Exploring Sarcoma Metastatic Potential

探索肉瘤的转移潜力

• 批准号: 8738624
• 负责人: Kurt Richard Weiss
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738624
• 关键词: Address; Adult; Affect; Amputation; Animal Model; Applications Grants; Area; Award; Basic Science; Behavior; Biological; Biological Response Modifier Therapy; Biology; Biometry; Cancer Center; Cell Line; Cells; Cellular biology; Childhood; Clinical; Clinical Data; Clinical Sciences; Collaborations; Collection; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Discipline; Disease; Disulfiram; Doxorubicin; Drug resistance; Educational process of instructing; Educational workshop; Environment; Exposure to; Failure; Flow Cytometry; Gene Expression; Generations; Goals; Grant; Growth; Growth Factor; Growth Factor Inhibition; Health; Histologic; Human; Hydrogen Peroxide; In Vitro; Institutes; Institution; Institutional Review Boards; International; Invaded; Knowledge; Laboratories; Leg; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Medical center; Mentors; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Molecular; Molecular Biology; Morphogenesis; Mus; Musculoskeletal; National Cancer Institute; Neoplasm Metastasis; North America; Oncologist; Operative Surgical Procedures; Orthopedic Surgery procedures; Oxidative Stress; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Population; Proliferating; Proteomics; Publishing; Recording of previous events; Recurrence; Research; Resistance; Resources; SECTM1 gene; Schedule; Scientist; Shapes; Signal Transduction; Solutions; Sorting - Cell Movement; Stem Cell Factor; Stem cells; Stress; Survival Rate; Survivors; Testing; Therapeutic; Tissue Banking; Tissue Banks; Training; Translating; Translational Research; Tumor Tissue; Tumorigenicity; Universities; University of Pittsburgh Cancer Institute; Work; Writing; aldehyde dehydrogenases; angiogenesis; bone; cancer stem cell; career development; cell behavior; chemotherapeutic agent; chemotherapy; clinical efficacy; clinically relevant; cytokine; disability; effective therapy; experience; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; meetings; migration; mortality; mouse model; neoplastic cell; novel; novel strategies; oncology; osteosarcoma; outcome forecast; programs; research study; sarcoma; skills; statistics; tool; treatment strategy; trend; tumor growth; tumor progression; tumor registry

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.

描述（由申请人提供）：Kurt R.医学博士韦斯是匹兹堡大学骨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培训，包括匹兹堡大学多伦多。除了这些临床成就，韦斯博士也是基础科学研究的丰富接触的接受者。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安德森癌症中心和国家癌症研究所以及多伦多和匹兹堡大学的肉瘤研究专家合作。 韦斯博士对推进转化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;这一经历塑造了他的目标，并教会他转化肉瘤研究是可能的，也是必要的。韦斯博士也经历了肉瘤手术的困难，最终导致他的右腿截肢。这种永久性的残疾并没有减少他发现新的治疗方法，解决肉瘤肺转移未解决的问题的愿望。他的短期目标是发展作为一个转化科学家的技能，这将使他能够在匹兹堡大学建立一个充满活力的，全面的肉瘤研究计划。他的长期目标是将实验室发现转化为转移性肉瘤患者的临床解决方案。 尽管他有着独特的个人、临床和科学背景，但韦斯博士明白，他的知识和技能还远远不够。在追求他的目标，发展一个独立的转化肉瘤研究计划，他提出了以下建议：目的I-专业发展：韦斯博士认识到，他需要额外的发展，以成为一个全面的转化肿瘤学家的领域。如果获得K 08奖，韦斯博士将继续生物统计学，蛋白质组学和信号转导的教学课程。他将参加有关赠款写作的课程和讲习班，并将经常提交赠款提案。他将在国家和国际会议上传达他的科学发现。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。 目标II-实验室开发：韦斯博士将扩展他对OS转移性疾病的初步发现，并将该研究作为了解其他肉瘤转移潜力的途径。骨肉瘤是最常见的原发性骨恶性肿瘤。尽管有积极的化疗和手术治疗，总生存率仅为60- 70%。诊断为转移性OS或在治疗过程中发生转移的患者的生存率特别差，生存率为15- 30%。这些统计数据在一代人的时间里没有改善。对于OS患者和一般肉瘤患者，转移性疾病的问题仍未解决。由于目前的治疗模式已经宣布自己不成功的转移患者，肉瘤治疗的进步需要一个精细的了解，管理肿瘤生长和转移的机制。需要新的生物智能治疗策略来改善OS和其他肉瘤患者的预后。 韦斯博士发表了具有不同转移潜能的OS细胞群表达并产生不同水平的生长因子，并且这些生长因子的抑制影响OS细胞转移行为。他最近发现，干细胞相关因子，特别是醛脱氢酶（ALDH）和Notch 1，在具有不同转移表型的OS细胞中差异表达。这些因子的抑制也影响OS细胞的体外转移表型。因此，韦斯博士建议在转移性OS小鼠模型的体外和体内研究临床相关的ALDH和Notch 1抑制剂。这些实验将评估ALDH和Notch 1抑制剂作为OS特异性抗转移治疗的可行性。在过去的一年中，韦斯博士和他的临床合作伙伴建立了肌肉骨骼肿瘤登记和组织库（MOTOR）。这是IRB批准的机制，通过该机制，患者的临床数据不断收集并与其肿瘤细胞的生物活性相关。韦斯博士已经从各种肉瘤组织学亚型的患者中开发了大约15种新的细胞系。这个不断扩大的收集是一个宝贵的科学资源，将使韦斯博士发现在肉瘤转移的基础生物学的共同主题，并使他能够测试新的，有针对性的抗转移治疗。 匹兹堡大学、匹兹堡大学医学中心、临床和转化科学研究所以及匹兹堡大学癌症研究所提供的环境对这些拟议的项目非常有利。作为他职业发展的一部分，韦斯博士将继续在这些机构内培养关系和合作，以建立一个充满活力和富有成效的肉瘤转化研究计划。