Targeting EWS/FLI1-driven pathways to improve therapeutic gains in Ewing's Sarcom

靶向 EWS/FLI1 驱动的途径以提高尤因肉瘤的治疗效果

基本信息

批准号：
8254320
负责人：
VICENTE NOTARIO
金额：
$ 30.9万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254320
关键词：
Adolescent Affect Aftercare Antineoplastic Agents Askin&apos s tumor Bone Tissue Bone neoplasms Cell Line Cells Child Chromosomes, Human, Pair 11 Complex Data Disease Disease Progression Dose Down-Regulation E-Cadherin Equilibrium Ewings sarcoma FLI1 gene FUS-1 Protein Family Genes Health High Dose Chemotherapy Human Chromosomes In Vitro Individual Ionizing radiation Laboratories Late Effects Localized Disease Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mediating Modality Modeling Molecular Mus Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Phospholipase D Phosphotransferases Play Poly(ADP-ribose) Polymerases Primary Neoplasm Primitive Neuroectodermal Tumor Production Property Protein Kinase Protein Kinase C Alpha Proteins Protocols documentation Radiation Radiation therapy Radiosensitization Relapse Reporting Resistance Role Signal Pathway Signal Transduction Signaling Protein Snails Solid Specificity Techniques Therapeutic Tumorigenicity Xenograft procedure bone caveolin 1 chemotherapy cohort design follow-up genetic regulatory protein human FRAP1 protein hybrid gene improved inhibitor/antagonist killings mTOR Inhibitor member neoplastic neoplastic cell novel outcome forecast phospholipase D2 prototype radiation resistance reconstitution research study response soft tissue tool transcription factor treatment strategy tumor tumor growth young adult

项目摘要

DESCRIPTION (provided by applicant): Tumors of the Ewing's sarcoma family (ESFT) are solid, highly malignant neoplasms of the bone and soft tissues that most often affect children and adolescents, being the second most common bone malignancies among young adults. Current treatment includes a combined modality with chemotherapy and radiotherapy. However, there are two important problems to consider: a) although ESFT are generally responsive to treatment, the overall cure rate is low because these tumors are very aggressive and patients frequently present with metastatic disease; and b) exposure of young patients to high doses of chemotherapy and/or radiation is frequently associated with a variety of adverse health effects that in some cases do not develop until many years after treatment completion. Consequently, treatment strategies are needed to maximize curability while simultaneously minimizing adverse late effects for the patients. In preliminary studies, we directly targeted EWS/FLI-1, the transcription factor known to be responsible for the malignant properties of most ESFT, using molecular tools designed to block its activity, either alone or in combination with chemotherapeutic drugs and/or radiation. Although experiments in vitro and in mouse xenografts demonstrated that these tools efficiently delayed tumor growth, it became clear that simultaneous targeting of additional molecules that act downstream of EWS/FLI-1 would be necessary to maximize antitumor activity and to allow the use of lower therapeutic doses, thus minimizing negative late effects as much as possible. In this context, the main objective of this proposal is to exploit a novel EWS/FLI-1-driven pathway recently established in our laboratory (EWS/FLI-1-[Caveolin->1-Snail-E-cadherin]) to sensitize ESFT cells to therapy, using ionizing radiation (IR) as a model anti-neoplastic agent that does not suffer from the specificity- related problems that frequently complicate studies with chemotherapeutic drugs. Since the extent of IR related late effects in normal tissues surrounding the tumor are directly related to the IR dose, in pediatric cancers it is important to employ the lowest dose possible to cure the tumors. Using EWS cells as the ESFT prototype, our central hypothesis is that (a) targeting caveolin-1 (CAV1) itself and/or its interactions with signaling or regulatory proteins relevant for ESFT molecular pathobiology (such as phospholipase D2 and protein kinase C1) will render EWS cells more sensitive to IR, and (b) that this response may be further improved by simultaneously targeting components of other pathways also known to radiosensitize EWS cells, such as poly (ADP-ribose) polymerase (PARP). Because we already identified CAV1 as a direct transcriptional target of EWS/FLI-1 and a key determinant of the tumorigenicity and chemotherapeutic response of EWS cells, targeting CAV1 signaling may have a dual effect: enhancing killing of EWS cells by low-dose IR and down- regulating their neoplastic properties.

描述（由申请人提供）：尤文氏肉瘤家族肿瘤（ESFT）是骨和软组织的高度恶性的实性肿瘤，最常影响儿童和青少年，是年轻人中第二常见的骨恶性肿瘤。目前的治疗包括化疗和放疗的联合治疗。然而，有两个重要问题需要考虑：a）虽然 ESFT 通常对治疗有反应，但总体治愈率较低，因为这些肿瘤非常具有侵袭性，并且患者经常出现转移性疾病； b) 年轻患者接受高剂量化疗和/或放疗通常会带来各种不良健康影响，在某些情况下，这些影响直到治疗完成多年后才会出现。因此，需要采取治疗策略来最大限度地提高治愈率，同时最大限度地减少对患者的后期不良影响。在初步研究中，我们直接针对 EWS/FLI-1（已知导致大多数 ESFT 恶性特性的转录因子），使用旨在阻断其活性的分子工具，无论是单独使用还是与化疗药物和/或放射组合使用。尽管体外和小鼠异种移植实验证明这些工具有效地延迟了肿瘤生长，但很明显，为了最大限度地提高抗肿瘤活性并允许使用较低的治疗剂量，有必要同时靶向作用于 EWS/FLI-1 下游的其他分子。剂量，从而尽可能减少负面的后期影响。在这种情况下，本提案的主要目标是利用我们实验室最近建立的一种新的 EWS/FLI-1 驱动途径 (EWS/FLI-1-[Caveolin->1-Snail-E-cadherin]) 来敏化ESFT 细胞使用电离辐射 (IR) 作为模型抗肿瘤药物进行治疗，该药物不会遇到通常使化疗药物研究复杂化的特异性相关问题。由于肿瘤周围正常组织中与 IR 相关的后期影响的程度与 IR 剂量直接相关，因此在儿科癌症中，采用尽可能低的剂量来治愈肿瘤非常重要。使用 EWS 细胞作为 ESFT 原型，我们的中心假设是，(a) 靶向 Caveolin-1 (CAV1) 本身和/或其与 ESFT 分子病理学相关信号或调节蛋白（例如磷脂酶 D2 和蛋白激酶 C1）的相互作用将使 EWS 细胞对 IR 更加敏感，并且 (b) 通过同时靶向也已知使 EWS 细胞放射增敏的其他途径的成分，例如聚 (ADP-核糖) 聚合酶，可以进一步改善这种反应（PARP）。因为我们已经确定 CAV1 是 EWS/FLI-1 的直接转录靶标，也是 EWS 细胞致瘤性和化疗反应的关键决定因素，因此靶向 CAV1 信号传导可能具有双重作用：通过低剂量 IR 增强对 EWS 细胞的杀伤作用，下调其肿瘤特性。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Caveolin-1 modulates the ability of Ewing's sarcoma to metastasize.

Caveolin-1 调节尤文氏肉瘤的转移能力。

DOI：
发表时间：
2010-11
期刊：
影响因子：
0
作者：
Sáinz;Lagares;Lasheras, Jaime;Navid, Fariba;Rodriguez;Mateo;Notario, Vicente;Sanjuan, Xavier;Garcia Del Muro, Xavier;Fabra, Angels;Tirado, Oscar M
通讯作者：
Tirado, Oscar M

The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential.

PEDF 对癌症生物学的影响：作用机制和治疗潜力。

DOI：
发表时间：
2013-04
期刊：
影响因子：
0
作者：
Becerra, S Patricia;Notario, Vicente
通讯作者：
Notario, Vicente

Caveolin-1 promotes resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells by modulating PKCalpha phosphorylation.

Caveolin-1 通过调节 PKCα 磷酸化促进尤文肉瘤细胞对化疗诱导的细胞凋亡的抵抗。

DOI：
发表时间：
2010-01-15
期刊：
影响因子：
6.4
作者：
Tirado, Oscar M.;MacCarthy, Caitlin M.;Fatima, Naheed;Villar, Joaquin;Mateo-Lozano, Silvia;Notario, Vicente
通讯作者：
Notario, Vicente

Identification of pigment epithelium-derived factor protein forms with distinct activities on tumor cell lines.

鉴定对肿瘤细胞系具有不同活性的色素上皮衍生因子蛋白形式。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Subramanian, P;Deshpande, M;Locatelli;Moghaddam;Gutierrez, D;Fitzgerald, D P;Guerrier, S;Rapp, M;Notario, V;Becerra, S P
通讯作者：
Becerra, S P

Auto-stimulatory action of secreted caveolin-1 on the proliferation of Ewing's sarcoma cells.

分泌的caveolin-1对尤文氏肉瘤细胞增殖的自刺激作用。