugs already approved for use in patients in a multi drug regimen as informed by pharmacokinetic data. Then these combinations will be tested in multiple human desmoid tumor cultures and in genetically modified mouse models.

New candidate drugs will also be analyzed to identify their underlying biologic mechanism, to identify novel pathways that are activated by beta-catenin in desmoid tumors. These data will be used to prioritize new research into the biology of how beta-catenin causes desmoid tumors.

This approach should rapidly identify a multi-drug combination that can then safely be tested for efficacy in patients. In addition, it will identify new pathways activated by beta-catenin and new agents not yet in use for patient care that target desmoid tumors, both of which can be developed in future work which might ultimately identify even more effective therapeutic approaches.

Aaron Weiss, DO, Main Medical Center, Portland, Maine


Deregulated mTOR in desmoid-type fibromatosis:   identification and validation of a new therapeutic target.


This is a pilot study examining the role of sirolimus in the treatment of children and young adults with desmoid tumor that is deemed likely to recur following resection.  Sirolimus directly targets and inhibits a pathway that may be critical for the development and growth of desmoid tumor.  Sirolimus and several related drugs have been used in children and adults to suppress the immune system following transplant and, more recently, as an anti-neoplastic agent in a variety of cancer types.  Sirolimus is attractive as a potential drug for desmoid tumor because it is well-tolerated in children and young adults and it can be given orally.  Sirolimus acts by blocking a growth promoting pathway called the mTOR pathway.  Dr. Weiss will determine whether sirolimus can decrease tumor size, decrease tumor-associated pain, and block the mTOR pathway.  The data obtained in this pilot study will be used to leverage additional resources to support a national collaborative study, such as one run through the Children’s Oncology Group (COG), in children and young adults.

*The above grant awards are subject to a mutually satisfactory grant agreement between the parties.

 

2012 Grant Awards

Mrinal Gounder, MD –Memorial Sloan-Kettering Cancer Center


A Phase III, double blind, randomized, placebo-controlled trial of sorafenib in desmoid tumors or aggressive fibromatosis (DT/DF).


First year of two-year project for correlative research to define novel biomarkers of response in desmoid tumors treated with sorafenib.

Desmoid tumors (DT/DF) are clonal connective tissue malignancies of fibroblastic origin. DT/DF lack metastatic potential however, can cause significant morbidity, loss of function and pain through mass effects. Mortality from DT/DF results from local infiltration of vital structures. There is no standard of care for the treatment of DT/DF. Surgery is curative however associated with high recurrences. In unresectable patients, systemic therapies range from anti-estrogens to cytotoxic chemotherapies. DT/DF over express c-KIT and PDGFR and a Phase II study of imatinib showed a partial response (PR) of 6%. Sorafenib is a multi-target kinase inhibitor of b-Raf, PDGFR and VEGFR and available through an expanded access program. We treated an index patient with recurrent, unresectable DT/DF with sorafenib. A PR and clinical benefit prompted us to evaluate our experience of sorafenib in 26 patients. We noted a 25% PR by RECIST 1.1 and improvement of symptoms in 70% of patients. We noted a 30% decrease in the MRI T2 signal in 90% of patients with extra-abdominal disease. We hypothesize that sorafenib will lead to improved response rates, symptoms and progression free survival (PFS) in DT/DF patients. This is a multicenter, Phase III, randomized, double-blind, placebo-controlled trial of sorafenib in DT/DF patients. The primary endpoint is to evaluate overall response rates (ORR) for patients treated with sorafenib versus those treated with placebo. This study will enroll 126 patients over 2 years and will have a 90% power to detect a 22% increase in response rates (1-sided a=0.05). The secondary endpoints are 1) PFS and 2) pain palliation by the Brief Pain Inventory scale (BPI). Patients on placebo will cross over to sorafenib. Explorative studies include pre- and post-treatment biopsies in responding patients to determine biomarkers of response and mechanism of action of sorafenib. Decrease in MRI T2 signal may be an early marker of RECIST response and may be a more sensitive imaging marker for clinical benefit than RECIST response. We will conduct an explorative study a novel imaging biomarker by correlating changes in T2 signal to RECIST response and clinical benefit by pain palliation.

Benjamin Alman, MD -The Hospital for Sick Children, Toronto


Identifying novel drug therapies for desmoid tumors. Year three of a three-year study.


A major focus of my research program is to study the molecular pathology of desmoid tumors (DTs), with a long-term goal of developing improved treatments. DTs are locally invasive soft tissue tumors, which we found are caused by mutations resulting in the stabilization of the protein, ß-catenin. Stabilized ß-catenin binds to TCF transcription factors to regulate the expression of genes in a cell type specific manner. We developed mouse models of DT based on this knowledge and used these to study the role of target genes in the DT phenotype. Our ultimate goal is to develop an improved approach to DT therapy.

In this project we will continue our ongoing work funded by the DTRF in which we identified pharmacologic agents that target DT cell viability by screening compound libraries composed of agents which have a high potential to be rapidly translated into patient care. We identified agents that decreased cell viability in DT cultures but not in normal fibroblasts. Over the past two years, we tested several compounds in multiple DT cell lines, tested one in a mouse model of DT, and this work is in press in PLoS One, and found three others that have strong potential to be used as a therapeutic approach to DTs.

Two agents target platelet derived growth factor (PDGF) signaling, a pathway we also found can modulate ß-catenin activity. The other targets Notch signaling. We also developed a new mouse model in which we can regulate expression of conditional stabilized ß-catenin alleles, which can be used to rapidly screen signaling pathway interactions in-vivo. We hypothesize that compound screening will identify agents that can be developed into novel therapies to treat DTs, and rapidly be brought to patient care. In this next phase of our ongoing work, we propose to test this hypothesis by answering the following two questions:

How does Platelet Derived Growth Factor (PDGF) and Notch signaling modulation target DT cell viability? In the initial phase of our DTRF work, we identified three compounds that decreased cell viability in DT cultures but not normal fibroblasts: suntinib and mastinib, both of which block PDGF signaling; and DAPT, a gamma-secretase inhibitor which blocks canonical notch signalling. In our preliminary data, we found that PDGF signaling regulates ß-catenin activity. Cells in culture will be tested for how they alter DT cell behavior, by studying proliferation rate, apoptosis rate, and ß-catenin protein level. A new mouse model we developed will be used to test the interaction of signaling pathways identified in the compound screen.

Can PDGF and Notch pharmacologic blockade be used to treat DTs? Suntinib, Mastinib, and DAPT will be tested using a genetically modified mouse that develops DTs and using xenografted human DT tumors in immunodeficient mice. The mechanistic data generated in aim one will also be verified in-vivo in this aim.

The role of these agents in modulating different cell subpopulations in DTs will also be analyzed. In our previous work, we found that DTs contain a small cell population, which excludes Hoechst dye (called side population, or SP, cells). The SP cells have an enhanced ability to form tumors when implanted into immunodeficient mice, and as such act as tumor initiating cells (TICs), also called cancer stem cells. TICs may be resistant to anti-neoplastic drugs, and as such SP cells may be responsible for the resistance to treatments, and for tumor recurrence. We will also test theses compounds for differential effects on SP and non-SP cell populations.

This work will identify compounds that can rapidly be developed as a novel DT treatment. Such agents will ultimately be translated to clinical trials, resulting in an improved pharmacologic approach to DT management. In addition, the various agents likely target different aspects of controlling DT viability (e.g. proliferation -vs- apoptosis), and as such, this knowledge could be used to develop a rationale multi-drug approach to DT treatment.

Dina Lev, M.D. et al, MD Anderson Cancer Center


A rational search for novel anti-drug therapies. Year three of a three-year study.


Desmoid tumors (DTs) are a locally aggressive tumor type that can cause remarkable morbidity and even mortality in afflicted patients. While desmoid clinical phenotype has been well characterized, the underlying tumor molecular biology is poorly understood. In studies conducted within the premise of our previously funded DTRF seed grant we were able to establish a large desmoid tissue and cell strain repository and have confirmed that β-catenin mutations are highly prevalent in sporadic desmoid tumors. Furthermore, we showed that a specific mutation, 45F possibly significantly correlates with dismal outcome for patients with primary lesions. This initial observation merits further confirmation and in the recent grant period, through an international collaboration, we have been able to assemble a large cohort (>160) of clinically annotated primary DT samples; all were sequenced for β-catenin. Interim results are promising, confirming our initial observation.

We have also evaluated the effects of agents commonly used for the treatment of DT such as tamoxifen, celecoxib, and Gleevec on the growth of a large panel of desmoids primary cultures. Sensitive and resistant cell strains were identified; therapeutic response was independent of β-catenin mutation status or type or the expression level of the presumed drug targets. Finally, we have identified a potential DT gene expression signature enriched for genes regulated by TCF/LEF highlighting the role of β-catenin deregulation in these tumors. Midkine is one of the DT overexpressed targets; our studies further identified a correlation between midkine expression level and primary DT recurrence potential and a role for this protein in DT cell migration and invasion.

In the current, third year of the project, we aim to:

1. Finalize our studies evaluating the role of β-catenin mutations as DT molecular prognosticators.
2. Identify molecular signatures corresponding with sensitivity/resistance to commonly utilized anti-DT systemic agents.
3. Determine the role of the notch pathway in DT and its utility as a node of DT therapeutic vulnerability.
4. Unravel additional gene mutations operative in DT through whole exome sequencing of human samples (including matched specimens). We hope that these studies will result in meaningful observations that will enhance the management of patients burdened by this devastating disease.

 

2011 Grant Awards

Benjamin Alman, MD -The Hospital for Sick Children, Toronto


Identifying novel drug therapies for desmoid tumors


Desmoid Tumors are locally invasive soft tissue tumors, which are found to be caused by mutations resulting in the stabilization of the protein, ß-catenin. Stabilized ß-catenin binds to TCF transcription factors to regulate the expression of genes in a cell type specific manner. Mouse models were developed based on this knowledge and used to study the role of target genes in the DT phenotype. The ultimate goal is to develop an improved approach to Desmoid Tumor therapy. Dr. Alman is continuing the work begun last year to screen compounds to identify pharmacologic agents that target Desmoid Tumor cell viability. He screened libraries composed of agents already in use for patient care to identify compounds that decreased cell viability in Desmoid Tumor cultures but not normal fibroblasts. In the past year, three compound libraries were screened, and three potential classes of compounds were identified that have the potential to be used as a therapeutic approach to Desmoid Tumors. Three of the compounds identified are drugs already approved for use by the FDA, and as such this work has the potential to be rapidly brought to patient care.

Dina Lev, M.D. et al, MD Anderson Cancer Center


A rational search for novel anti-drug therapies.


Dr. Lev proposes a three-pronged research design based on her findings stemming from the previously funded DTRF seed grant that will address these knowledge deficits. Her studies will focus on improving the understanding of the role of ß-catenin, a protein which is highly deregulated in desmoids, on tumor progression and recurrence. Studies will use cell strains and also siRNA screens to identify potential anti-desmoid therapeutic targets.

  • Aim 1: To validate the prognostic impact of the specific beta-catenin 45F mutation in predicting the outcome of patients with primary desmoids.
  • Aim 2: To identify the molecular deregulations contributing to sensitivity or resistance to the commonly used anti-desmoid therapies mainly tamoxifen, NSAIDs (sulindac), and Gleevec.
  • Aim 3: To identify potential novel anti-desmoid therapeutic targets using a rational siRNA screen.


2010 Grant Awards

Benjamin Alman, MD -The Hospital for Sick Children, Toronto


Identifying novel drug therapies for desmoid tumors


One way to identify new drug therapies is to screen known drugs on cell cultures from tumors to see which drugs will kill the tumor cells. In the past Alman et al had tested 1,000 drugs on desmoid tumor cells and identified one such agent. Unfortunately, this agent is not readily available for use in North America. In this 2010 DTRF-funded study Dr. Alman plans to under take a comprehensive screen of agents to identify drugs that specifically target cell viability in DTs. Building on previous work, Dr. Alman will focus on drugs that inhibit DT cell growth presumably by blocking Beta catenin signaling in mesenchymal cells. The agents identified will be tested for their ability to alter DT cell proliferation, Beta catenin protein level and differential affects on stem cells. Such drugs will be tested using DT cell cultures from patients and also transgenic mice that develop DTs. Identified agents can then be investigated in clinical trials. The exciting part is that the agents found to have clinical benefit will already have been FDA-approved for use in patients and can therefore be rapidly brought to patient care.

Stephen X. Skapek, MD- The University of Chicago


Deregulated mTOR in desmoid-type fibromatosis: identification and validation of a new therapeutic agent.


This is a pilot study examining the role of Rapamycin in the treatment of children and young adults with DT deemed likely to recur following resection. Rapamycin directly targets and inhibits mTOR, a growth promoting pathway that may be critical in the development and growth of DT. The mTOR cell proliferation/survival pathway was shown to be activated and essential for tumorigenesis when the APC gene is mutated (affecting the Beta catenin signaling pathway). It is an oral drug being evaluated as an anti-neoplastic agent in a variety of cancer types.

Skapek et al plan to determine how effectively rapamycin blocks mTOR activation in desmoid tumors and whether mTOR inhibition blocks desmoid tumor blood vessel growth. Skapek et al plan to determine how effectively rapamycin blocks mTOR activation in desmoid tumors . If Rapamycin is found to be active, they intend to extend this pilot study to a national collaborative study run through the Children's Oncology Group (COG).

Dina Lev, M.D. et al, MD Anderson Cancer Center


A rational search for novel anti-drug therapies.


The goal is to investigate the molecular driving forces behind the development and progression of desmoid tumors. Lev et al are trying to identify potential targets that modify beta-catenin transcriptional activity using an siRNA screen. Identifying genes and their cognate proteins whose alteration would inhibit beta-catenin activity might provide future targets for novel molecular therapies relevant to DT patients.

  • Aim 1: To validate previous findings of the prognostic power of beta-catenin 45F mutation in predicting the outcome of patients with primary desmoids.
  • Aim 2: To identify the molecular deregulations contributing to the sensitivity or resistance to the commonly used anti-desmoid therapies, mainly Tamoxifen, NSAIDS and Gleevec.
  • Aim 3: To identify potential novel anti-desmoid therapeutic targets using a rational siRNA screen. Potentially these targets harbor the capacity to modify the transcriptional effect of beta-catenin.

Note: Dr. Lev has previously identified significant associations between the presence of 45F mutations and an increased rate of of desmoid recurrence as well as shorter time intervals to recurrence. Analysis of a large primary desmoid subset showed that desmoids having a 45 F mutation had an estimated five year recurrence -free survival rate of only 47% and a median time to recurrence of 3.16 years. In sharp contrast, the estimated five year recurrence free survival rate for all other desmoid primary tumors was 83%; median time to recurrence not yet being reached.

Andrew Beck, MD- Post Doc Fellow at Stanford University


Evaluation of Large Intergenic Non-coding RNAs in Desmoid Type Fibromatosis.


DTRF-funded investigators at Stanford have developed a novel technique to analyze RNA from paraffin embedded tissue. This is important as many more paraffin embedded samples are available for study than frozen. Currently this technology is being used to study "usual" coding mRNA in desmoids in the Stanford lab. In this study they will be including the study of a new class of "non-coding RNA" and to examine the role of these molecules in the clinical behavior of desmoids. Conventional standard microarray expression profiling has been limited in that it only measures known genes that contain probes on the array platform. The new method being used allows for identification of novel transcripts. The new class of RNA (large intergenic non-coding RNA (lincRNA)) is thought to be a major regulator of gene expression. In the past year it has been shown that over one thousand evolutionarily conserved lincRNA's are expressed in mammalian cells and that expression of these lincRNA's correlates significantly with genes important in carcinogenesis. The long term goal is that the characterization of lincRNA's in DT will lead to new diagnostic markers and treatment strategies for DT.

 

2009 Grant Awards

Matt van de Rijn at Stanford University


ROR2, a potential novel therapeutic target in desmoid tumors.


This is a grant for a three-year project studying Receptor tyrosine (RTK's) which are proteins that are expressed on the surface of cells and are known to play an important role in cellular differentiation and tumor growth. ROR2 is a RTK which is expressed at high levels in a significant subset of desmoid tumors. It is a receptor for the Wnt family of proteins, proteins that are known to play a role in a pathway in the development of desmoid tumors. They will generate a novel monoclonal antibody against the extracellular part of ROR2 and study its effect on desmoid tumor cell growth in vitro.

Richard D. Lackman at University of Pennsylvania


The role of hydroxyurea as first line treatment for primary and recurrent/refractory desmoid tumors.


This is a three year grant studying the role of hydroxyurea in the treatment of primary and recurrent Desmoid Tumors in adults and children.  Hydroxyurea is a generally well tolerated anti-neoplastic agent used in the treatment of myeloproliferative disease, CML and small group of carcinomas.  This study builds on the  favorable efficacy:toxicity experience in an earlier study in children in which preliminary results showed partial response or stable disease in 79% of patients. This is a non-randomized trial.

Benjamin A. Alman, MD at the University of Toronto


Identifying the Desmoid Initiating Cell.


This is the third year of a three-year study. A small portion of stem cells in a given tissue give rise to all of the cells that make up that tissue. These cells help regenerate and maintain the tissue over its lifespan. These stem cells have been identified in a variety of tumor types and are called tumor initiating cells (TIC). These investigators will be testing the hypothesis that desmoid tumors contain a subpopulation of TIC and that desmoid tumors are derived from mesenchymal stem cells (MSC) that have a mutation leading to elevated levels of beta catenin, a protein thought to be instrumental in the development of familial adenomatous polyposis along with a mutation in the APC gene. In familial cases, desmoid tumors are associated with an APC mutation. Preliminary data suggest that desmoid tumors may be derived from MSC's in which beta catenin signaling is misregulated. Dr. Alman and his team currently have 22 desmoid tumor cell lines with which to work. They will be (1) attempting to identify cell lines of TICs in desmoid tumors using established surface markers, and (2) using mice to determine if the tumors arise from misregulated MSC's.  Their goal is to ultimately develop a novel strategy of targeting desmoid tumor initiating cells.

Dina Lev, M.D. et al, MD Anderson Cancer Center


Molecular Determinants of Desmoid Tumor Development and Progression.


This is the third year of a three-year study. These investigators will be studying three molecular factors believed to be important in desmoid tumors: beta catenin, TCF-3 (a transcription factor) and ER-beta (an estrogen receptor). They are using a three-pronged approach. Aim 1 is the establishment of multiple desmoid tumor cell lines.  Aim 2 is the examination of the role of beta catenin, TCF-3 and ERbeta interactions in desmoid proliferation using the cell lines developed in Aim 1. Aim 3 is the identification of desmoid tumor related molecular markers using oligoarrays and tissue microarrays.

 

2008 Grant Awards

Matt van de Rijn at Stanford University


ROR2, a potential novel therapeutic target in desmoid tumors.


This is a new grant for a three-year project studying Receptor tyrosine (RTK's) which are proteins that are expressed on the surface of cells and are known to play an important role in cellular differentiation and tumor growth. ROR2 is a RTK which is expressed at high levels in a significant subset of desmoid tumors. It is a receptor for the Wnt family of proteins, proteins that are known to play a role in a pathway in the development of desmoid tumors. They will generate a novel monoclonal antibody against the extracellular part of ROR2 and study its effect on desmoid tumor cell growth in vitro.

David E. Joyner, PhD et al, Huntsman Institute, University of Utah


Do Factors Mediate Desmoid Tumor Invasiveness and Drug Sensitivity

Conclusions: 
1. MMP1 (matrix metallopeptidase) expression predominant in highly invasive FAP-related DT while MMP3 more representative of less invasive sporadic DT. (two manuscripts in progress)
2.FAP desmoids are more likely resistant to chemo than sporadic DT.

Dr. David Joyner will continue to contribute to the DTRF collaborative effort that was initiated during the May 2008 Symposium

Orthopaedic Research Society abstracts

Benjamin A. Alman, MD et al, Hospital for Sick Children


Identifying the Desmoid Initiating Cell.


This is the second year of a three-year study. A small portion of stem cells in a given tissue give rise to all of the cells that make up that tissue. These cells help regenerate and maintain the tissue over its lifespan. These stem cells have been identified in a variety of tumor types and are called tumor initiating cells (TIC). These investigators will be testing the hypothesis that desmoid tumors contain a subpopulation of TIC and that desmoid tumors are derived from mesenchymal stem cells (MSC) that have a mutation leading to elevated levels of beta catenin, a protein thought to be instrumental in the development of familial adenomatous polyposis along with a mutation in the APC gene. In familial cases, desmoid tumors are associated with an APC mutation. Preliminary data suggest that desmoid tumors may be derived from MSC's in which beta catenin signaling is misregulated. Dr. Alman and his team currently have 22 desmoid tumor cell lines with which to work. They will be (1) attempting to identify cell lines of TICs in desmoid tumors using established surface markers, and (2) using mice to determine if the tumors arise from misregulated MSC's.  Their goal is to ultimately develop a novel strategy of targeting desmoid tumor initiating cells.

Dina Lev, M.D. et al, MD Anderson Cancer Center, University of Texas


Molecular Determinants of Desmoid Tumor Development and Progression.


This is the second year of a three-year study. These investigators will be studying three molecular factors believed to be important in desmoid tumors: beta catenin, TCF-3 (a transcription factor) and ER-beta (an estrogen receptor). They are using a three-pronged approach. Aim 1 is the establishment of multiple desmoid tumor cell lines.  Aim 2 is the examination of the role of beta catenin, TCF-3 and ERbeta interactions in desmoid proliferation using the cell lines developed in Aim 1. Aim 3 is the identification of desmoid tumor related molecular markers using oligoarrays and tissue microarrays.

 

2007 Grant Awards

David E. Joyner, PhD et al, Huntsman Institute, University of Utah


Do Factors Mediate Desmoid Tumor Invasiveness and Drug Sensitivity.


Desmoid tumors can grow rapidly and be highly invasive or they can remain static for many years. These investigators are studying whether the proteins EGF (epidermal growth factor) and TGF-alpha (transforming growth factor) influence the invasive nature of desmoids and if either factor determines desmoid drug sensitivity. They hypothesize that these factors exert an influence on relevant genes.  They have a three-pronged approach (1) measuring the mRNA and protein levels of relevant genes using polymerase chain reaction and tissue staining, (2) testing cell cultures for the influence of EGF and TGF-alpha on cell invasiveness and doxorubicin toxicity and (3) performing microarrays on lab-altered desmoid cell cultures in order to identify genes responsive to growth factor modulation.  They anticipate that this may provide a list of potential therapeutic targets for use against desmoid tumors.

Benjamin A.Alman, MD et al, Hospital for Sick Children


Identifying the Desmoid Initiating Cell.


A small portion of stem cells in a given tissue give rise to all of the cells that make up that tissue. These cells help regenerate and maintain the tissue over its lifespan. These stem cells have been identified in a variety of tumor types and are called tumor initiating cells (TIC). These investigators will be testing the hypothesis that desmoid tumors contain a subpopulation of TIC and that desmoid tumors are derived from mesenchymal stem cells (MSC) that have a mutation leading to elevated levels of beta catenin, a protein thought to be instrumental in the development of familial adenomatous polyposis along with a mutation in the APC gene. In familial cases, desmoid tumors are associated with an APC mutation. Preliminary data suggest that desmoid tumors may be derived from MSC's in which beta catenin signaling is misregulated. Dr. Alman and his team currently have 22 desmoid tumor cell lines with which to work. They will be (1) attempting to identify cell lines of TICs in desmoid tumors using established surface markers, and (2) using mice to determine if the tumors arise from misregulated MSC's.  Their goal is to ultimately develop a novel strategy of targeting desmoid tumor initiating cells.

Dina Lev, M.D. et al, MD Anderson Cancer Center, University of Texas


Molecular Determinants of Desmoid Tumor Development and Progression.


These investigators will be studying three molecular factors believed to be important in desmoid tumors: beta catenin, TCF-3 (a transcription factor) and ER-beta (an estrogen receptor). They are using a three-pronged approach. Aim 1 is the establishment of multiple desmoid tumor cell lines.  Aim 2 is the examination of the role of beta catenin, TCF-3 and ERbeta interactions in desmoid proliferation using the cell lines developed in Aim 1. Aim 3 is the identification of desmoid tumor related molecular markers using oligoarrays and tissue microarrays.