Targeting AML Mitochondria by Ceramide
通过神经酰胺靶向 AML 线粒体
基本信息
- 批准号:10546239
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAffectAntineoplastic AgentsApoptosisBCL2 geneBone Marrow CellsCell DeathCell Membrane PermeabilityCeramidesChargeClinicalComplexDataDefectDevelopmentDrug KineticsDrug TargetingDrug resistanceElectronsEventExhibitsExposure toFLT3 geneFatty AcidsFeasibility StudiesFunctional disorderGenerationsGoalsGrowthHumanIn SituIn VitroIsocitrate DehydrogenaseLeadLegal patentLengthLipidsMalignant NeoplasmsMaximum Tolerated DoseMediatingMetabolismMitochondriaModelingMolecularMusNamesNon-MalignantNucleotidesPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacotherapyPhasePublishingReceptor ActivationReceptor Protein-Tyrosine KinasesResistanceSignal TransductionSodium SeleniteSolubilitySphingolipidsStimulusStressSystemTherapeuticTissuesToxic effectTumor SuppressionTumor Suppressor ProteinsTyrosine Kinase InhibitorUnited StatesWarburg EffectXenograft procedureacute myeloid leukemia cellanalogbasecancer celldesigndihydroceramide desaturasedrug-sensitiveimprovedin vivoinhibitorinnovationmacromoleculenovelpharmacokinetics and pharmacodynamicspreclinical studyreconstitutionresponsesurvival outcometargeted treatmenttooltumoruptakewater solubility
项目摘要
SUMMARY
This proposal's long-term objective is to develop a mechanism-based therapeutic drug for the treatment of
human acute myeloid leukemias (AML), which are among the deadliest cancers in the United States. Despite
some advances in treatment, survival for AML has not improved significantly in decades, with rare exceptions
for specific subclasses. While targeted therapies with FLT3, IDH, and Bcl-2 inhibitors have increased response
rates significantly, survival has been extended only by several months. Thus, novel and innovative therapeutic
drugs are needed to improve the survival outcomes of AML patients. The sphingolipid ceramide, an emerging
tumor suppressor lipid, mediates anti-proliferative signaling events in response to various stress stimuli,
including tyrosine kinase inhibitors (TKIs). Our published and unpublished data suggest that decreased levels
of C18-ceramide might be critical in the pathophysiology, progression and drug-resistance of AML. These data
also revealed that reconstitution of C18-ceramide by molecular and pharmacologic tools results in the
suppression of AML growth, and help overcome drug resistance. Because of pharmacologic challenges of the
conventional exogenous short-chain ceramides, we have developed novel mitochondrial targeted pyridinium-
C18-ceramide (Pyr-Cer) analogs that induce cancer cell mitophagy and tumor suppression. These Pyr-Cer
analogs exhibit increased water solubility, cell-membrane permeability, and cancer cell-selective mitochondrial
uptake, compared to uncharged conventional ceramides. Pyr-Cer analog drugs, such as LCL461 (patented
Class I) or LCL768 (Class II), contain a positive charge at a delocalized pi-electron system. This then results in
preferential localization of the drug into highly negatively charged mitochondria in cancer cells/tissues due to
the Warburg effect. The accumulation of Pyr-Cer in mitochondria results in cancer cell death via induction of
mitophagy by reducing cellular energy generation and decreasing the synthesis of other vital macromolecules,
such as nucleotides. This effect of Pyr-Cer on mitophagy induction is further increased when cancer cells are
exposed to general ROS/RNS inducer sodium selenite that causes Drp1 activation and mitochondrial fission.
Thus, we have generated a new (Class II) Pyr-Cer analog drugs conjugated with sodium selenite, named as
SoSe-C18-Pyr-Cer (LCL768), which selectively induced mitophagy-dependent cell death in AML in situ and in
vivo. Based on these data, our goal is to develop LCL768 as an anti-cancer drug for the treatment of AML. In
these feasibility studies, we will: 1) Validate the mechanism by which Pyr-Cer drugs target AML mitochondria
by mitophagy in vitro; and 2) Determine bioactivity, toxicity, pharmacokinetics and anti-AML activity of LCL768
in vivo. We will determine the possible off-target effects, maximum tolerated dose (MTD),
pharmacokinetic/pharmacodynamic profiles and anti-AML effects of LCL768 in various models. These include
drug sensitive versus resistant AML xenografts, AML PDXs, and primary AML blasts. This Phase I feasibility
study will help the commercial development of LCL768 for a Phase II application.
概括
该提案的长期目标是开发一种基于机制的治疗药物来治疗
人类急性髓系白血病 (AML),这是美国最致命的癌症之一。尽管
尽管治疗方面取得了一些进展,但几十年来,除极少数例外情况外,AML 的生存率并未显着改善
对于特定的子类。虽然 FLT3、IDH 和 Bcl-2 抑制剂的靶向治疗增加了反应
率显着提高,生存期仅延长了几个月。因此,新颖且创新的治疗
需要药物来改善 AML 患者的生存结果。鞘脂神经酰胺是一种新兴的
肿瘤抑制脂质,介导抗增殖信号事件以响应各种应激刺激,
包括酪氨酸激酶抑制剂(TKI)。我们已发表和未发表的数据表明,水平下降
C18-神经酰胺可能在 AML 的病理生理学、进展和耐药性中至关重要。这些数据
还揭示了通过分子和药理学工具重建 C18-神经酰胺会导致
抑制 AML 生长,并帮助克服耐药性。由于药理挑战
与传统的外源性短链神经酰胺相比,我们开发了新型线粒体靶向吡啶鎓-
C18-神经酰胺 (Pyr-Cer) 类似物可诱导癌细胞线粒体自噬和肿瘤抑制。这些Pyr-Cer
类似物表现出增加的水溶性、细胞膜通透性和癌细胞选择性线粒体
与不带电的传统神经酰胺相比,吸收率更高。 Pyr-Cer 类似物药物,例如 LCL461(专利
I 类)或 LCL768(II 类)在离域 pi 电子系统中包含正电荷。这会导致
由于以下原因,药物优先定位到癌细胞/组织中带高负电荷的线粒体中
瓦尔堡效应。 Pyr-Cer 在线粒体中的积累通过诱导导致癌细胞死亡
通过减少细胞能量产生和减少其他重要大分子的合成来进行线粒体自噬,
例如核苷酸。当癌细胞被破坏时,Pyr-Cer 对线粒体自噬诱导的作用会进一步增强。
暴露于一般 ROS/RNS 诱导剂亚硒酸钠,导致 Drp1 激活和线粒体裂变。
因此,我们生成了一种新的(II类)Pyr-Cer类似物与亚硒酸钠缀合的药物,命名为
SoSe-C18-Pyr-Cer (LCL768),可原位和在 AML 中选择性诱导线粒体自噬依赖性细胞死亡
体内。基于这些数据,我们的目标是开发LCL768作为治疗AML的抗癌药物。在
在这些可行性研究中,我们将: 1) 验证 Pyr-Cer 药物靶向 AML 线粒体的机制
通过体外线粒体自噬; 2) 测定LCL768的生物活性、毒性、药代动力学和抗AML活性
体内。我们将确定可能的脱靶效应、最大耐受剂量(MTD)、
LCL768 在各种模型中的药代动力学/药效学特征和抗 AML 作用。这些包括
药物敏感与耐药的 AML 异种移植物、AML PDX 和原发性 AML 母细胞。本期一期可行性
研究将有助于 LCL768 的 II 期应用的商业开发。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Besim Ogretmen其他文献
Besim Ogretmen的其他文献
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{{ truncateString('Besim Ogretmen', 18)}}的其他基金
Sphingolipid Metabolism and Signaling in the Regulation of Senescence and Aging
鞘脂代谢和信号传导在衰老和衰老调节中的作用
- 批准号:
10253130 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Ceramide Signaling in the Regulation of Head & Neck Cancer Cell Death and Therapy
头部调节中的神经酰胺信号传导
- 批准号:
9930853 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis
神经酰胺代谢和调节 TGF-β 受体信号传导以控制转移
- 批准号:
10411382 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of PD-L1 signaling to control metastasis and resistance to immunotherapy in TNBC
神经酰胺代谢和 PD-L1 信号调节以控制 TNBC 的转移和免疫治疗耐药
- 批准号:
10801345 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis
神经酰胺代谢和调节 TGF-β 受体信号传导以控制转移
- 批准号:
9977980 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis
神经酰胺代谢和调节 TGF-β 受体信号传导以控制转移
- 批准号:
10222592 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis
神经酰胺代谢和调节 TGF-β 受体信号传导以控制转移
- 批准号:
10460230 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis
神经酰胺代谢和调节 TGF-β 受体信号传导以控制转移
- 批准号:
9441547 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
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项目2:系统性S1P和补体信号调节肿瘤转移
- 批准号:
9072014 - 财政年份:2016
- 资助金额:
$ 40万 - 项目类别:
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