Darolutamide in Combination with Radium-223 Exhibits Synergistic Antitumor Efficacy in LNCaP Prostate Cancer Models.

Despite treatment, prostate cancer commonly progresses into castration-resistant prostate cancer (CRPC), which remains largely incurable, requiring the development of new interventions. Darolutamide is an orally administered second-generation androgen receptor inhibitor indicated for patients with non-metastatic CRPC or metastatic hormone-sensitive prostate cancer. Here, we evaluated the effect of androgen receptor (AR) inhibition by darolutamide in combination with DNA double-strand-break-inducing targeted radium-223 alpha therapy in vitro and in an intratibial LNCaP xenograft model mimicking prostate cancer metastasized to bone.

Zoledronic Acid Prevents Bone Resorption Caused by the Combination of Radium-223, Abiraterone Acetate, and Prednisone in an Intratibial Prostate Cancer Mouse Model.

An increased risk of non-pathological fractures in patients with prostate cancer and bone metastases has been associated with combination treatment with radium-223, abiraterone, and prednisone/prednisolone in the absence of bone-protecting agents. Here, we investigated possible mechanisms leading to this outcome using an intratibial LNCaP model mimicking prostate cancer bone metastases. Male NOD.

Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model.

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy.

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model.

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis.

The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis.

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly.

Human Immune System Increases Breast Cancer-Induced Osteoblastic Bone Growth in a Humanized Mouse Model without Affecting Normal Bone.

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups ( = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals.

Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis.

Background: Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis.

Methods: We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis.

Improved statistical modeling of tumor growth and treatment effect in preclinical animal studies with highly heterogeneous responses in vivo.

Purpose: Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated.

Experimental Design: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework.

Short-term changes in serum PINP predict long-term changes in trabecular bone in the rat ovariectomy model.

Serum procollagen I N-terminal propeptide (PINP) is a sensitive bone formation marker in humans. We have developed a nonradioactive immunoassay for rat PINP and studied PINP as a bone formation marker in the rat ovariectomy (OVX) model. Two OVX studies were performed with 3-month-old rats, both including measurement of PINP, C-terminal cross-linked telopeptide of type I collagen (CTX), and N-terminal mid-fragment of osteocalcin.

Secreted tartrate-resistant acid phosphatase 5b is a Marker of osteoclast number in human osteoclast cultures and the rat ovariectomy model.

Purpose: To study the effects of estrogen withdrawal on osteoclast number and osteoclast activity in the rat ovariectomy (OVX) model.

Methods: We first cultured human CD34+ osteoclast precursor cells on bovine bone slices, allowing them to differentiate into mature resorbing osteoclasts. Secreted tartrate-resistant acid phosphatase 5b (TRACP 5b) and C-terminal cross-linked telopeptides of type I collagen (CTX) were determined from the culture medium.