Exploring Sarcoma Metastatic Potential

描述(由申请人提供)：Kurt R.Weiss，医学博士，匹兹堡大学整形外科肌肉骨骼肿瘤科的肌肉骨骼肿瘤学家。韦斯博士曾在北美一些最负盛名的临床中心接受过培训，包括多伦多匹兹堡大学。除了这些临床成就，韦斯博士还接触到了大量的基础科学研究。他自1994年以来一直从事分子和细胞生物学研究，自1999年以来一直从事肿瘤学研究。他曾与MD Anderson癌症中心和国家癌症研究所以及多伦多大学和匹兹堡大学的肉瘤研究专家合作。Weiss博士对推进转译肉瘤研究领域的热情必然是他作为转移性骨肉瘤(OS)幸存者的个人历史的产物。他的癌症之旅包括参与复发性OS转移的II期临床试验；这段经历塑造了他的目标，并教会了他，翻译肉瘤研究既可能也是必要的。韦斯医生还经历了肉瘤手术的困难，最终他的右腿被截肢。这种永久性的残疾并没有削弱他寻找新的治疗方法来解决肉瘤肺转移这一尚未解决的问题的愿望。他的短期目标是培养翻译科学家的技能，使他能够在匹兹堡大学建立一个充满活力的、全面的肉瘤研究项目。他的长期目标是将桌上的发现转化为转移性肉瘤患者的临床解决方案。尽管韦斯博士有着独特的个人、临床和科学背景，但他明白自己的知识和技能远远不完整。为了追求开发独立的翻译肉瘤研究计划的目标，他提出了以下建议：Aim I-专业发展：Weiss博士认识到他需要进一步发展的领域，才能成为一名全面的翻译肿瘤学家。如果获得K08奖项，韦斯博士将继续学习生物统计学、蛋白质组学和信号转导方面的教学课程。他将参加有关编写赠款的课程和研讨会，并将经常提交赠款提案。他将在国内和国际会议上交流他的科学发现。定期安排与他的导师、共同导师和合作者的会议将加强跨多个临床和科学学科的专业关系。AIM II-实验室发展：Weiss博士将对他关于OS转移疾病的初步发现进行扩展，并利用这项研究作为了解其他肉瘤转移潜力的途径。OS是最常见的骨原发恶性肿瘤。尽管进行了积极的化疗和手术治疗，但总体存活率只有60%-70%。被诊断为OS转移或在治疗过程中发生转移的患者预后特别差，存活率为15%-30%。这些统计数据在超过一代人的时间里没有改善。对于特殊的OS患者和一般的肉瘤患者，转移疾病的问题仍然没有解决。由于目前的治疗模式已经宣布对转移患者不成功，肉瘤治疗的进展需要对控制肿瘤生长和转移的机制有更深入的了解。需要新的、生物智能的治疗策略来改善OS和其他肉瘤患者的预后。Weiss博士发表文章指出，具有不同转移潜能的OS细胞群体表达和产生不同水平的生长因子，这些生长因子的抑制会影响OS细胞的转移行为。他最近发现干细胞相关因子，特别是乙醛脱氢酶(ALDH)和Notch1，在不同转移表型的OS细胞中有不同的表达。这些因素的抑制也影响OS细胞的体外转移表型。因此，Weiss博士建议在体外和体内用OS转移性小鼠模型来询问临床上相关的ALDH和Notch1抑制剂。这些实验将评估ALDH和Notch1抑制作为OS特异性抗转移治疗的可行性。在过去的一年里，韦斯博士和他的临床合作伙伴建立了肌肉骨骼肿瘤学肿瘤注册和组织库(MOTOR)。这是IRB批准的一种机制，通过它可以不断收集患者的临床数据，并将其与肿瘤细胞的生物活性相关联。Weiss博士已经从不同肉瘤组织亚型的患者中开发了大约15个新的细胞系。这一不断扩大的收集是一个无价的科学资源，它将使韦斯博士能够揭示肉瘤转移的基本生物学中的共同主题，并使他能够测试新的、有针对性的抗转移治疗方法。匹兹堡大学、匹兹堡大学医学中心、临床与转化科学研究所和匹兹堡大学癌症研究所提供的环境非常有利于这些拟议的项目。作为其职业发展的一部分，Weiss博士将继续在这些机构中培养关系和合作，以建立一个充满活力和富有成效的肉瘤转化研究项目。

DESCRIPTION (provided by applicant): Kurt R. Weiss, MD is a musculoskeletal oncologist in the University of Pittsburgh Department of Orthopaedic Surgery, Division of Musculoskeletal Oncology. Dr. Weiss has trained at some of the most prestigious clinical centers in North America including the Universities of Pittsburgh Toronto. Besides these clinical accomplishments, Dr. Weiss is also the recipient of a rich exposure to basic science research. He has been involved in molecular and cell biology research since 1994, and oncology research since 1999. He has worked with sarcoma research experts at the MD Anderson Cancer Center and the National Cancer Institute as well as the Universities of Toronto and Pittsburgh. Dr. Weiss's passion to advance the field of translational sarcoma research is necessarily the product of his personal history as a survivor of metastatic osteosarcoma (OS). His journey with cancer included participation in a Phase II clinical trial for recurrent OS metastases; an experience that shaped his goals and taught him that translational sarcoma research is both possible and essential. Dr. Weiss has also experienced the difficulties of sarcoma surgery which culminated in the amputation of his right leg. This permanent disability has not lessened his desire to discover novel treatments that address the unmet problem of sarcoma pulmonary metastases. His short-term goal is to develop skills as a translational scientist that will enable him to build a vigorous, comprehensive sarcoma research program at the University of Pittsburgh. His long-term goal is to translate bench top discoveries into clinical solutions for patients with metastatic sarcoma. Despite his unique personal, clinical, and scientific background, Dr. Weiss understands that his knowledge and skills are far from complete. In pursuit of his goal to develop an independent translational sarcoma research program, he proposes the following: AIM I- PROFESSIONAL DEVELOPMENT: Dr. Weiss recognizes the areas in which he requires additional development in order to become a well-rounded translational oncologist. If granted a K08 award, Dr. Weiss will pursue didactic courses in biostatistics, proteomics, and signal transduction. He will attend courses and workshops on grant-writing and will submit frequent grant proposals. He will communicate his scientific findings at national and international meetings. Regularly scheduled meetings with his mentor, co-mentors, and collaborators will enhance professional relationships across multiple clinical and scientific disciplines. AIM II- LABORATORY DEVELOPMENT: Dr. Weiss will expand upon his preliminary findings on OS metastatic disease, and use this research as a pathway toward understanding metastatic potential in other sarcomas. OS is the most common primary malignancy of bone. Despite aggressive chemotherapeutic and surgical treatments, overall survival is only 60-70%. Patients who are diagnosed with metastatic OS or develop metastases during the course of their treatment have particularly poor prognoses with survival rates of 15-30%. These statistics have not improved in over a generation. For patients with OS specifically and sarcoma in general, the problem of metastatic disease remains unsolved. As current treatment paradigms have declared themselves unsuccessful for patients with metastases, advancement in sarcoma treatment demands a refined understanding of the mechanisms that govern tumor growth and metastasis. Novel, biologically intelligent treatment strategies are required to improve the prognoses of patients with OS and other sarcomas. Dr. Weiss has published that that OS cell populations with differing metastatic potentials express and produce different levels of growth factors, and the inhibition of these growth factors affects OS cell metastatic behavior. He has recently discovered that stem cell-associated factors, specifically aldehyde dehydrogenase (ALDH) and Notch1, are differentially expressed in OS cells with different metastatic phenotypes. The inhibition of these factors also affects the in vitro metastatic phenotypes of OS cells. Dr. Weiss therefore proposes to interrogate clinically relevant ALDH and Notch1 inhibitors both in vitro and in vivo with the murine model of metastatic OS. These experiments will assess the feasibility of ALDH and Notch1 inhibition as specific anti- metastatic therapies for OS. In the past year, Dr. Weiss and his clinical partners have instituted the Musculoskeletal Oncology Tumor Registry and Tissue Bank (MOTOR). This is an IRB-approved mechanism by which patients' clinical data are constantly gathered and correlated with the biological activity of their tumor cells. Dr. Weiss has already developed approximately fifteen novel cell lines from patients with various sarcoma histologic subtypes. This ever-expanding collection is an invaluable scientific resource that will allow Dr. Weiss to uncover common themes in the basic biology of sarcoma metastases, and enable him to test novel, targeted anti-metastatic treatments. The environment provided by the University of Pittsburgh, the University of Pittsburgh Medical Center, the Clinical and Translational Science Institute, and the University of Pittsburgh Cancer Institute could hardly be more conducive to these proposed projects. As part of his career development, Dr. Weiss will continue to cultivate relationships and collaborations within these institutions in order to build a vigorous and productive sarcoma translational research program.