Delineation of the Role of CAMKK2 in Bone-metastatic Prostate Cancer and its Therapeutic Implications

项目总结 致命的前列腺癌优先扩散到骨骼。骨转移瘤的护理标准治疗 前列腺癌包括雄激素剥夺疗法(ADT)。虽然最初是有效的，但ADT并不能治愈， 此外，它还与骨骼并发症的增加有关。因此，新的治疗策略不仅 针对转移性肿瘤，但也治疗相关的骨骼合并症是迫切需要的。我们之前 钙/钙调素依赖的蛋白激酶2在癌细胞中的重要作用 全身性CAMKK2抑制后，CAMKK2在前列腺癌进展和骨强度改善中的作用。 然而，靶向CAMKK2是否可以抑制前列腺癌的骨转移和对抗疾病-或者 与治疗相关的合并症尚不清楚。这一知识鸿沟需要解决，以确定 目前正在开发的CAMKK2抑制剂可以用于治疗这种晚期疾病和 因此，通知未来的临床试验。这项提议的目的是确定CAMKK2在前列腺癌骨骼中的S角色 转移和相关的骨病。这些发现将有助于推动新的CAMKK2- 靶向治疗，并可为未来的临床试验提供信息。此外，我们预计抑制CAMKK2可能 还可以提高现有治疗方法的安全性和有效性。我们的中心假设是CAMKK2促进 前列腺癌通过改变骨肿瘤微环境和通过癌细胞的进展 自主机制。我们还提出，抑制CAMKK2既会损害前列腺癌 骨转移和对抗ADT介导的骨并发症。为了检验我们的假设，我们提出了 目的1：明确CAMKK2的S细胞在骨骼中的自主和非自主作用。 转移性前列腺癌。目的2：确定CAMKK2抑制对与治疗相关的前列腺的影响 癌症和骨骼并存。在第一个目标下，我们将测试CAMKK2在宿主(细胞外)中的破坏情况 自主)和/或癌症(细胞自主)对前列腺癌不同阶段骨转移的影响 荷尔蒙幼稚和去势抵抗的前列腺癌同基因和异种移植小鼠模型 设置。在第二个目的中，将抑制CAMKK2对荷瘤骨微结构的影响 使用微型CT进行评估，骨质量/强度将在体外进行评估。这个建议很有新意 因为它探索了CAMKK2在骨转移前列腺癌中的新作用，通过检测对两者的影响 肿瘤本身和周围的骨骼。这些研究意义重大，因为它们不仅将描绘出 CAMKK2的新作用，但也确立了它作为治疗骨的优秀药物靶点的潜力。 转移性、耐阉割的前列腺癌，单独或与现有治疗方法结合使用。

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.