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Research at Mass General
Our patients are offered Dana-Farber/Partners clinical trials dealing with sarcoma. Some of the investigational agents we are currently offering include: Apomab, Perifosine, AP23573, and Trabectedin (Yondelis®). We also plan to open a clinical trial using R1507- an antibody to IGF1-R and Dasatinib an inhibitor of SRC, PDGFR, C-kit, and ephrin receptor kinases. We also study the use of drugs FDA approved for other cancers to see if they are effective in sarcomas; these include: Avastin®, Sutent®, Gemcitabine and Taxotere. Some these trials include radiation/surgical protocols solely offered by the Massachusetts General Hospital. An Massachusetts General Hospital clinical trial of Avastin® in conjunction with pre-operative radiation therapy and surgery for high risk soft tissue sarcomas is currently in progress. We also have clinical trials in progress for patients with spine sarcomas undergoing combined modality treatments that include proton beam radiation therapy that are only offered at the institution.
Sarcoma basic research is conducted within two areas:
Research activities focus on sarcomas and encompass diverse areas, ranging from biochemical studies and translational research aimed at developing new therapies for treating sarcomas, to biochemical predictors of disease. Our laboratories investigate the relationship between biological parameters and clinical parameters for sarcomas, including:
We have recorded data regarding our patients with bone and soft tissue tumors for the past 35 years. To date, we have information on 15,000 patients that includes demographic data, diagnosis, stage, anatomical site, operative procedures, use of adjuvant therapy, laboratory data, and outcome in terms of local recurrence, metastasis, and death.
At the molecular level, we are focusing on chemotherapeutic drug resistance and mechanisms of antiangiogenesis agents. The sensitivity of sarcoma cells to the novel marine chemotherapeutic, Yondelis, has led us and others to consider this compound as an important component of future treatment options for sarcomas such as chondrosarcoma. However, as with other chemotherapeutics, the propensity of tumor cells to develop resistance to Yondelis poses a significant challenge for employing this drug over an extended period of time as a cancer treatment.
Human sarcoma cell lines developed in our laboratories have been treated successively with marine compounds yielding variant cell lines displaying a significant degree of resistance to the cytotoxic action of drugs. Various experiments were performed to identify molecular aberrations between the parent and resistant cell lines. Although no significant differences in the activity of membrane transporters such as P-glycoprotein or multidrug resistance protein were detected, the cell migratory ability of the Yondelis-resistant cell variants were reduced, as was cell attachment capability to gelatin-coated culture dishes. Staining of the actin containing cytoskeleton with fluorescent-labeled phalloidin revealed significant differences in the cytoskeleton architecture between the parent and resistant cell lines. Comparison of serum-free conditioned medium from both cell lines showed conspicuous differences in the levels of several proteins, including a quartet of high molecular weight proteins (140 kDa). The protein sequences of two of these high molecular weight proteins, present at significantly higher concentrations in conditioned medium obtained from the parent cell lines, corresponded to subunits of type I and type IV collagen. Analysis of type I collagen alpha1 chain mRNA revealed a significantly lower level in the Yondelis cells . Thus, prolonged exposure to Yondelis may cause distinct changes in cell function through cytoskeleton rearrangement and/or modulation of collagen levels. Our goal is to further dissect the molecular mechanisms underlying the development of chemoresistance, in order to formulate strategies to minimize or prevent this phenomenon, as well as develop diagnostic tests for indicating the onset of chemoresistance.
We have also been studying the properties of a novel, protein designated plasminogen-related protein B (PRP-B), encoded for by plasminogen-related gene B (PRG-B), with the goal of extending our understanding of the antiangiogenic process as it relates to tumor growth as well as gaining insights into biological processes that are insensitive to the action of antiangiogenesis inhibitors. We have been accumulating evidence that PRP-B may function as part of a host defense mechanism to thwart tumor growth, most likely by inhibiting angiogenesis. To understand the function of this 9kDa protein, we prepared and characterized a recombinant form of the protein (rPRP-B), which we have employed in mouse tumor studies. These in vivo experiments have clearly demonstrated a marked antitumor activity. When administered systemically, rPRP-B significantly inhibited growth of different tumors when grown in mice, although the corresponding homologous region in plasminogen (i.e., the plasminogen activation peptide) was much less effective at curtailing tumor growth. Interestingly, when rPRP-B was administered in combination with a chemotherapeutic, tumor necrosis of a human chondrosarcoma in an athymic mouse xenograft model was significantly enhanced relative to individual chemotherapeutic or antiangiogenic treatment, suggesting that rPRP-B may have utility as an adjunctive cancer therapeutic, similar to Avastin®. Noteworthy was our finding that tumor vascularization was severely depressed only in the combination therapy, suggesting that a partial block in angiogenesis, which was observed in the individual therapies, is capable of slowing tumor growth substantially but is inadequate in terms of producing tumor necrosis.
Tumor angiogenesis in different organ environments: implications for anti-angiogenic therapy for soft tissue sarcomas The process of new blood vessel formation, or angiogenesis, is regulated by a balance between pro-angiogenic and antiangiogenic factors. Tumor cells interact with their host environment (e.g. soft tissue, lung, liver) and must create a positive angiogenic balance in order to promote the ingrowth of new blood vessels. Our laboratory is currently investigating whether the primary angiogenic factors driving tumor angiogenesis for soft tissue sarcomas vary according to the site in which the tumor or metastasis is growing. Soft tissue sarcomas represent a model cancer to study angiogenesis in different organ environments as well as the possible variable effects of antiangiogenic therapies. These tumors arise from tissues usually of mesenchymal origin throughout the body and metastasize most frequently to the lung and liver. Corresponding mouse models of soft tissue sarcoma growth in primary and metastatic locations have been well characterized. After collecting some interesting preliminary data, our laboratory has received a National Cancer Institute K12 grant to investigate tumor angiogenesis in different organ environments with three specific aims:
Using novel antiangiogenic and anti-tumor agents to improve the efficacy of radiation therapy for soft tissue sarcomas Radiation therapy is an essential treatment component for the local control of many primary tumors including breast cancer, rectal cancer, head/neck cancer, and soft tissue sarcoma. Local recurrence for primary soft tissue sarcomas after surgery alone can be as high as 33% for extremity tumors and 37-82% for retroperitoneal tumors. The addition of radiation therapy has been prospectively demonstrated to decrease the risk of local recurrence. Sarcomas often have areas of low oxygen, or hypoxia, and significantly higher doses of radiation are required to kill cancer cells in low oxygen environments. Vascular endothelial growth factor (VEGF) is over-expressed by the vast majority of human cancers including soft tissue sarcomas, and excess VEGF causes tumors to have highly irregular, porous tumor blood vessels with areas of hypoxia. Inhibition of VEGF leads to "normalization" of tumor blood vessels and improvement in tumor oxygenation. Numerous pre-clinical studies have demonstrated improvement in the tumoricidal effect of radiation therapy when radiation therapy is combined with anti-VEGF agents, but there is limited data in humans. Bevacizumab (Avastin®) is a humanized anti-VEGF monoclonal antibody that binds VEGF and potently inhibits its activity. Bevacizumab has been used in over 30 Phase I, II, and III trials, but no published clinical trial has yet examined the use of bevacizumab combined with radiation therapy (and in the absence of chemotherapy) in the adjuvant setting.
We are currently examining the hypothesis that the anti-angiogenic effects of bevacizumab can increase the efficacy of radiation therapy in patients with soft tissue sarcomas through a clinical trial with correlative science studies. The bevacizumab/radiation protocol is already IRB approved and supported by an NCI R21 QuickTrials grant. Serial blood samples, tumor biopsies, and perfusion CT scans will be used to assess the effects of bevacizumab on tumor gene expression, angiogenic factor secretion, blood flow and oxygenation.
Sarcomas & Soft Tissue Tumors - Surgical Oncology Research
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13 Rosenthal DI, Marota JJ, Hornicek FJ Osteoid osteoma: elevation of cardiac and respiratory rates at biopsy needle entry into tumor in 10 patients. Radiology. 01/03/2003; 226(1); 125-8.
14 Morioka H, Morii T, Vogel T, Hornicek FJ, Weissbach L Interaction of plasminogen-related protein B with endothelial and smooth muscle cells in vitro. Exp Cell Res. 06/11/2003; 287(1); 166-77.
15 DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, Hornicek FJ, Mankin HJ, Rosenberg AL, Rosenthal DI, Miryousefi F, Ancukiewicz M, Harmon DC Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys. 06/27/2003; 56(4); 1117-27.
16 Rosenthal DI, Hornicek FJ, Torriani M, Gebhardt MC, Mankin HJ Osteoid osteoma: percutaneous treatment with radiofrequency energy. Radiology. 10/01/2003; 229(1); 171-5.
17 Kepka L, Suit HD, Goldberg SI, Rosenberg AE, Gebhardt MC, Hornicek FJ, Delaney TF Results of radiation therapy performed after unplanned surgery (without re-excision) for soft tissue sarcomas. J Surg Oncol. 09/28/2005; 92(1); 39-45.
18 Park L, Delaney TF, Liebsch NJ, Hornicek FJ, Goldberg S, Mankin H, Rosenberg AE, Rosenthal DI, Suit HD Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor. Int J Radiat Oncol Biol Phys. 07/25/2006; 65(5); 1514-21.
19 Delaney TF, Kepka L, Goldberg SI, Hornicek FJ, Gebhardt MC, Yoon SS, Springfield DS, Raskin KA, Harmon DC, Kirsch DG, Mankin HJ, Rosenberg AE, Nielsen GP, Suit HD Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys. 03/30/2007; 67(5); 1460-9.
20 Delaney TF, Kepka L, Goldberg SI, Hornicek FJ, Gebhardt MC, Yoon SS, Springfield DS, Raskin KA, Harmon DC, Kirsch DG, Mankin HJ, Rosenberg AE, Nielsen GP, Suit HD Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys. 03/30/2007; 67(5); 1460-9.
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