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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：
Daniel Edward Frigo
金额：
$ 8.03万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
https://reporter.nih.gov/project-details/10593983
关键词：
Address Age Autopsy Bone Diseases Bone neoplasms Bone remodeling Ca(2+)-Calmodulin Dependent Protein Kinase Cancer Etiology Castration Cells Cessation of life Clinical Trials Data Deterioration Development Disease Disease Progression Future Genetic Engineering Goals Hormones Human Impairment Individual Knowledge Laboratories Link Magnetic Resonance Imaging Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Monitor Neoplasm Metastasis Oncogenic Osteoblasts Outcome Patients Phosphotransferases Play Prostate Cancer therapy Protein Kinase Protein-Serine-Threonine Kinases Refractory Resistance Role Safety Series Serine Site Testing Therapeutic Up-Regulation Xenograft Model Xenograft procedure advanced prostate cancer androgen deprivation therapy bioluminescence imaging bone bone healing bone loss bone quality bone strength cancer cell cancer seeding castration resistant prostate cancer combat comorbidity density hormone therapy improved in vivo evaluation inhibitor innovation interest men microCT mouse model novel novel therapeutic intervention novel therapeutics pre-clinical preference prostate cancer cell prostate cancer model prostate cancer progression response skeletal standard of care targeted treatment therapeutic candidate therapeutic target tumor tumor growth tumor 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。