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
• 负责人: Daniel Edward Frigo
• 金额: $ 9.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10435266
• 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-Serine-Threonine Kinases; Refractory; Resistance; Role; Safety; Series; 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

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.

项目概要 致命的前列腺癌优先扩散到骨骼。骨转移的护理治疗标准 前列腺癌包括雄激素剥夺疗法（ADT）。虽然 ADT 最初有效，但并没有疗效， 此外，还与骨合并症的增加有关。因此，新的治疗策略不仅 迫切需要针对转移性肿瘤，同时治疗相关的骨骼合并症。我们之前 证明 Ca2+/钙调蛋白依赖性蛋白激酶激酶 2 具有重要的癌细胞内在作用 (CAMKK2) 参与前列腺癌进展，并在全身抑制 CAMKK2 后改善骨强度。 然而，靶向CAMKK2是否可以抑制前列腺癌骨转移并抵抗疾病或 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是否 目前正在开发的 CAMKK2 抑制剂可用于治疗该疾病的晚期阶段 因此，为未来的临床试验提供信息。该提案的目标是确定 CAMKK2 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 CAMKK2 的开发- 靶向治疗可以为未来的临床试验提供信息。此外，我们预计 CAMKK2 抑制可能 还提高了现有治疗的安全性和有效性。我们的中心假设是 CAMKK2 促进 通过改变骨肿瘤微环境以及癌细胞来促进前列腺癌的进展 自主机制。我们还建议抑制 CAMKK2 会损害前列腺癌 骨转移并抵消 ADT 介导的骨并发症。为了检验我们的假设，我们提出 遵循两个具体目标： 目标 1：描绘 CAMKK2 在骨细胞中的细胞自主和非自主作用 转移性前列腺癌。目标 2：确定 CAMKK2 抑制对治疗相关前列腺的影响 癌骨合并症。在第一个目标下，我们将测试宿主（非细胞）中 CAMKK2 的破坏情况。 自主）和/或癌症（细胞自主）影响前列腺癌骨转移的不同阶段 未经激素处理且去势抵抗的前列腺癌同基因和异种移植小鼠模型 设置。在第二个目标中，CAMKK2 抑制对荷瘤骨微结构的影响将是 使用显微 CT 进行评估，骨质量/强度将进行离体评估。这个提议很有创新性 因为它通过检查 CAMKK2 对骨转移性前列腺癌的影响来探索 CAMKK2 在骨转移性前列腺癌中的新作用 肿瘤本身和周围的骨骼。这些研究非常重要，因为它们不仅描绘了 CAMKK2 的新作用，同时也确立了其作为治疗骨关节炎的优秀药物靶点的潜力 单独或与现有疗法联合治疗转移性去势抵抗性前列腺癌。