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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

Selective protein kinase C-ß inhibitor (Enzastaurin) suppresses tumor growth, bone osteolysis, cancer -induced bone pain, and enhance radiosensitivity of the bone tumor.

University of Minnesota, Minneapolis, MN and Medical University of Vienna, Vienna, Austria

Abstract

B10

The most common site of breast cancer metastasis is skeleton. In bone metastasis, metastatic cells stimulate osteoclast-mediated bone osteolysis, and bone derived growth factors stimulate tumor growth. The role of tumor angiogenesis in bone environment is, however, unknown. In our study, using experimental model of metastatic breast cancer into bone produced by murine 4T1 breast cancer cells that closely mimic the conditions likely to occur in human metastatic breast cancer, we demonstrate that combination treatment with selective protein kinase C-ß inhibitor and local irradiation significantly decreased tumor burden and cancer induced bone pain. Currently available therapies are focused on decreasing tumor proliferation, reducing bone osteolysis, surgical stabilization of painful bones with skeletal metastases, and administering analgesics. Localized irradiation is one the most effective treatments found to reduce cancer -induced bone pain, with 90% of patients receiving some pain relief and 50% of patients having complete relief. Neoangiogenesis is necessary for the growth and spread of solid tumors. Anti-angiogenic regimens have been shown to be very effective in the treatment of a wide variety of solid tumors in animals. In this study we have shown that suppressing AKT signaling pathway decreases tumor burden, cancer induced bone pain and expression of GFAP and DYN in dorsal horn of the spinal cord. Materials and Methods: Experiments were performed on C3H/SCID mice. Seven days after intrafemoral injection of the tumor cells mice were randomised into one of the following groups (n=15); 1. p.o. Enzastaurin (75 mg/kg) twice daily, 2. local irradiation of the femur 30 Gy; 3. p.o. Enzastaurin and local irradiation 30 Gy; and 4. p.o. 3% DMSO in saline. X-rays of the femur were performed 7, 13 and 16 days after tumor cells injection. Destruction of bone was determined using numeric scale from 0 to 4 where grade 0 represents no lesion, and 4 bicortical destruction of bone with involvement of soft tissue. We monitored pain-related behavior of mice on days 7, 9, 13, and 16. Ongoing pain was recorded as time of guarding and number of flinches, and functional impairment of limb was assessed by rotarod. Results: Radiation or Enzastaurin alone showed no significant reduction on Bone Destruction Scores while a significant decrease in Bone Destruction Scores was noted in mice treated with the combination treatment (Enzastaurin + irradiation). Combination treatment significantly reduced bone pain as evaluated by both guarding and flinching, compared to control group. We noticed also very strong correlation between bone destruction and skeletal pain. Mean microvessel number (MVD) assessed using specific antibodies against CD 31 was significantly reduced in Enzastaurin treated animals and in combined radiation and Enzastaurin therapy. In animals treated with 30 Gy radiation on day 7, microvessel number was not significantly different, as compared to control group. Immunohistochemistry of the spinal cord revealed increased expression of GFAP and DYN in dorsal horn of the spinal cord in control group (ipsilateral side) as compared to treatments groups. Conclusion: Interfering with AKT signaling in combination with local irradiation may be an approach to control aggressive growth of murine 4T1 breast cancer in bone microenvironment and thus decrease bone destruction and cancer-induced bone pain.