SBIR-STTR Award

Bone growth is critical to a favorable prognosis in the 70% breast cancer patients that have skeletal metastases, or approximately 175,000 patients per year in the US. Lytic lesions, or voids in the bone, result from local bone destruction caused by tumor cell-directed, osteoclastic bone re-absorption and lead to pathologic fracture and increased patient morbidity. Surgical intervention is necessary to prevent initial fracture or other skeletal related events, and involves stabilizing the defect created by the tumor. Currently, failure rates with these interventions are 42% for patients who survive more than 1-year after fixation for pathological fracture. Because of the high failure rates and increased patient survival, lytic lesions are affecting a growing patient population and account for approximately $2 billion in US healthcare expenditure per year. Patients with breast cancer bone metastases (i.e. a skeletal related event) require surgical intervention that stabilizes the tumor-directed defect using intra-medullar nails, total joint prostheses and bone cement. However, hardware and bone cement don't promote bone formation. Growth factors have become a popular option to increase bone healing, however, these therapies, such as BMP2 (Infuse®) or PTH (Forteo®) have been given a black-box warning by the FDA for patients with active tumor or patients who have been treated for tumor. In particular, BMP2 has been associated with increased tumor risk in patients who are undergoing X- radiation therapy or possess nascent undetected tumor. In response to this unmet need, Fusologics, LLC, a New York-based startup company is commercializing Nalovent™, a novel surgical implant with demonstrated ability to treat lytic lesions by effectively growing bone and inhibiting local growth of cancer cells. Based on the discovery of a novel molecular pathway for bone growth, Nalovent induces osteogenesis via the local administration of an implant that contains the opioid antagonist, naloxone, embedded in a collagen delivery vehicle. If validated, Nalovent would empower clinicians with a much-needed solution to heal lytic lesions and fight residual tumor in order to deliver significantly improved outcomes to the large and growing population of breast cancer patients with skeletal metastases. This proposal consists of two aims: 1) optimization of the Nalovent osteogenic implant around local inhibition of tumor growth, and 2) validation of the Nalovent implant in relevant in vivo studies. If successful, this proposal will demonstrate commercial proof-of-concept for the Nalovent implant and establish the foundation for a Phase II proposal to support remaining preclinical development in preparation for human trials.

Public Health Relevance Statement:


Project narrative:
Bone growth is critical to a favorable prognosis in the 70% breast cancer patients that have skeletal metastases or 175,000 patients per year in the US. Lytic lesions, or voids in the bone, result from local bone destruction caused by tumor cell-directed osteoclastic bone re-absorption. These lesions do not heal well after therapy, which result in pathologic fracture and increased patient morbidity, and require surgical fixation to stabilize the defect. Because current failure rates (re-operation) with these surgical interventions are 42% for patients who survive more than 1-year after fixation and due to increased patient survival, lytic lesions are affecting a growing patient population and account for approximately $2 billion in US healthcare expenditure per year. In response to this unmet need, Fusologics, LLC, a New York-based startup company is commercializing Nalovent™, a novel surgical implant with demonstrated ability to treat lytic lesions by effectively growing bone and inhibiting local growth of cancer cells.

Project Terms:
absorption; Address; Adjuvant; Affect; animal data; Animal Model; base; Binding; Biological Assay; BMP2 gene; bone; bone cell; Bone Growth; bone healing; Breast Cancer Cell; Breast Cancer Patient; Cancer Cell Growth; Cancer Patient; Cell Count; Cell Death; cell growth; Cell Proliferation; Clone Cells; Collagen; cytotoxicity; Defect; Diffusion; Disease remission; Dose; experimental study; Exposure to; Failure; fighting; Forteo; Foundations; Fracture; Goals; Growth; Growth Factor; healing; Health Care Costs; Health Expenditures; Human; Implant; improved; improved outcome; in vivo; inhibitor/antagonist; Intervention; Joint Prosthesis; Lead; Lesion; Lytic; Lytic Lesion; malignant breast neoplasm; Mammary Neoplasms; Marrow; MCF7 cell; MDA MB 231; Mediating; Mesenchymal Stem Cells; Metastatic breast cancer; Metastatic Neoplasm to the Bone; methionine-enkephalin receptor; Modeling; Molecular; monocyte; Morbidity - disease rate; Mus; Muscle; Nail plate; Naloxone; neoplastic cell; New York; novel; operation; Operative Surgical Procedures; Opioid; Opioid Antagonist; Osteoclasts; Osteogenesis; osteogenic; outcome forecast; Pathological fracture; Pathway interactions; patient population; Patients; Pharmaceutical Preparations; Phase; physical property; Population; Pre-Clinical Model; preclinical development; Preparation; prevent; Radiation therapy; Recurrence; Research; Residual state; Residual Tumors; response; Risk; Roentgen Rays; sample fixation; sarcoma; skeletal; skeletal-related events; Stem cells; Survivors; Testing; treatment strategy; triple-negative invasive breast carcinoma; tumor; Tumor Burden; tumor growth; Validation; Vascular Endothelial Cell; Work

Bone growth is critical to a favorable prognosis in the 70% of de novo metastatic breast cancer patientsthat have skeletal metastases, or approximately 115,000 new patients per year in the US. Lytic lesions, orvoid-defects in the bone, result from local bone destruction caused by tumor cell-directed osteoclastic bone re-absorption and lead to pathologic fractures and increased patient morbidity. Surgical intervention is necessaryto prevent initial fracture or other skeletal related events and involves stabilizing the defect created by thetumor. Unfortunately, a growing population of patients are at risk for implant failure due to the inability ofhardware or bone cement to promote bone formation. Because of high failure rates and increased patientsurvival, lytic lesions account for approximately $2-billion in US healthcare expenditures per year. Patients with breast cancer bone metastases (i.e. a skeletal related event) require surgical interventionto stabilize the tumor-directed defect using intra-medullar nails, total joint prostheses, and/or bone cement.However, hardware and bone cement don't promote bone formation. The underlying unfilled bone defects canresult in implant loosening and loss of mechanical stability. Growth factors have become a popular option toincrease bone healing. However, these therapies, such as BMP-2 (Infuse®) and PTH (Forteo®), have safetyrisks for cancer patients and some have been contraindicated for use or given a black-box warning by the FDAfor patients with active tumor or patients with history of tumor. In particular, BMP-2 has been associated withincreased tumor risk in patients who are undergoing X-radiation therapy or possess nascent undetected tumor. In response to this unmet need, Zetagen Therapeutics, Inc., a New York regenerative medicine startupis commercializing the Nalovent™ Bone Graft, a new combination product with a demonstrated ability totreat lytic lesions by inducing osteogenesis while inhibiting local growth of cancer cells. Based on thediscovery of a novel molecular pathway for bone growth, Nalovent induces osteogenesis via the localimplantation of a calcium phosphate bioceramic / bovine collagen-based bone graft that contains the opioidantagonist, naloxone. If validated, the Nalovent Bone Graft would empower clinicians with a much-neededsolution to heal lytic bone defects and fight residual tumor in order to deliver significantly improved outcomes tothe large and growing population of breast cancer patients with skeletal metastases. This proposal consists of three AIMs meant to drive the Nalovent Bone Graft towards FDA approvalusing standard safety, bioavailability, and efficacy assessments: 1) Assess the safety of Nalovent, 2) Test thebioavailability of Nalovent and 3) Validate that the Nalovent Bone Graft promotes bone growth. If successful,this proposal will demonstrate commercial validation for the Nalovent Bone Graft implant and establish thefoundation for the preparation for first-in-man trials.

Public Health Relevance Statement:


Project narrative:
Bone growth is critical to a favorable prognosis in the 70% of de novo metastatic breast cancer patients that have skeletal metastases. Destructive bone defect - or lytic lesion - result from local bone destruction caused by tumor cell directed osteoclastic bone re-absorption. The Nalovent Bone Graft, a combination device that delivers a small molecule drug, has demonstrated the ability to grow bone in a lytic bone tumor defect adjacent to an active breast cancer tumor in mice. Further, following the completion of product development and generating data per the FDA's guidance, Zetagen will be ready to meet with the FDA again to gain approval for first-in-man clinical studies.

Project Terms: