Delineation of the Role of CAMKK2 in Bone-metastatic Prostate Cancer and its Therapeutic Implications
CAMKK2 在骨转移性前列腺癌中的作用及其治疗意义的描述
基本信息
- 批准号:10593983
- 负责人:
- 金额:$ 8.03万
- 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:2022-04-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAutopsyBone DiseasesBone neoplasmsBone remodelingCa(2+)-Calmodulin Dependent Protein KinaseCancer EtiologyCastrationCellsCessation of lifeClinical TrialsDataDeteriorationDevelopmentDiseaseDisease ProgressionFutureGenetic EngineeringGoalsHormonesHumanImpairmentIndividualKnowledgeLaboratoriesLinkMagnetic Resonance ImagingMalignant Bone NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMediatingMetastatic Neoplasm to the BoneMetastatic Prostate CancerModelingMonitorNeoplasm MetastasisOncogenicOsteoblastsOutcomePatientsPhosphotransferasesPlayProstate Cancer therapyProtein KinaseProtein-Serine-Threonine KinasesRefractoryResistanceRoleSafetySeriesSerineSiteTestingTherapeuticUp-RegulationXenograft ModelXenograft procedureadvanced prostate cancerandrogen deprivation therapybioluminescence imagingbonebone healingbone lossbone qualitybone strengthcancer cellcancer seedingcastration resistant prostate cancercombatcomorbiditydensityhormone therapyimprovedin vivo evaluationinhibitorinnovationinterestmenmicroCTmouse modelnovelnovel therapeutic interventionnovel therapeuticspre-clinicalpreferenceprostate cancer cellprostate cancer modelprostate cancer progressionresponseskeletalstandard of caretargeted treatmenttherapeutic candidatetherapeutic targettumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
Lethal prostate cancer preferentially spreads to the bone. Standard of care treatment for bone-metastatic
prostate cancer includes androgen-deprivation therapy (ADT). While initially effective, ADT is not curative and,
moreover, is associated with increased bone comorbidities. As such, new therapeutic strategies that not only
target the metastatic tumor, but also treat associated skeletal comorbidities are urgently needed. We previously
demonstrated an important cancer cell-intrinsic role for Ca2+/calmodulin-dependent protein kinase kinase 2
(CAMKK2) in prostate cancer progression and improved bone strength following systemic CAMKK2 inhibition.
However, whether targeting CAMKK2 can inhibit prostate cancer bone metastasis and counteract disease- or
therapy-linked comorbidities are unknown. This knowledge gap needs to be addressed to determine whether
CAMKK2 inhibitors, currently under development, can be used to treat this advanced stage of the disease and
hence, inform future clinical trials. The goal of this proposal is to define CAMKK2’s role in prostate cancer bone
metastasis and associated bone disease. These findings will help drive the development of new CAMKK2-
targeted therapies and can inform future clinical trials. Moreover, we anticipate that CAMKK2 inhibition may
also improve the safety and efficacy of existing treatments. It is our central hypothesis that CAMKK2 promotes
prostate cancer progression by altering the bone-tumor microenvironment as well as through cancer cell
autonomous mechanisms. We additionally propose that inhibition of CAMKK2 will both impair prostate cancer
bone metastasis and counteract ADT-mediated bone complications. To test our hypothesis, we propose the
following two specific aims: Aim 1: Delineate CAMKK2’s cell autonomous and non-autonomous roles in bone-
metastatic prostate cancer. Aim 2: Determine the effect of CAMKK2 inhibition on therapy-linked, prostate
cancer-bone comorbidities. Under the first aim, we will test how disruption of CAMKK2 in the host (cell non-
autonomous) and/or cancer (cell autonomous) impacts different stages of prostate cancer bone metastasis in
syngeneic and xenograft mouse models of prostate cancer under hormone-naïve and castration-resistant
settings. In the second aim, the effects of CAMKK2 inhibition on tumor-bearing bone microarchitecture will be
assessed using micro-CT and bone quality/strength will be assessed ex vivo. This proposal is innovative
because it explores new roles for CAMKK2 in bone-metastatic prostate cancer by examining effects on both
the tumor itself and surrounding bone. These studies are highly significant because they will not only delineate
new roles for CAMKK2, but also establish its potential as an excellent drug target for the treatment of bone-
metastatic, castration-resistant prostate cancer, alone or in combination with existing therapies.
项目摘要
致命的前列腺癌优先扩散到骨骼。骨转移的标准治疗
前列腺癌包括雄激素剥夺疗法(ADT)。虽然最初有效,但ADT不是治愈性的,
而且与骨合并症的增加有关。因此,新的治疗策略,不仅
靶向转移性肿瘤,但也迫切需要治疗相关的骨骼合并症。我们之前
证明了Ca 2 +/钙调蛋白依赖性蛋白激酶激酶2在癌细胞中的重要内在作用,
在前列腺癌进展和改善骨强度后,全身性CAMKK 2抑制。
然而,靶向CAMKK 2是否可以抑制前列腺癌骨转移并对抗疾病-或
与治疗相关的合并症尚不清楚。需要解决这一知识差距,以确定
目前正在开发的CAMKK 2抑制剂可用于治疗这种晚期疾病,
从而为未来的临床试验提供信息。该提案的目标是确定CAMKK 2在前列腺癌骨中的作用。
转移和相关的骨疾病。这些发现将有助于推动新的CAMKK 2的开发,
靶向治疗,并可以为未来的临床试验提供信息。此外,我们预计CAMKK 2抑制可能
也提高了现有治疗的安全性和有效性。我们的中心假设是CAMKK 2促进
通过改变骨肿瘤微环境以及通过癌细胞
自主机制。我们还提出,抑制CAMKK 2既会损害前列腺癌,
骨转移和对抗ADT介导的骨并发症。为了验证我们的假设,我们提出了
以下两个具体目标:目标1:描绘CAMKK 2在骨中的细胞自主和非自主作用。
转移性前列腺癌目的2:确定CAMKK 2抑制对治疗相关的前列腺增生的影响。
癌症-骨共病。在第一个目标下,我们将测试如何破坏宿主(非细胞)中的CAMKK 2。
自主的)和/或癌症(细胞自主的)影响前列腺癌骨转移的不同阶段,
未去势和去势抵抗前列腺癌同系和异种移植小鼠模型
设置.在第二个目标中,将研究CAMKK 2抑制对荷瘤骨微结构的影响。
使用微CT评估,并将离体评估骨质量/强度。这一建议具有创新性
因为它通过检测CAMKK 2对骨转移性前列腺癌和前列腺癌的影响,
肿瘤本身和周围的骨头这些研究非常重要,因为它们不仅可以描述
CAMKK 2的新作用,而且还建立了其作为治疗骨肿瘤的优良药物靶点的潜力。
转移性、去势抵抗性前列腺癌,单独或与现有疗法组合。
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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Daniel Edward Frigo其他文献
Daniel Edward Frigo的其他文献
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{{ truncateString('Daniel Edward Frigo', 18)}}的其他基金
Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism
重新审视抗血管生成疗法以靶向激素敏感的前列腺癌代谢
- 批准号:
10671250 - 财政年份:2023
- 资助金额:
$ 8.03万 - 项目类别:
Delineation of the Role of CAMKK2 in Bone-metastatic Prostate Cancer and its Therapeutic Implications
CAMKK2 在骨转移性前列腺癌中的作用及其治疗意义的描述
- 批准号:
10435266 - 财政年份:2022
- 资助金额:
$ 8.03万 - 项目类别:
FASEB's "The Steroid Hormones and Receptors in Health and Disease Conference - Jointly hosted by FASEB and the International Committee on Rapid Responses to Steroid Hormones (RRSH)"
FASEB 的“健康和疾病中的类固醇激素和受体会议 - 由 FASEB 和国际类固醇激素快速反应委员会 (RRSH) 联合主办”
- 批准号:
10063235 - 财政年份:2020
- 资助金额:
$ 8.03万 - 项目类别:
Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer
遗传
- 批准号:
8818191 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer
遗传
- 批准号:
9179334 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Androgen Receptor- and Myc-Mediated Glutamine Metabolism in Prostate Cancer
前列腺癌中雄激素受体和 Myc 介导的谷氨酰胺代谢
- 批准号:
8809478 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer
遗传
- 批准号:
9207070 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Genetic & Metabolic Dissection of the CaMKKbeta Signaling Axis in Prostate Cancer
遗传
- 批准号:
9000138 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Androgen Receptor- and Myc-Mediated Glutamine Metabolism in Prostate Cancer
前列腺癌中雄激素受体和 Myc 介导的谷氨酰胺代谢
- 批准号:
8997483 - 财政年份:2015
- 资助金额:
$ 8.03万 - 项目类别:
Modulation of Branched-Chain Fatty Acids for the Prevention of Prostate Cancer
调节支链脂肪酸预防前列腺癌
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8469411 - 财政年份:2012
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$ 8.03万 - 项目类别:
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