BeatSarcoma has funded the following projects:
Ongoing research at Stanford University Medical Center
Research in the laboratory that is run by Drs. Matt van de Rijn and Rob West in the pathology department at Stanford University Medical Center has focused for the past ten years on using novel technologies to identify new diagnostic markers, prognostic markers and potential therapeutic targets in sarcoma.
The technology that we used initially was that of gene microarrays with which we can study the level of expression of tens of thousands mRNAs. An mRNA is essentially a message molecule that tells the cell which protein to make; the study of these mRNAs was revolutionized by the invention of the gene microarray technology by Dr. Pat Brown at Stanford University. For the first time we were able to study in a single experiment of a level of not just one but 20,000 messenger RNAs. More recently the gene array technology has been replaced with the so-called “high throughput sequencing” or “next generation sequencing technology.” With this technology a person’s whole genome can be sequenced in a matter of days but we have adapted this technology in our lab to use it to determine precise levels of messenger RNA for all known human genes. Over the years we have applied these technologies to find novel diagnostic markers.
A diagnostic marker is essentially a tool that a pathologist can use to help him or her reach the best possible diagnosis for a tumor. Especially in sarcomas this is an important role as there are many different forms of sarcoma (over 100 different sarcomas have been recognized) and sarcomas overall are quite rare. As a result most pathologists do not have extensive experience with sarcomas and can use the help that they can get from these diagnostic markers. One example of these diagnostic markers is one we developed. It is a marker called “DOG1” and it is now used in pathology departments throughout the world to help diagnose gastrointestinal stromal tumors (GIST).
Another goal in our laboratory is to identify so-called “prognostic markers.” These are markers that can help clinicians determine how a particular malignant tumor can be expected to behave. This has repercussions for the treatment options that will be offered to the patient. Tumors that can be expected to behave in a very malignant fashion will be treated more aggressively than tumors that do not show expression of such a prognostic marker. Over the past years we have focused on the presence of a particular inflammatory cell (a “macrophage”) in leiomyosarcoma and gastrointestinal stromal tumors as a tool to determine how aggressive these tumors will behave. Perhaps more importantly this study has led us to identify two potential therapeutic targets in leiomyosarcoma. The first target is a protein called CSF1, a protein that is secreted by tumor cells to attract macrophages. These macrophages can help the tumor grow by aiding in the generation of an active blood circulation within the tumor that will provide the tumor with nutrients and oxygen. We are currently testing inhibitors of CSF1 in vitro and in mouse tumor models to study this approach to see whether this may be a useful application in sarcoma patients.
Macrophages can be “good” or “bad.” The so-called “bad” macrophages help tumors to grow by increasing their blood supply as mentioned above. Macrophages can be coaxed into becoming “good” cells by treatment with an antibody that stimulates them to eat tumor cells. This study was most recently published in the journal Proceedings of the National Academy of Sciences and in this study we could show a dramatic decrease in not only primary size but also in the number and size of metastases that occurred in a mouse model system. This work was done in collaboration with the Weissman laboratory at Stanford University and together we hope to be able to start a clinical trial using this approach in the next year or so.
Leiomyosarcoma and Endometrial Stromal Sarcoma Research Under the Direction of Drs. Robert West and Matt Van de Rijn at Stanford University
Stanford has developed a new technique called 3SEQ to determine expression levels for all human genes in tumor samples. The novel aspect of this technology is that it is possible to use paraffin embedded tissue and it does not require fresh frozen tissue. The latter is often difficult to obtain especially for rare tumors such as uterine sarcomas. Stanford has obtained funding through an NIH RO1 grant and through BeatSarcoma to study leiomyosarcomas (the most common form of uterine sarcoma) and has used the funding for a study a number of uterine leiomyosarcomas (LMS) as a follow-up to its recent paper in Oncogene. Stanford is still in the process of collecting additional samples but preliminary data analysis has begun. Stanford expects that over the next years it will study about 200 LMS cases in this manner. This is not an unrealistic expectation as it already has identified 60 cases from Stanford alone and is in addition collaborating with Dr. Chris Fletcher who already has sent another 25 cases.
Stanford is now also in the process of analyzing a significant number (paraffin blocks for ten cases so far have been identified) of endometrial stromal sarcomas (ESS). ESS is the second most common sarcoma of the uterus and BeatSarcoma will help fund this important aspect of our research. The hope is that by comparing LMS to ESS and to normal uterine tissue Stanford will be able to develop better diagnostic tools to separate these tumors and to develop novel potential therapeutic targets for each.
UCSF Sarcoma Research, led by Dr Eric Nakakura
Dr. Eric Nakakura is a surgeon-scientist who specializes in the treatment gastrointestinal neuroendocrine tumors and soft tissue sarcomas, including tumors of the retroperitoneum, trunk and extremities. As a member of the UCSF Helen Diller Family Comprehensive Cancer Center and the Gastrointestinal (GI) Oncology Research Program, he also conducts research into basic sarcoma biology.
As a sarcoma surgeon, Dr. Nakakura has ongoing, direct access to human sarcoma samples from resected specimens. In collaboration with the laboratory of Dr. Kevin Shokat, the GI Oncology Research Program has had success using a new model of animal studies that makes use of excess tumor tissue following resection. Using state-of-the-art techniques, they are implanting these human tumors in mice. Researchers have found that this model more accurately represents the growth of human cancers than trying to grow the samples in the culture dish, which can change the character of the cancer specimens. This is a powerful tool in helping identify which therapies might be most effective for individual patients, and to identify possible vulnerabilities in cancer stem cells.
Currently, due to BeatSarcoma funding, research is underway to determine the role of the mTOR pathway as it relates to sarcoma growth. Prior investigations focused on studying the role of the mTOR pathway in neuroendocrine tumors found this to be an important signaling pathway and researchers hypothesize it may be responsible for sarcoma growth.
As a result of BeatSarcoma’s initial investment of $5,000, Dr. Nakakura and his colleagues have been able to advance their studies at the UCSF Helen Diller Family Comprehensive Cancer Center in the battle against sarcoma. A major challenge in sarcoma research is a paucity of models to study the disease and to develop new therapies. In order to develop new models to study this rare disease, researchers take limited samples obtained from patients undergoing surgical resection at UCSF. These limited samples are immediately implanted into immunodeficient mice, which provide a permissive environment for the growth and expansion of small amounts of sarcoma tissue.
Dr. Nakakura and his colleagues have successfully established these so called “sarcoma xenografts” from two patients and are planning to use them to develop new cell lines. New sarcoma xenografts and cell lines will be invaluable models to evaluate new treatment strategies. One strategy currently being evaluated at UCSF is targeting the mTOR pathway, a critical regulator of cell growth. Researchers have successfully optimized the conditions to measure mTOR pathway activity in human samples. With the continued partnership of BeatSarcoma, Dr. Nakakura and his colleagues will be able expand their analysis of the mTOR pathway in human sarcoma. Moreover, it will help determine if mTOR inhibition with drugs that target this pathway affect sarcoma growth and progression using these novel models.