Abstract 3927: Bone Metastasis Technology Platform: Establishing clinically relevant bone metastasis models for breast and prostate cancer and multiple myeloma

BMP7: A New Bone Metastases Prevention?

Should bisphosphonates be used routinely in patients with prostate cancer metastatic to bone?

ACR Appropriateness Criteria® on Metastatic Bone Disease

MOLECULAR INSIGHTS INTO PROSTATE CANCER PROGRESSION: THE MISSING LINK OF TUMOR MICROENVIRONMENT

Most cancer deaths are due to metastases, and bone metastases are a considerable problem especially in breast and prostate cancer, being developed in 70-90% of advanced-stage patients. Despite major investments in oncology drug development, bone metastases are currently incurable and a high unmet medical need with only 5% of patients being alive 5 years after the diagnosis. Development of therapies for bone metastasis has been challenging due to lack of appropriate preclinical models available to support decision making in next phases of drug development. In the absence of clinically relevant preclinical bone metastasis models, the current strategy is to rely on preclinical efficacy data obtained with subcutaneous models that lack the clinically relevant local tissue microenvironment, which has a major impact on tumor growth. The use of clinically non-relevant models in preclinical-stage development may be one important reason for the current >95% failure rate of oncology drugs in clinical trials. To support predictive evaluation of therapies for bone metastatic cancers, we describe a preclinical bone metastasis technology platform for evaluating efficacy of novel therapies on bone metastases. The platform utilizes tumors growing in bone microenvironment, mimicking growth of bone metastases in patients. Syngeneic or humanized mouse models with tumor and immune cells of same species are needed for supporting development of immunotherapies, allowing interactions of tumor and immune cells in the bone metastatic microenvironment, according to the novel osteoimmuno-oncology concept. The platform provides a predictive tool for studying unique biological features associated with different types of bone metastases in cancer-type specific manner. Here we summarize case examples where results from preclinical bone metastasis studies align with clinical findings of different therapies approved or evaluated for bone metastasis. Zoledronic acid, an anti-resorptive bisphosphonate that is currently used in breast cancer patients with bone metastases to prevent cancer-induced bone loss, showed improved bone health but no effects on tumor growth. Radium-223 dichloride, an approved treatment for bone metastatic castration-resistant prostate cancer in patients, showed reduced prostate cancer growth and decreased tumor-induced bone changes. As for immunotherapies, an IDO1 inhibitor had no effects on breast cancer bone metastases and the anti-PD-1 antibody pembrolizumab had no effects on breast and prostate cancer bone metastases, predicting recent clinical findings that demonstrate lack of efficacy of anti-PD-1 in clinical prostate cancer trials. We conclude that the bone metastasis technology platform is a biologically relevant tool for preclinical evaluation of the efficacy of experimental therapies on bone metastasis, and it has been validated with positive and negative case examples, demonstrating its clinically predictive power. Citation Format: Tiina E Kähkönen, Jussi M Halleen, Jenni Bernoulli. Preclinical bone metastasis technology platform – Predictive evaluation of experimental therapies on bone metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A007.

Real-world patient-reported outcomes of breast cancer or prostate cancer patients receiving antiresorptive therapy for bone metastases: Final results of the PROBone registry study

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.

Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

To investigate the features, adverse effects, bone marker changes in patients with breast cancer, prostate cancer, and multiple myeloma with bone metastases under Zometa® therapy. This post-marketing study included 414 Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, or multiple myeloma who received Zometa® for 48 weeks. The patients' characteristics, medication and adverse events were recorded, meanwhile changes in four serum bone metabolic markers and pain reduction were assessed every three months for one year. A total of 3,711 doses of Zometa® were infused, accounting for 294.5 patient-years. Adverse events occurred in 9.4% of patients, with bone pain, insomnia, constipation, and pyrexia as the most frequently reported. There was no osteonecrosis of the jaw. The incidence of skeletal-related events decreased significantly from 44.9% to 18.8%. Serum NTx, BAP, and TRACP5b steadily decreased to nadir at six months, but serum OPG was persistently elevated until the end of one year. The average decrease in pain score was 14.1, 14.3, and 16.7 for prostate cancer, breast cancer, and multiple myeloma patients, respectively. Zometa® can be safely administered in Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, and multiple myeloma. There are concomitant decreases in skeletal-related events and bone pain.

Prostate cancer that is hormone refractory and has metastasized preferentially to bone is the main cause of prostate cancer death, especially in African American men. Receptor activator of nuclear factor kappa B ligand (RANKL) and its receptor (RANK) contributes to bone metastatic lesions and bisphosphonates such as Zometa and Fosamax have been used as antagonists of RANKL for the treatment of breast and prostate cancer metastasis. African American men have the highest bone mineral density compared to any other race, and the role this may play in prostate cancer metastasis to bone is not clear. A better understanding of bone metastasis may lead to alternative treatment options for metastatic prostate cancer. Snail transcription factor is important early in development and in cancer cells and promotes cancer cell migration and progression by inducing epithelial mesenchymal transition (EMT). We have observed increased expression of Snail in prostate cancer bone metastatic human patient samples. We hypothesized that Snail can mediate EMT-mediated prostate cancer migration towards bone of high bone mineral density and mediate the vicious cycle of tumor-tumor microenvironment reciprocal interactions through calcium and RANKL signaling. We generated an EMT model for prostate and breast cancer utilizing the ARCaP human prostate and MCF-7 breast cancer cells overexpressing Snail and identified increased RANKL expression that was associated with increased osteoclastogenesis both in vitro and in vivo, as well as decreased bone volume and density. We utilized pre-molded bone discs which are allograft bone/polyurethane (PUR) composite bone void fillers with tunable properties that have advantage over existing bone implant models in that it contains bigger pore sizes that support rapid cellular infiltration and remodeling. We treated the bone discs with hydrochloric acid which decreased the bone density to a ratio of 1:1.18 for low (HCL-treated): high (untreated) bone density, which is quite close to the 1: 1.2 ratio seen in Caucasian vs African American men. Incubation of these bone discs with prostate or breast cancer cells overexpressing Snail led to increased calcium release from bone of high density as compared to low density. We are currently testing whether this increased calcium release in response to Snail may promote paracrine cell proliferation. Since Snail is not required by adult cells except during injury, targeting Snail that is mainly expressed by cancer cells may antagonize metastatic lesions in bone without affecting normal bone in other areas of the body. Citation Format: Basil A. Smith, Veronica Henderson, Christopher Coke, Jerald Dumas, Cimona Hinton, Manu Platt, Leland K. Chung, Majd Zayzafoon, Valerie A. Odero-Marah. Snail transcription factor contributes to bone metastasis in prostate and breast cancer cells. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C60. doi:10.1158/1538-7755.DISP13-C60

Oncolytic Adenovirus Expressing Soluble TGFβ Receptor II-Fc-mediated Inhibition of Established Bone Metastases: A Safe and Effective Systemic Therapeutic Approach for Breast Cancer

Bone is one of the most common sites of metastasis from advanced solid tumors. Bone metastasis is a leading cause of pain and increases the risk of skeletal-related events (SREs) in cancer patients. In addition to affecting the quality of life, it also increases the medical costs and mortality risk. We aimed to examine the occurrence of bone metastasis and SREs in Korean cancer patients using a nationwide health database. Using claims data from the National Health Insurance Service-National Sample Cohort (2002-2013), we extracted the data of bone metastasis patients diagnosed with any of the seven major cancers in Korea from January 2002 to December 2010. Selected SREs included pathologic fracture, spinal cord compression, radiation therapy, and palliative bone surgery. We used time-to-event analysis to estimate patient survival after bone metastasis. A total of 21,562 newly diagnosed cancer patients were identified; bone metastases developed in 1,849 patients (breast cancer, 18.8%; prostate cancer, 17.5%; lung cancer, 13.7%). The median time from primary cancer diagnosis to bone metastasis was 18.9 months. The cumulative incidence of SREs was 45.1% in all bone metastasis patients. The most common cancer type was lung cancer (53.4%), followed by liver (50.9%), prostate (45.9%), breast (43.6%), and colorectal (40.2%) cancers. Almost all SREs developed 1 month after bone metastasis, except in patients with breast and prostate cancers (median: 5.9 months in breast cancer and 4.7 months in prostate cancer). Survival duration after the development of bone metastasis was < 6 months in stomach, liver, colorectal, and lung cancer patients. Breast and prostate cancer patients survived for > 1 year after the occurrence of SREs. This study reveals the epidemiology of bone metastasis and SREs in Korean cancer patients, and the findings can be used to assess the actual bone health status of cancer patients.

Bone is one of the most common sites of metastasis from advanced solid tumors. Bone metastasis is a leading cause of pain and increases the risk of skeletal-related events (SREs) in cancer patients. In addition to affecting the quality of life, it also increases the medical costs and mortality risk. We aimed to examine the occurrence of bone metastasis and SREs in Korean cancer patients using a nationwide health database. Using claims data from the National Health Insurance Service-National Sample Cohort (2002–2013), we extracted the data of bone metastasis patients diagnosed with any of the seven major cancers in Korea from January 2002 to December 2010. Selected SREs included pathologic fracture, spinal cord compression, radiation therapy, and palliative bone surgery. We used time-to-event analysis to estimate patient survival after bone metastasis. A total of 21,562 newly diagnosed cancer patients were identified; bone metastases developed in 1,849 patients (breast cancer, 18.8%; prostate cancer, 17.5%; lung cancer, 13.7%). The median time from primary cancer diagnosis to bone metastasis was 18.9 months. The cumulative incidence of SREs was 45.1% in all bone metastasis patients. The most common cancer type was lung cancer (53.4%), followed by liver (50.9%), prostate (45.9%), breast (43.6%), and colorectal (40.2%) cancers. Almost all SREs developed 1 month after bone metastasis, except in patients with breast and prostate cancers (median: 5.9 months in breast cancer and 4.7 months in prostate cancer). Survival duration after the development of bone metastasis was < 6 months in stomach, liver, colorectal, and lung cancer patients. Breast and prostate cancer patients survived for > 1 year after the occurrence of SREs. This study reveals the epidemiology of bone metastasis and SREs in Korean cancer patients, and the findings can be used to assess the actual bone health status of cancer patients.

Advanced prostate cancers consistently display common features, i.e., progression to androgen resistance, rising prostate-specific antigen (PSA), and metastases to the skeleton. In this issue of Clinical Cancer Research , Nadiminty et al. report a provocative mechanistic link between PSA and bone

Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment