Novel Bone-Targeted Strategies in Oncology

Abstract

Most patients with bone metastases experience skeletal complications, resulting in significant morbidity and increased risk of death. Although the use of bisphosphonates is a well-established form of supportive care treatment for bone metastasis, complications arising from long-term use require schedule optimization and a search for alternative strategies. Moreover, the scope of use of bone-targeted agents in oncology has widened to include therapy-induced bone loss and antitumor effects. Indeed, bone provides a permissive niche to tumor growth, and targeting the interactions within the bone microenvironment is a promising antitumor strategy. In addition, the pathogenesis of cancer-related bone disease has been partially unraveled with a focus on the anabolic bone compartment, and the rapid benchto-bedside translation has resulted in the identification of novel therapeutically amenable targets. This review focuses on studies optimizing bisphosphonate use and recent clinical data on denosumab in the treatment of bone disease. We also provide data on trials that have evaluated the antitumor effects of bisphosphonates and summarize the most recent discoveries on the role of the bone niche in cancer development, with insights into the preclinical rationale and clinical assessment of novel antiresorptive and anabolic bone-targeted agents. Clin Cancer Res; 16(16); 4084-93. ©2010 AACR. Scope of the ProblemBone involvement is a common feature in solid and hematologic cancers. Multiple myeloma localizes to the bone in nearly all patients, and the incidence of bone metastasis in solid cancers ranges between 20% and 75% (1, 2). Disease-related skeletal complications result in significant morbidity due to pain, pathologic fractures and spinal cord compression (3). In addition, the occurrence of pathologic fractures increases the risk of death by 20% to 40% (4). Not only is bone involvement due to metastatic disease of significance, but the increasing incidence of therapy-related bone loss has widened the scope of use of bone-targeted agents in oncology (5). In addition, recent preclinical and clinical studies have suggested that bone provides a permissive niche to tumor cell growth, and targeting the interactions within the bone milieu may represent an important strategy to suppress tumor development (6, 7). Therefore, restoring a balanced bone environment may not only positively impact bone disease but may also help reduce tumor burden.In this review, we provide an overview of novel, biologically based therapeutic strategies aimed at preventing and/or decreasing disease-related skeletal complications and discuss the evidence for antitumor effects from restored bone homeostasis. Biology of Bone Disease and MetastasisThe skeleton is a dynamic organ that undergoes extensive remodeling throughout life. Modest changes in the kinetics of bone resorption and formation result in dramatic net effects on bone architecture (8). In the cancer setting, the cross-talk between tumor and bone cells disrupts normal bone homeostasis...

A novel Bruton’s tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity

“…13,[55][56][57] Thus, the MM bone niche provides a microenvironment that propagates tumor growth. Developing novel therapeutic targets or new treatment combination therapies that target both the tumor cells as well as the microenvironment or niche components are critical not only for the improvement of osteolytic bone disease but importantly for anti-MM activity and long-term disease control.…”

“…8 Nearly 90% of patients with MM develop osteolytic bone lesions, resulting in consequent sequelae including severe bone pain, pathological fractures, vertebral collapse, hypercalcemia and spinal cord compression, all of which are associated with increased morbidity and mortality. [9][10][11][12][13][14] MM bone disease results from the disruption of the delicate balance between OC, osteoblast (OB) and BM stromal cell activity where MM cells stimulate OC function and inhibit OB differentiation, resulting in bone resorption and formation of osteolytic lesions. The BM microenvironment provides a permissive niche that enables myeloma cell growth; targeting the interactions within the bone microenvironment may represent an important strategy to suppress aberrant (or abnormal) plasma cell development.…”

Analysis on Survival and Prognostic Factors for Cancer Patients with Malignancy-associated Hypercalcemia

“…A recombinant version of osteoprotegerin (OPG) showed the ability to suppress the activity of RANKL in vitro and both to prevent MAH and normalize bone turnover in mice (Croucher et al, 2001;Morony et al, 2005). There are other new agents currently under evaluation: a humanized anti-PTHrP antibody, tyrosine-kinase inhibitors such as dasatinib, cathepsin K inhibitor Odanacatib, endothelin 1 inhibitor atrasentan, monoclonal antibodies against DKK1 or Activin A (Sato et al, 2003;Body et al, 2010;Vallet et al, 2010).…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…48 As bone destruction is also an oncological problem (bones are a common site for metastases), it has been hypothesized that the anti-resorptive properties of denosumab might also be beneficial to cancer patients. 49 Results from recent clinical trials suggest that denosumab can help prevent bone metastases in prostate cancer better than zoledronate, a bisphosphonate that had previously been shown to be superior to denosumab in the therapy of multiple myeloma. 50 Today, denosumab is under evaluation for the prevention of bone metastasis in women with high risk early breast cancer receiving neoadjuvant or adjuvant therapy ( Table 3, NCT01077154).…”