Lipid Metabolism and KSHV-associated Lymphoma Pathogenesis

脂质代谢和 KSHV 相关淋巴瘤发病机制

• 批准号: 8053727
• 负责人: Christopher H Parsons
• 金额: $ 30万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053727
• 关键词: Address; Animal Model; Apoptosis; Appearance; Attenuated; B lymphoid malignancy; B-Lymphocytes; Cancer cell line; Cell Death; Cell Survival; Cells; Ceramides; Clinic; Clinical Trials; Data; Development; Dose; Drug Combinations; Event; Failure; Future; Gene Activation; Gene Expression; Generations; Greater sac of peritoneum; Growth; HIV; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune; Immune system; In Vitro; Knowledge; Link; Lymphoma; Lytic; MAPK8 gene; Malignant Neoplasms; Mediating; Metabolism; Methods; Mus; NF-kappa B; Oncogenic; Pathogenesis; Pathway interactions; Patients; Performance; Physiological Processes; Pilot Projects; Play; Pleural cavity; Preclinical Testing; Process; Protein Isoforms; Publishing; Role; Safety; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sphingolipids; Switch Genes; Testing; Therapeutic Agents; Toxic effect; Viral; Viral Oncogene; Virus; base; cancer cell; cell growth; chemotherapy; effective therapy; effusion; gammaherpesvirus; in vivo; inhibitor/antagonist; insight; kinase inhibitor; lipid metabolism; lytic replication; mortality; neoplastic cell; novel; novel therapeutics; outcome forecast; public health relevance; research study; sphingosine 1-phosphate; sphingosine kinase; standard of care; tumor; tumor progression

DESCRIPTION (provided by applicant): The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of cancers arising preferentially within immune compromised hosts, including patients infected with HIV. One of these cancers, a clonal B-cell malignancy known as primary effusion lymphoma (PEL), is associated with significant mortality, and there are currently no effective therapies for reducing the progression of PEL or prolonging survival. Pathogenesis of PEL involves KSHV gene expression and activation of specific signal transduction pathways which induce proliferation and prolong survival of tumor cells. Therefore, the development of novel compounds targeting these pathways specifically activated by KSHV may result in more effective and safe treatment options for PEL. Bioactive sphingolipids play an important role in many physiologic processes, but aberrant sphingolipid metabolism related to the action of sphingosine kinase (SK) and the generation of sphingosine-1-phosphate (S1P) also contribute to cancer progression. We have generated an active compound, ABC294640, that specifically targets multiple SK isoforms and effectively impairs S1P- mediated signal transduction while inducing tumor cell death in vitro and in vivo. With the knowledge that ABC294640 inhibits signal transduction relevant to PEL pathogenesis, we performed preliminary studies to determine whether ABC294640 inhibits PEL cell growth. Our in vitro studies revealed that ABC294640 selectively inhibits KSHV-infected lymphoma cell growth but not the growth of KSHV-negative lymphoma cells. These data compliment our additional data wherein ABC294640 induces apoptosis in KSHV-infected primary cells but not uninfected cells. Moreover, ABC294640 induced a dose-dependent increase in ceramides-lipid moieties known to induce apoptosis in other cancer cell lines. ABC294640 also upregulated proapoptotic JNK activation while reducing constitutive NF-kB activation in PEL cells, two events previously implicated in the initiation of cancer cell apoptosis. Finally, ABC294640 induced lytic KSHV gene expression in PEL cells-a process known to cause cell death. Therefore, we hypothesize that ABC294640 induces apoptosis and cell death preferentially in PEL cells through the accumulation of ceramides and/or the induction of lytic KSHV gene expression and downstream proapoptotic signaling, and that ABC294640 reduces progression of PEL in vivo. To evaluate the feasibility of reducing PEL formation in vivo with the systemic administration of ABC294640 and to better understand how ABC294640 selectively targets KSHV-infected cells, we propose three aims: 1) to synthesize sufficient amounts of ABC294640 for in vivo studies; 2) to evaluate the ability of ABC294640 to inhibit PEL formation in immune deficient mice; and 3) to determine mechanisms for ABC294640 reduction of KSHV-infected cell growth and survival. Through the completion of these studies, we hope to move toward the performance of clinical trials to evaluate the efficacy and safety of ABC294640 administration in HIV-infected patients with PEL. Our additional mechanistic studies should also provide inroads for future studies to address the role of ABC294640 in selectively targeting virus-infected cells. PUBLIC HEALTH RELEVANCE: Tumors etiologically linked to the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), including primary effusion lymphoma (PEL), are among those HIV-associated illnesses which portend a poor prognosis for HIV-infected patients. Current PEL therapies are not efficacious and incur significant toxicity. Therefore, preclinical testing of promising compounds in animal models which inhibit PEL cell growth and which selectively target KSHV-infected cells would provide a basis for testing these compounds in future clinic trials for PEL.

描述（由申请人提供）： 卡波西肉瘤相关疱疹病毒 (KSHV) 是癌症的病原体，优先在免疫受损的宿主（包括感染 HIV 的患者）中产生。其中一种癌症是一种克隆性 B 细胞恶性肿瘤，称为原发性渗出性淋巴瘤 (PEL)，与显着的死亡率相关，目前尚无有效的治疗方法可以减少 PEL 的进展或延长生存期。 PEL 的发病机制涉及 KSHV 基因表达和特定信号转导途径的激活，从而诱导肿瘤细胞增殖并延长生存期。因此，开发针对 KSHV 特异性激活的这些途径的新型化合物可能会为 PEL 提供更有效、更安全的治疗选择。生物活性鞘脂在许多生理过程中发挥着重要作用，但与鞘氨醇激酶 (SK) 的作用和 1-磷酸鞘氨醇 (S1P) 的生成相关的异常鞘脂代谢也有助于癌症进展。我们已经生成了一种活性化合物 ABC294640，它特异性靶向多种 SK 同工型并有效损害 S1P 介导的信号转导，同时在体外和体内诱导肿瘤细胞死亡。了解 ABC294640 抑制与 PEL 发病机制相关的信号转导后，我们进行了初步研究以确定 ABC294640 是否抑制 PEL 细胞生长。我们的体外研究表明，ABC294640 选择性抑制 KSHV 感染的淋巴瘤细胞的生长，但不抑制 KSHV 阴性淋巴瘤细胞的生长。这些数据补充了我们的额外数据，其中 ABC294640 诱导 KSHV 感染的原代细胞凋亡，但不诱导未感染的细胞凋亡。此外，ABC294640 诱导神经酰胺-脂质部分呈剂量依赖性增加，已知这些神经酰胺-脂质部分可诱导其他癌细胞系凋亡。 ABC294640 还上调促凋亡 JNK 激活，同时减少 PEL 细胞中的组成型 NF-kB 激活，这两个事件先前与癌细胞凋亡的启动有关。最后，ABC294640 在 PEL 细胞中诱导裂解性 KSHV 基因表达——这一过程已知会导致细胞死亡。因此，我们假设 ABC294640 通过神经酰胺的积累和/或诱导裂解性 KSHV 基因表达和下游促凋亡信号传导优先诱导 PEL 细胞凋亡和细胞死亡，并且 ABC294640 减少体内 PEL 的进展。为了评估全身施用 ABC294640 减少体内 PEL 形成的可行性，并更好地了解 ABC294640 如何选择性地靶向 KSHV 感染的细胞，我们提出三个目标：1）合成足够量的 ABC294640 用于体内研究； 2)评价ABC294640抑制免疫缺陷小鼠中PEL形成的能力； 3) 确定 ABC294640 减少 KSHV 感染细胞生长和存活的机制。通过完成这些研究，我们希望能够开展临床试验，以评估 ABC294640 在 HIV 感染 PEL 患者中给药的有效性和安全性。我们额外的机制研究也应该为未来的研究提供线索，以解决 ABC294640 在选择性靶向病毒感染细胞中的作用。 公共卫生相关性：与卡波西肉瘤相关疱疹病毒 (KSHV/HHV8) 病原学相关的肿瘤，包括原发性渗出性淋巴瘤 (PEL)，属于 HIV 相关疾病，预示着 HIV 感染者预后不良。目前的 PEL 疗法并不有效并且会产生显着的毒性。因此，在动物模型中对抑制 PEL 细胞生长并选择性靶向 KSHV 感染细胞的有希望的化合物进行临床前测试，将为在未来的 PEL 临床试验中测试这些化合物提供基础。