2015 RIS Sarcoma Research Grants

The RIS Board authorized $125,000 at its January 2015 Board meeting for 5 new sarcoma research projects through the U of M Masonic Cancer Center and three RIS Sarcoma Cancer Fellowships for the 2015-2016 Academic year. In addition the Board authorized 2015-2016 RIS Maudlin Sarcoma Scholarship for both the University of Minnesota and the Mayo Medical Schools. These awards are the direct result of the broad and deep support that RIS received from so many of you in 2014. Thank you.
The awarded research grants for 2015 are:

Ed Chang 2015 Grant Award of $29,000: The use of FDG-PET CT metabolic response to increase the therapeutic ratio of treatment for high grade, large soft tissue sarcomas
– Principal Investigator Ed Cheng, MD, Mairs Family Professor Department of Orthopaedic Surgery

Project Summary:
First line chemotherapy agents for soft tissue sarcomas are only effective in 40-50% of patients yet are associated with adverse side effects of varying severity in 100% of patients. For tumors responsive to chemotherapy, a reduction in local relapse has been demonstrated which may provide the opportunity to reduce local radiation and thereby minimize radiation-associated toxicity. This clinical trial will test the ability of using FDG-PET scan to assess treatment response and therefore guide an early decision (after 1 cycle of chemotherapy) of continuing chemotherapy only in patients for whom it is considered effective with the goal of achieving equivalent or superior survival results while reducing toxicity for patients in whom chemotherapy is not effective. Furthermore, local radiation will be randomized for the chemotherapy responsive patients.
Additional biologic correlative goals would be to (1) investigate the difference in the pseudocapsule formation in the tumors on each treatment arm and correlate with FDG-PET CT metabolic response and, (2) collect tissue from both biopsy and primary tumor excision for microarray studies. In those patients who do not respond to 1st line chemotherapy agents, the protocol will allow expansion to using an appropriate 2nd line chemotherapy agent prior to surgical resection and measuring metabolic response.
Hendrickson, Eric2015 Grant Award of $24,000: The role of ATRX and ALT in sarcoma
– Principal Researcher Eric Hendrickson, Professor Academic Dept: Biochemistry, Molecular Biology & Biophysics (BMBB)

Project Summary:
All human cancers need to maintain their telomeres, the repetitive tract of DNA at the ends of chromosomes, in order to continue to proliferate. The majority of human tumors maintain the length of their telomeres through telomerase, an enzyme capable of adding new telomeric DNA directly onto the ends of chromosomes. A minority of human cancers utilize a telomerase-independent mechanism of telomere maintenance called Alternative Lengthening of Telomeres (ALT). The relative usage of ALT, however, varies considerably with tumor type. Importantly for this application, ALT is extremely prevalent in sarcomas, with 30% of all soft tissue sarcomas, 50% of all osteosarcomas and perhaps an even higher percentage of chondrosarcomas being ALT positive. Thus, understanding the mechanism of ALT — and elucidating ways to inactivate it — is extremely relevant to sarcoma research and treatments. Recently a gene, ATRX, was implicated as being a key regulator for the genesis of ALT. We used gene targeting to disrupt this gene in human cells and then used those ATRX-null cells to demonstrate that the absence of ATRX is sufficient to induce ALT. To our knowledge, we are the only laboratory in the world with a model system in which ALT can be induced and studied and as a consequence, we are poised to make contributions that cannot be made anywhere else. An understanding of how ALT occurs and is maintained in tumor cells will almost certainly lead to novel therapeutic treatments of, specifically, sarcomas.
Dr. Jaime F. Modiano2015 Grant Award of $24,000: Mechanism-Based Expansion of the Tumor Repertoire for an Effective Sarcoma Therapy
– Principal Investigator Jaime F. Modiano, VMD, PhD Professor, Department of Veterinary Clinical Sciences College of Veterinary Medicine and Masonic Cancer Center

Project Summary:
SRCBST (sarcoma bispecific toxin) is a drug with excellent safety profile that is effective against spontaneous canine vascular sarcomas. Our goal is to determine the therapeutic mechanism of SRCBST so we can rationally expand its use to treat human sarcomas where it will provide similar benefits. This project has two aims: Aim 1 will establish the requirement of urokinase receptor (uPAR) expression by sarcoma cells to create a tumor niche and promote tumor formation. Aim 2 will determine whether uPAR expression is necessary in tumor cells, in supporting stromal cells, or in both to achieve a therapeutic response with SRCBST. We will implant three genetically engineered cell lines representing distinct sarcomas, each overexpressing or lacking uPAR, into wild type or uPAR-KO mice. We will evaluate tumor growth using imaging and physical methods. SRCBST will be administered in the minimal residual disease setting. We predict that uPAR expression in tumor cells will enhance tumor engraftment and growth. We also anticipate that the uPAR in the microenvironment will not be essential, but will accelerate tumor growth and significantly improve the therapeutic efficacy of SRCBST. The project is designed to provide synergy with, and to expand our translational sarcoma program: understanding the SRCBST mechanisms of action will help us define the spectrum of tumors that will respond, and potentially allow us to devise paired biomarkers. This will also support comprehensive applications to the NIH to further delineate the mechanisms and set parameters for an investigational new drug application to the FDA.

Moriarity, Branden2015 Grant Award of $24,000: The Role of NFIB in Metastatic Pediatric Osteosarcoma”
– Principal investigator Branden S. Moriarity, Ph.D., Assistant Professor Department of Pediatrics, University of Minnesota, Twin Cities

Project Summary:
The goal of this project is to study the role of the gene NFIB in metastatic pediatric osteosarcoma (OS). The results of this study have the potential to improve patient management, increase our understanding of the role NFIB in pediatric OS, and its potential to be therapeutically targeted. NFIB has never been implicated in human OS previously but our collaborator, Dr. Lisa Mirabello, and our lab independently identified it as having a role in OS using two different methods; one using human OS tumors and the other using a novel genetic mouse model of OS.
Both methods found that NFIB is acting to suppress OS development and metastasis, thus we hypothesize that NFIB has a dual role in both the initiation of OS and its likelihood to become metastatic. We plan to study the role of NFIB using two methods, removing the gene from human OS cell lines and developing a new mouse model of OS that specifically relies on loss of Nfib. The use of human OS cell lines will confirm the role of NFIB in human OS, while the mouse model will provide a functional validation of Nfib loss in OS development and metastasis and provide a new model to test potential therapies for OS that have reduced NFIB expression in the future. Importantly, through the study of NFIB we may identify susceptibilities of OS tumors having low NFIB expression that could be targeted with new therapies.

Dusenbery, KatieKWRISF 2015 Grant Award: $24,000: Enhancement of the response of sarcoma to SBRT
– Co-Principal Investigators: Kathryn Dusenbery, M.D. Associate Professor and Head, Department of Therapeutic Radiology/Radiation Oncology and Chang W. Song, Ph.D. Professor, Radiobiology Lab. Department of Therapeutic Radiology/Radiation Oncology

Project Summary:
Stereotactic body radiation therapy (SBRT) is highly effective at achieving local control of sarcoma and other radioresistant tumors. The recent impressive improvements in tumor imaging technology and linear accelerator accuracy have made it possible to treat many sarcomas or sarcoma metastases with SBRT. With SBRT, the tumors are irradiated only 2-5 times with high radiation dose per treatment whereas conventional radiotherapy irradiates sarcoma 30-50 times with low dose per treatment. However, it has not been clear why SBRT is so much more effective than conventional radiotherapy. We recently revealed that SBRT causes massive secondary cell death, in addition to directly killing tumor cells, by inducing severe damage in tumor blood vessels. Destruction of blood vessels depletes the supply of oxygen and other nutrients which are essential for the survival of tumor cells. The low oxygen environment, i.e. hypoxia, due to vascular destruction activates HIF-1α and VEGF, which are essential for reconstruction of tumor vascular net-works. This means that hypoxic tumor cells that survive the direct and indirect effect of SBRT modulate the intratumor environment and promote their proliferation and tumor recurrence. The purpose of our study is to find means to improve the efficacy of SBRT against sarcoma (a) by eradicating the hypoxic sarcoma cell which survive SBRT using drugs which are toxic specifically on hypoxic tumor cells and (b) by preventing recurrence of sarcoma after SBRT treatment using inhibitors of HIF-1α.

For Listing of other RIS Research Grants, click here.