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; 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.

项目摘要 致命的前列腺癌优先扩散到骨骼。骨骼的护理标准治疗 前列腺癌包括雄激素剥夺疗法（ADT）。虽然最初有效，但ADT无法治愈，并且 此外，与骨骼合并症的增加有关。因此，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。我们以前 证明了Ca2+/钙调蛋白依赖性蛋白激酶激酶2的重要癌细胞中性作用2 （CAMKK2）在全身CAMKK2抑制后，前列腺癌的进展和骨强度改善。 但是，靶向CAMKK2是否可以抑制前列腺癌骨转移并抵消疾病或 治疗连接的合并症尚不清楚。需要解决此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高级阶段和 因此，请告知未来的临床试验。该提案的目的是定义CAMKK2在前列腺癌骨骼中的作用 转移和相关的骨病。这些发现将有助于推动新的CAMKK2-的发展 有针对性的疗法，可以告知未来的临床试验。而且，我们预计CAMKK2抑制可能 还提高现有治疗的安全性和效率。我们的核心假设是CAMKK2促进 前列腺癌的进展通过改变骨肿瘤微环境以及通过癌细胞 自主机制。我们还建议抑制CAMKK2都会损害前列腺癌 骨转移和ADT介导的骨并发症。为了检验我们的假设，我们提出了 以下两个具体目的：目标1：描绘Camkk2在骨中的细胞自主和非自动角色 转移性前列腺癌。目标2：确定CAMKK2抑制对治疗连接的前列腺的影响 癌性合并症。在第一个目标下，我们将测试宿主中CaMKK2的破坏（单元非 - ） 自主）和/或癌症（细胞自主）影响前列腺癌骨转移的不同阶段 前列腺癌的合成和异种移植小鼠模型在不接受马匹和cast割的下 设置。在第二个目的中，CAMKK2抑制对承重肿瘤骨微结构的影响将是 使用Micro-CT和骨骼质量/强度评估将在离体中评估。该建议是创新的 因为它通过检查对这两种影响的影响，探讨了caMKK2在骨 - 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，因为它们不仅会描述 CAMKK2的新作用，但也确定了其作为治疗骨骼的极好药物靶标的潜力 单独或与现有疗法结合使用转移性，耐法前列腺癌。