Cognitive Impairments Associated with Prostate Cancer and Androgen Deprivation Therapy in Aged Male Copenhagen Rats

Abstract ID 129870 Poster Board 338 Androgen deprivation therapy (ADT) is a mainstay treatment for late-stage prostate cancer. However, ADT induces cognitive impairment in over half of patients receiving treatment and increases the likelihood of the onset of Alzheimer's Disease or other dementia. Unfortunately, few options exist to prevent or treat these impairments. The clinical literature indicates that ADT-induced impairments typically occur in the cognitive domains of spatial memory and executive function, which are associated with the function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC), respectively. We have shown previously that ADT also induced impairments in spatial memory and executive function in healthy male Sprague-Dawley rats. However, cancer pathophysiology may also contribute to cognitive dysfunction. Thus, in the current study, we aim to develop a rodent model of cognitive impairment attributable to prostate cancer and/or ADT treatment using male Copenhagen rats implanted orthotopically (s.c.) with syngeneic prostate tumors derived from Dunning R3327-G rat prostate cancer cells. Our hypothesis is that both the presence of the cancer itself and ADT treatment will produce cognitive deficits, with the largest effects seen in the combined cancer plus ADT group. As the average age of onset in prostate cancer patients is approximately 65 years, we used 14- to 18-month-old Copenhagen rats. Tumor fragments were implanted subcutaneously on the flank. After 3-4 weeks, tumors were palpable at approximately 1 cm3, at which time the tumor-bearing and sham-implanted rats were treated with the GnRH antagonist degarelix (3 mg/kg, s.c.) for ADT, or vehicle (5% mannitol). Behavioral tests were conducted starting 21 days after the onset of ADT. DGX treatment reduced plasma testosterone to below detection and suppressed tumor growth compared to vehicle controls (p = 0.002; n = 12-15/group). Preliminary results (n = 9-11/group) indicate that the presence of tumor alone significantly impaired cognitive set-shifting, an executive function mediated in the mPFC (p=0.02). The effect of ADT alone is trending toward a similar deficit (p=0.11). Preliminary data also indicate a trend toward a deficit in the Novel Object Location Test, a measure of spatial memory mediated in the hippocampus, in all treatment groups (p=0.16; 7-15/group). Measures of locomotion and anxiety were unchanged. Analyses of neuroinflammatory signaling and neuropathology markers in hippocampus and mPFC are ongoing. Establishing this tumor model will allow us to test new potential therapeutics to treat or prevent cognitive deficits caused by cancer and ADT, while monitoring tumor growth to ensure they do not interfere with the effectiveness of cancer treatment. For example, previous data collected in healthy Sprague-Dawley rats suggested that vortioxetine may be effective in alleviating ADT-induced cognitive impairments. We will now test vortioxetine in Copenhagen rats with prostate tumors. Supported by NIH/NCI grant CA173213