Search

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically-engineered mouse model of the disease. We performed pre-clinical studies to examine the consequences of combinatorial inhibition of these signaling pathways using Rapamycin, an inhibitor of mTOR, and PD0325901, a MEK inhibitor, is potently anti-tumorigenic in mouse models of castration-resistant prostate cancer. Current studies reported herein demonstrate that this combination is also effective for tumor suppression of advanced prostate cancer models and can improve survival. Studies in progress are evaluating new combinations and also evaluating molecular changes in response to therapy., The original document contains color images.

With docetaxel as effective chemotherapy for hormone refractory prostate cancer (HRPC), the number of new treatment combinations for HRPC is expanding demanding a fast-track screening system. This review elaborates on the use of xenograft models to select the most promising combination therapies for entering into phase II clinical trials.

N-cadherin is a cell surface marker that is overexpressed in hormone refractory prostate cancer and targeting this protein either diagnostically or therapeutically may have clinical utility. We initially observed that the cadherin profiles of certain prostate cancer cell lines and xenografts correlated with their level of invasiveness. In addition, we saw that amongst certain hormone refractory xenograft models, there was a consistent upregulation of N-cadherin when compared to its androgen dependent counterpart. We generated specific monoclonal antibodies against different domains of N-cadherin in an attempt to determine if blockade could decrease invasion and metastasis. For the second year of the grant, there has been an increased focus on the in vitro and in vivo effects of two specific antibodies that were generated., The original document contains color images.

The overall goal of this project is to validate novel targets and develop new antibody reagents for the diagnostic imaging and treatment of prostate cancer. N-cadherin is a cell surface marker that is overexpressed in hormone refractory prostate cancer which could have possible diagnostic or therapeutic utility. We observed that the cadherin profiles of certain prostate cancer cell lines and xenografts correlated with their level of invasiveness and that amongst certain hormone refractory xenograft models, there was a consistent upregulation of N-Cadherin when compared to its androgen dependent counterpart. We sought to validate N-Cadherin as a target in hormone refractory prostate cancer and determine if blockade of this pathway could decrease invasion and metastasis. We generated specific monoclonal antibodies against different domains to determine if blockade could decrease invasion and metastasis. Ongoing in vitro and in vivo studies will determine if this protein can be validated as an effective imaging and therapeutic target., The original document contains color images.

The goals of this proposal were to examine the clinical effectiveness of vitamin D analog therapy (l-alpha hydroxyvitamin D2 in patients with advanced androgen-independent prostate cancer. We performed a phase II study of l-alpha hydroxyvitamin D2 administered daily at doses from 12.5 to 5.0 ug/day and examined various laboratory correlative studies for any correlation with outcome. Daily administration of l-alpha hydroxyvitamin D2 was well tolerated with occasional grade 1 and rare grade 2 hypercalcemia. No objective tumor responses were observed but 6 out of 20 evaluable patients had stable disease for greater than or less than 6 months. Treatment with 1-alpha hydroxyvitamin D2 was associated with decreased serum PTH levels and increased urine calcium levels. Plasma TGF-beta-1 levels and T cell receptor zeta chain analysis in peripheral T cells did not correlate with clinical outcome as related to vitamin D-based therapy. These findings support further study of the potential clinical effectiveness of vitamin D-based therapies in advanced prostate cancer.