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The Desmoid Tumor Research Foundation

“Deregulated mTOR in desmoid-type fibromatosis: identification and validation of a new therapeutic target.” Year 1 of 1

2013

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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.

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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.

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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 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.

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Project resulted in poster here
Access poster here.

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.

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Project resulted in article here.
Access article here. 

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.

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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.