The World Health Organization estimates that the number of women living with breast cancer globally will rise to 15 million by the year 2020 with a significant portion of these patients in advanced stages of the disease. Breast cancer is the most frequent malignant tumor in women in the U.S. with nearly 200,000 women diagnosed each year. The U.S. NIH estimate overall costs of cancer in the U.S. in 2006 to be $206.3 billion with $78.2 billion in direct medical costs. Breast cancer commonly metastasizes to the bone resulting in excruciating pain, bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. A recent study in cancer patients demonstrated a significant and severe deficit in treatment options for cancer pain, with a much higher incidence in minority patients. Reports also highlight the importance of patient quality of life in late stages of cancer, as well as the effects on surrounding family and physicians. Unfortunately, current therapies for cancer-induced bone pain result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. This application addresses this unmet need by investigating the novel cathepsin inhibitor VBY-825 (Patent WO 2006/102 243) in attenuating breast cancer-induced bone pain and bone resorption without resulting in unwanted side effects seen with current analgesic therapies. The potential for broad application to bone cancer metastases and the associated pain derived from other types of tumors is significant for this potential therapeutic. The cathepsins (11 cysteine protease subtypes) include cathepsins B, S, and K, the three subtypes thought to be involved in bone cancer pain. Cathepsin B is involved in cancer metastasis, initiating the breakdown of connective barriers of the extracellular matrix and basement membrane, thereby allowing cancerous cells to invade new tissues and organ sites by entering the bloodstream. Cathepsin K is selectively expressed in osteoclasts and is essential in osteoclast-mediated bone resorption. Importantly in bone cancer, cathepsin K may also be involved in the formation of osteolytic lesions. Cathepsin S has recently become associated with nociception. Rodents with a partial ligation of the left sciatic nerve (PNL), showed increased expression of cathepsin S in the dorsal horn of the spinal cord. Cathepsin S inhibitors have analgesic efficacy in this model and a number of models of neuropathic pain implicating cathepsin S, as a significant new target for analgesic efficacy in neuropathic and inflammatory pain. Virobay Inc. has developed a spectrum-selective cathepsin inhibitor of K/S/B (CatK, Ki=2.3 nM) (CatS, Ki=130pM) and (CatB, Ki=330pM) for use as a potential therapeutic in oncology with specific utility in the inhibition of bone cancer pain. Here we propose that a spectrum- selective cathepsin inhibitor will result in a significant reduction in spontaneous and evoked pain behaviors in a murine model of breast-induced bone cancer pain while lacking the unwanted side effects seen with current opioid analgesic therapies. Three aims are proposed, including testing of the VBY-825 in a well established murine model of breast-induced bone cancer for efficacy in reducing pain behavior (Aim 1), bone loss, clinically relevant serum markers, and bone mineral density measures (Aim 2), and the pharmacokinetics and pharmacodynamics of VBY-825 with comparisons to current clinical treatments of morphine and the bisphosphonate zoledronic acid (Aim 3). In summary, a significant number of human and murine breast cancers express cathepsins and the investigation of VBY-825 (a spectrum-selective inhibitor of cathepsins K/S/B) may offer a novel therapeutic to many bone cancer patients that suffer from pain, bone loss and the unwanted side effects of current therapies including the very high doses of opioids for pain used in almost all patients.
Public Health Relevance Statement: Public Health Relevance: Breast cancer is the most frequent malignant tumor in women in the U.S. with nearly 200,000 women diagnosed each year. In advanced stages, skeletal metastasis is associated with bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. Pain is the first symptom in 20- 50% f all cancer patients and is prominent in 75-90% of advanced or terminal cancer patients, while struggling with failed treatment and/or tumor progression. Unfortunately, current pain therapies result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. There is a great need for novel therapeutic intervention in treating the pain and bone loss in advanced breast cancer patients. Here we propose to use the proprietary cathepsin inhibitor (VBY-825) in a murine model of breast-induced bone cancer to determine whether there is significant pain relief and a decrease in bone loss.
Project Terms: Address; Adverse effects; Analgesics; Animals; Attenuated; Basement membrane; Behavioral; Biochemical; Biological Markers; bisphosphonate; Blood Circulation; bone; Bone Density; bone loss; Bone neoplasms; Bone Pain; Bone remodeling; Bone Resorption; bone turnover; Breast; Breast Cancer Treatment; cancer pain; Cancer Patient; cancer therapy; Cancerous; cathepsin K; Cathepsins; Cathepsins B; Cells; Clinical Research; Clinical Treatment; clinically relevant; Controlled Study; cost; Cysteine; Cysteine Protease; Cytochrome P450; Data; design; Deterioration; Diagnosis; Diagnostic Neoplasm Staging; Disease; Dose; Drug Kinetics; Extracellular Matrix; Family Physicians; Felis catus; Fractalkine; Fracture; Human; Hypersensitivity; Image; Immune; In Vitro; in vivo; Incidence; inflammatory neuropathic pain; inhibitor/antagonist; Invaded; invariant chain; Investigation; Left; Legal patent; Life; Ligation; Lytic Metastatic Lesion; Malignant Bone Neoplasm; malignant breast neoplasm; Malignant Neoplasms; Measures; Mechanics; Mediating; Medical; Metastatic Neoplasm to the Bone; migration; Minority; Modeling; Morphine; Morphine Users; Motor Activity; Mus; Neoplasm Metastasis; neoplastic cell; nerve injury; Neuropathy; Nociception; novel; novel therapeutic intervention; novel therapeutics; oncology; Opioid; Opioid Analgesics; Organ; Osteoclasts; Osteogenesis; Pain; pain behavior; pain inhibition; Pain management; painful neuropathy; Patients; Peptide Hydrolases; Pharmacodynamics; Plasma; Play; prevent; protective efficacy; Protein Isoforms; public health relevance; Quality of life; Receptors, Opioid, mu; Reporting; response; Risk; Rodent; Rodent Model; sciatic nerve; Sedation procedure; selective expression; Serum; Serum Markers; Site; Spinal cord posterior horn; spontaneous pain; Staging; Study models; Symptoms; Testing; Therapeutic; Time; Tissues; tumor; Tumor Cell Invasion; tumor progression; tumorigenesis; United States National Institutes of Health; Woman; World Health Organization; Zoledronic Acid
