Therapy For Metastatic Prostate Cancer Research Articles

Treating people right: Who goes untreated with systemic therapy for metastatic prostate cancer (mPC)?

125 Background: We investigated the use of systemic therapies (androgen deprivation therapy and chemotherapy) for men with mPC in the community, comparing those treated and untreated. Methods: 8,295 men diagnosed with mPC at presentation from the 2000-05 Surveillance, Epidemiology, and End Results (SEER) database were linked to Medicare claims. We excluded those diagnosed with other primary malignancies, disenrolling from Medicare Parts A or B (n=3,293), or who died within 1 month of diagnosis (n=468), leaving 4,534 patients. Treatment, service use and comorbidities were measured in Medicare claims, demographic and clinical data in SEER. We compared characteristics of patients by treatment group using univariate and logistic regression to estimate the predicted probability of receiving systemic therapies for black and nonblack patients. Differences across hospital service areas (HSAs) were computed, using logistic regression to adjust for demographic and clinical characteristics. Results: 3,657 patients (80.7%) received systemic therapy and 877 (19.3%) did not. Mean time to systemic treatment was 2.5 months. Follow up was 28.8 months for the treated, 19.2 months for the untreated. Among the treated, 20.4% received ADT and chemotherapy, 78.3% ADT only and 1.3% chemo only. Untreated patients were statistically older (78.6 versus 77.3 years), less likely to be married (48% versus 61%), and more likely residents of lower income areas and black race (26% versus 13%). The two groups scored similarly on a comorbidity index (0.51 versus 0.43). The model predicted a 66% probability of receiving systemic treatment for blacks versus 82% for whites, controlling for other factors. Systemic treatment use varied across regions from 62% to 94%. There was an 8-14% greater likelihood of receiving systemic treatment for men living in above versus below median regions. Conclusions: One in 5 men with mPC in this sample survived long enough to be treated systemically, yet was not. Untreated men with mPC are more likely to be black, unmarried and reside in low income areas, raising concerns for equal access to treatment. Some regions are better at initiating systemic treatment for men with mPC than others.

Abstract B68: The microenvironment decides how prostate tumors respond to castration treatment

Abstract Although androgen deprivation is the standard therapy for metastatic prostate cancer the mechanisms for the initial response and subsequent relapse are largely unknown. The stroma and vasculature are necessary for castration-induced involution of the normal prostate, and androgen-independent tumors respond to castration when surrounded by normal prostate tissue. This suggests that the microenvironment is highly important for the therapeutic effect of castration. To further explore this, androgen-sensitive rat prostate tumor cells (Dunning G) were injected into the rat prostate and/or bone marrow (to simulate bone metastasis) and analyzed for response to castration. Tumors in the prostate responded well to castration with decreased tumor size, both in already established tumors and when tumor cells were injected in castrated animals. The size of bone metastases was, however, unaffected by castration. Both groups developed lung metastasis but castration tended to increase rather than decrease pulmonary tumor burden. To further explore the mechanisms behind this we have established in vitro cell lines from bone metastasis of both castrated and control rats. In our ongoing experiments we are examining if these cells are responsive to castration if instead placed within the prostate environment or if the resistance to therapy has become stable. The response to castration is also further explored in lung metastasis. Our results suggest that the metastatic environment is highly important for the establishment of castration resistant prostate cancer and that the mechanisms behind this need to be further explored. Citation Format: Sofia Halin Bergström, Stina Rudolfsson, Tove Dahl Scherdin, Anders Bergh. The microenvironment decides how prostate tumors respond to castration treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B68.

Abstract C13: Phase I trial of anti-PSMA designer T cells in advanced prostate cancer

Abstract Introduction: We created chimeric antigen receptors (CAR) specific for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” (dTc) specifically kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate 2004:61:12-25). A Phase I clinical trial was approved by the FDA under BB-IND 12084. With the recent publicity surrounding use of this technology to suppress and potentially cure CLL [Porter et al. NEJM 2011:365:725-33], the current aim to apply dTc in metastatic HRPC gains a heightened impetus and significance. Methods: Patient T cells are retrovirally transduced and expanded ex vivo to span the dose range of 10⁁9 to 10⁁11 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create a “hematologic space” into which dTc are infused for stable engraftment and improved in vivo efficacy. Patients are co-administered continuous infusion IL2. Patients are monitored for safety and response. Outcomes include Phase Ia goals of safety and toxicity and Phase Ib goals of establishing an optimal biologic dose in terms of dTc engraftment and tumor response. Results: To date five subjects have been treated, three at the 10⁁9 cell dose and two at the 10⁁10 cell dose. Excellent T cell modifications of 30-60% were obtained. After NMA conditioning, T cells were infused and stable engraft—ments of 1-20% were observed one-month post recovery, thus affirming one of the study end-points, even at the lowest 10⁁9 dose level, reflecting near 100-fold expansions of dTc in vivo. Two of five patients (40%) had PSA reductions of 50 and 70% in the two months following treatment, whereas four patients (80%) had delays in PSA progression of 2-5 months. Patients experienced neutropenia and lymphopenia after conditioning, but no designer T cell related toxicities. Patient treatments will continue under the dose escalation plan. Conclusion: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with exciting early results. We postulate that the greater potency of higher dTc doses under adequate IL2 support will induce PSA reductions of 100%, potentially with durable remissions of metastatic prostate cancer that is refractory to all other treatments. Patients are being actively recruited. For referrals, contact by phone: (401) 456-2507 or email: RDavies@rwmc.org. This clinical trial received partial funding from US Army/DOD. Preclinical work was supported by the Prostate Cancer Foundation. Note: This abstract was not presented at the conference because the presenter was unable to attend. Citation Format: Richard P. Junghans, Qiangzhong Ma, Ritesh Rathore, Robin Davies, Anthony Bais, Erica Gomes, Ryan Harvey, Steven I. Cohen. Phase I trial of anti-PSMA designer T cells in advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C13.

Abstract A3: A tumorgraft model of castration-resistant primary prostate cancer

Abstract Androgen receptor (AR) signaling plays a central role in all stages of prostate cancer (PCa). Androgen deprivation therapy (ADT) is used as adjuvant therapy for high-risk PCa as well as the first-line therapy for metastatic PCa. However, tumor remissions are temporary and patients almost inevitably progress to become castration resistant prostate cancer (CRPC). Most CRPC still expresses AR and depends on AR for growth, therefore, there is an urgent need to understand the regulation of AR expression and to find novel ways of inhibiting this pathway in CRPC. We developed a novel realistic model for primary CRPC by establishing tumorgrafts with thin, precision-cut tissue slices derived from high-grade primary PCa under the renal capsule of immunodeficient mice supplemented with subcutaneous testosterone pellets. One month after the implantation, the testosterones pellets were removed and the mice were castrated. Tumorgrafts from control and castrated mice were harvested one month after castration and fixed in formalin. Immunohistochemistry was performed to examine the expression of genes of interest in the grafts. Tumorgrafts derived from high-grade primary PCa resemble the original tumors in expression of all genes examined. Specifically, they are positive for AR, prostate specific antigen (PSA), cytokeratin 18, and AMCAR, but negative for p63. After castration, cancer cells remained in grafts derived from two of four tumors, whereas cancer cells in grafts derived from the other two tumors were almost completely eliminated, suggesting that some tumors respond to androgen deprivation therapy (ADT) better than the others. In the castration-resistant tumorgrafts (CRTs), PSA expression was diminished in cancer cells, but AR and cytokeratin 18 expression remained, similar to responses of human prostate to ADT. In addition, cancer cells in CRTs were less proliferative than in control grafts as determined by Ki67 staining consistent with the observation that ADT inhibit cell proliferation in human prostate. More importantly, CRTs expressed AR target genes that have been reported to be upregulated under androgen ablation in other experimental models. For example, the number of cyclin A-expressing cells was significantly higher in CRTs than in control grafts. Our results demonstrated that our novel CRT model has the appropriate characteristics to serve as a useful tool to model primary CRPC. Our results demonstrated that our novel CRT model has the appropriate characteristics to serve as a useful tool to model primary CRPC and may be used as a surrogate model for clinical trials to achieve rapid and less expressive screening of therapeutic agents for neoadjuvant or adjuvant therapy of PCa. Citation Format: Hongjuan Zhao, Alan Thong, Rosie Nolley, Stephen Reese, Jennifer Santos, Donna Peehl. A tumorgraft model of castrationresistant primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A3.

Treatment of prostate carcinoma with (Galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates

Galectin-3 (Gal-3), over-expressed on a variety of human tumor cells, is a potential binding site for targeted metastatic prostate cancer therapy. The aim of this study was to develop a G3-C12-mediated drug delivery system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers targeting to Gal-3-expressed human PC-3 prostate carcinoma cells. 5-Fluorouracil (5-Fu), an anti-tumor agent, was selected as a model drug. G3-C12, a binding peptide, which specifically binds to the carbohydrate-recognition domain (CRD) of Gal-3, was attached to HPMA copolymers as a targeting moiety. Compared with non-targeted conjugates (P-Fu), Gal-3-targeted HPMA copolymer-(G3-C12)-5-Fu conjugates (P-(G3-C12)-Fu) displayed a superior intracellular internalization followed by enhanced cytotoxicity and apoptosis-induction. Subsequently, the in vitro migration study on PC-3 cells indicated that P-(G3-C12)-Fu was able to efficiently inhibit the cell migration ability after wounding. On PC-3 tumor-bearing mice model, G3-C12-modified copolymers showed a higher tumor accumulation coupled with a faster clearance from blood circulation than non-modified ones. Finally, Gal-3-targeted conjugates significantly improved the anti-tumor activity of 5-Fu in nude mice bearing PC-3 tumor xenografts. Consequently, G3-C12 would be a promising targeting moiety for cell-specific prostate cancer therapy in future.

Dimethyl Sulfoxide–Sodium Bicarbonate Infusion for Palliative Care and Pain Relief in Patients With Metastatic Prostate Cancer

ABSTRACTProstate cancer (adenocarcinoma of the prostate) is the most widespread cancer in men. It causes significant suffering and mortality due to metastatic disease. The main therapy for metastatic prostate cancer (MPC) includes androgen manipulation, chemotherapy, and radiotherapy and/or radioisotopes. However, these therapeutic approaches are considered palliative at this stage, and their significant side effects can cause further decline in patients’ quality of life and increase non–cancer-related morbidity/mortality. In this study, the authors have used the infusion of dimethyl sulfoxide–sodium bicarbonate (DMSO-SB) to treat 18 patients with MPC. The 90-day follow-up of the patients having undergone the proposed therapeutic regimen showed significant improvement in clinical symptoms, blood and biochemistry tests, and quality of life. There were no major side effects from the treatment. In searching for new and better methods for palliative treatment and pain relief, this study strongly suggested therapy with DMSO-SB infusions could provide a rational alternative to conventional treatment for patients with MPC.

Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer

ObjectivesTo analyze the predictive value of PSA for progression and the role of testosterone for quality of life (QOL) in patients with androgen deprivation therapy (ADT) for metastatic prostate cancer. Materials and methodsPSA and testosterone data were used from a phase III trial randomizing patients without progression and PSA < 4 ng/ml (n = 193), after 6 months induction course, between continuous (CAD) (n = 96) and intermittent (IAD) (n = 97) ADT. The 2-year risk of progression was calculated for baseline PSA, ‘fast’ and ‘slow’ PSA decline to < 4 ng/ml (60 days cut-off), PSA nadir, performance status and pain. Testosterone kinetics and QOL were also evaluated. Univariate Kaplan Meier survival analysis and log rank tests were used to compare the risk of progression. ResultsFor progression analysis, 173 patients' data were available. The 2-year risk of progression for baseline PSA < 50 ng/ml, 50 to <500 ng/ml, and ≥500 ng/ml was 25%, 55%, and 76% (P = 0.03) in CAD, and 38%, 64%, and 85% (P = 0.006) in IAD, respectively. The 2-year risk of progression for PSA nadir ≤ 0.2 ng/ml, and > 0.2 to 4 ng/ml in CAD was 31% and 70% (P < 0.001), respectively. In the IAD group, a similar trend was seen. Patients with PSA nadir ≤ 0.2 ng/ml, though had significantly higher 2-year risk of progression compared to CAD (53% vs. 31% (P = 0.03), respectively. PSA decline showed no predictive value. Patients without pain had a significantly lower 2-year risk of progression in both groups. Without ADT testosterone remained at castrate level for 4 months. After the first and second IAD cycle 92% and 46%, respectively, had a normalized testosterone. No QOL difference was found, although more side effects occurred in CAD. ConclusionsMetastatic prostate cancer patients with high baseline PSA, pain, and high PSA nadir have a poor prognosis with ADT. Patients with low PSA nadir do significantly worse with IAD compared with CAD. Low testosterone after ADT and incomplete testosterone recovery may explain similar QOL. Therefore, IAD is not a good treatment option for many metastatic prostate cancer patients.

Phase I trial of anti-PSMA designer T cells in advanced prostate cancer.

130 Background: We created chimeric immunoglobulin-T cell receptors (IgTCR) specific for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” (dTc) specifically kill prostate cancer cells in vitro and in vivo in animal models, with 5/9 (55%) of xenografted mice experiencing complete remissions (Ma et al. Prostate 2004:61:12–25). A phase I clinical trial was approved by the FDA. Methods: Patient T cells are retrovirally transduced and expanded ex vivo to span dose levels of 10^9 to 10^11 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create “hematologic space” into which designer T cells are infused for stable engraftment and prolonged in vivo efficacy. Patients are co-administered continuous infusion IL2. Outcomes include Phase Ia goals of safety and Phase Ib goals of establishing an optimal biologic dose in terms of designer T cell engraftment. Results: Five patients have been treated, three at 10^9 and two at 10^10 cell dose levels. Excellent T cell modifications of 30%-60% were obtained. After NMA conditioning, T cells were infused. Stable engraftments of 1%-20% post-recovery at one month after T cell infusion, thus affirming one of the study end-points. Patients experienced neutropenic fever after conditioning, but no designer T cell-related toxicities. Two patients had partial responses with PSA reductions of 50 and 70% in the two months following treatment with projected benefits of 4 months gain of time to return to starting PSA levels. Results will be updated at the conference. Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. Patients are being actively recruited. This clinical trial received partial funding from the US Army/DOD. Preclinical work was supported by the Prostate Cancer Foundation. No significant financial relationships to disclose.

Response to degarelix after resistance to luteinizing hormone–releasing hormone agonist therapy for metastatic prostate cancer

Androgen deprivation with a luteinizing hormone-releasing hormone (LH-RH) agonist is the standard treatment for patients with metastatic prostate cancer who prefer nonsurgical options. Therapy with these agents is usually successful in achieving and maintaining castrate levels (< 50 ng/dl) of serum testosterone, but failures have been reported in up to 10% of patients. Traditionally, these patients are offered surgical castration with bilateral orchiectomy. However, the novel LH-RH antagonists may offer a nonsurgical alternative. We describe two patients with advanced prostate cancer who failed to achieve castrate levels of testosterone while on an LH-RH agonist, but subsequently responded to the LH-RH antagonist, degarelix. The first patient is a 63-year-old man who was treated with leuprolide for metastatic prostate cancer. He initially responded with prostate-specific antigen (PSA) that fell to 0.6 ng/ml. However, after 15 months of therapy, his PSA rose to 18.3 ng/ml and his testosterone was noted to be 208 ng/dl. He was switched to degarelix, and 4 weeks later his testosterone was adequately suppressed at 16 ng/dl. The second patient is a 41-year-old man with metastatic prostate cancer who was started on leuprolide, but after 3 months of therapy, was found to have a rising PSA and a testosterone of 96 ng/dl. Four weeks after switching to degarelix, his testosterone was 18 ng/dl and his PSA decreased concordantly. With continued monthly injections of degarelix, his testosterone has consistently remained to be at less than 20 ng/dl over 7 months of follow-up.

Controversies about Hormonal Therapy for Metastatic Prostate Cancer

Controversies about Hormonal Therapy for Metastatic Prostate Cancer

Hormonal Therapy in Metastatic Prostate Cancer

Hormonal Therapy in Metastatic Prostate Cancer

Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer

Androgen ablation is highly effective palliative therapy for metastatic prostate cancer but eventually all men relapse. New findings demonstrating that androgen receptor (AR) expression continues in androgen ablated patients has resulted in the classification "Castration Resistant Prostate Cancer" (CRPC) and has led to the development of new second-line "anti-ligand" hormonal agents. In this background is the paradoxical observation that the growth of some AR-expressing "androgen sensitive" human prostate cancer cells can be inhibited by supraphysiologic levels of androgens. This response may be due to effects of high-dose androgen on inhibiting re-licensing of DNA in cells expressing high levels of AR. It may also be due to recently described effects of androgen in inducing double strand DNA breaks. Based on available preclinical data described in this review demonstrating the effects of supraphysiologic levels of testosterone on inhibition of growth of CRPC xenografts, we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel-based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy. This "bipolar androgen therapy" will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions. The goal is to determine if a clinical response can be achieved through this non-adaptive rapid cycling approach in men with CRPC.

New frontiers in therapy for metastatic prostate cancer

New frontiers in therapy for metastatic prostate cancer

Bone-targeted therapy in metastatic prostate cancer: osteoclast inhibitors and bone-seeking radiopharmaceuticals

Metastatic prostate cancer has a tropism for bone and often spares soft tissues. Drugs that target the bone have a unique niche in metastatic prostate cancer. A variety of pharmaceutical agents have been investigated in this disease with endpoints including pain, skeletal related events, and overall survival. Herein we focus on two broad classes: osteoclast inhibitors, such as bisphosphonates and antibodies to receptor activator of nuclear factor-κβ ligand; and bone-seeking radiopharmaceuticals, such as strontium-89 chloride, samarium-153 lexidronam, and radium-223 chloride. Pertinent clinical trials as well as currently ongoing trials will be reviewed.

Phase I trial of anti-PSMA designer T cells in advanced prostate cancer.

e13614 Background: We created chimeric immunoglobulin-T cell receptors (IgTCR) specific for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” specifically kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate 2004:61:12-25). A phase I clinical trial was approved by the FDA in metastatic prostate cancers. Methods: Patient T cells are retrovirally transduced and expanded ex vivo to span dose levels of 10^9 to 10^11 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create a “hematologic space” into which the designer T cells are infused to expand and stably engraft for prolonged in vivo efficacy. Patients are co-administered continuous infusion outpatient IL2 at 75,000 IU/kg/d ×28d. Outcomes include phase Ia goals of safety and toxicity and phase Ib goals of establishing an optimal biologic dose in terms of designer T cell engraftment and tumor response. Results: Three patients were treated at the 10^9 cell dose and one at the 10^10 cell dose. All patients experienced neutropenia and fever post conditioning, but no designer T cell-related toxicities. T cells were infused and engraftments of 1-20% were observed one-month post recovery, thus affirming one of the study end-points. Two patients (both at the 10^9 cell level) had PSA reductions of 50 and 70% in the two months following treatment, whereas two had no response (<20%) (one at 10^9 and one at 10^10 cells). Systemic IL2 was more than 10-fold lower in the two non-responders than in the two responders (2 IU/ml versus 30 IU/ml), suggesting need for adequate IL2 to realize designer T cell therapeutic activity. Patient enrollments are ongoing; data will be updated at conference time. Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. Patients are being actively recruited. This clinical trial received partial funding from the US Army/DOD. No significant financial relationships to disclose.

Trends and racial differences in the use of androgen deprivation therapy for metastatic prostate cancer.

Androgen deprivation therapy (ADT) is widely used to manage the symptoms of advanced prostate cancer and has been shown to slow the progression of the disease. Previous research investigating racial differences in the use of ADT has reported inconsistent findings. The purpose of this study was to assess use trends for ADT overall and by type (orchiectomy and luteinizing hormone-releasing hormone [LHRH] agonists) and the factors associated with time to receipt for metastatic prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and Medicare claims database were obtained for 5,273 men, aged 65 years and older and diagnosed with Stage IV prostate cancer during 1991-1999 from seven SEER regions. An accelerated failure time regression model with log-normal distribution was used to examine factors associated with mean time to receipt of ADT. African-American men were less likely than white men to receive any ADT after diagnosis (P<0.001). Differences were noted in the time to receipt of ADT, with African-American men having a longer mean time to receipt of orchiectomy (time ratio [TR]=1.50; 95% confidence interval [CI]=1.03, 2.17) or LHRH agonist (TR=1.42; 95% CI=1.06, 1.89) than white men. African-American men with metastatic prostate cancer were significantly less likely to receive ADT and, when treated, had a slightly longer time to receipt than white men, which has implications for patients and physicians involved in the palliative management of metastatic prostate cancer.

Abstract 2404: A DNA vaccine encoding the androgen receptor ligand binding domain elicits anti-tumor immune responses in vivo

Abstract The androgen receptor (AR) is a nuclear receptor that plays a critical role in both androgen-dependent and -independent prostate cancer, and remains the primary target of therapy for metastatic prostate cancer. We have shown that the AR may be a potential immunological target antigen, identifying some prostate cancer patients that have concurrent antibody and cellular immune responses specific for the AR ligand-binding domain (LBD). We have also identified that some patients have cytotoxic T lymphocytes (CTL) that are specific for ARLBD-derived HLA-A2 epitopes, some of which can lyse prostate tumor cell lines. Moreover, we demonstrated that these epitope-specific CTL could be elicited in HLA-A2 transgenic mice by means of a DNA vaccine encoding the ARLBD (pTVG-AR). In this report, we sought to evaluate whether this DNA vaccine could elicit anti-prostate tumor responses in relevant rodent models in which the ARLBD is expressed as a “self” antigen. First, Copenhagen rats immunized with the pTVG-AR vaccine four to six times at 14-day intervals were challenged with a syngeneic prostate tumor cell line subcutaneously implanted. These animals were found to develop T-cell responses specific for the ARLBD and have a significant delay in tumor growth compared with control vaccinated animals (p=0.018). In a separate autochthonous model, HLA-A2 transgenic mice were crossed with TRAMP mice and the resulting transgenic hybrid (A2/TRAMP) expressed HLA-A2 and developed prostate tumors driven by the SV40 large T antigen under a prostate-specific promoter. A2/TRAMP mice were similarly immunized with pTVG-AR, or control vector, at 14-day intervals and evaluated at 16 weeks of age. Mice immunized with pTVG-AR were found to develop HLA-A2 epitope-specific CD8+ T cell responses, and had fewer well-differentiated adenocarcinomas compared with control immunized mice. Finally, A2/TRAMP mice were immunized repetitively over time and followed for survival. Mice immunized with pTVG-AR (n=8) had a median survival of 218 days, compared with a median survival of 198 days for control (n=7) immunized animals (p=0.040, log-rank test). These combined data show that not only can the ARLBD be safely targeted in vivo (none of the immunized animals had any sign of autoimmunity or overt toxicity), but more significantly that vaccines targeting the ARLBD can elicit an anti-prostate tumor responses in separate animal models. These findings suggest that the ARLBD is a potentially attractive immunological target antigen for the treatment of human prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2404.

Schedule treatment design and quantitative in vitro evaluation of chemotherapeutic combinations for metastatic prostate cancer therapy

Preclinical evaluation is essential for a rational design of combination chemotherapy as some agents, with known mechanisms of action and non-overlapping toxicities may increase the therapeutic index of anticancer drugs, whose clinical success is hindered by side effects and drug resistance. The present study investigated new drug combinations with potential outcome for the treatment of metastatic prostate cancer. This final clinical stage exhibits predominantly hormone-refractory prostate cancer (HRPC) cells but also a minority of hormone responsive cells. Growth inhibition activity of simultaneous and sequential combinations was evaluated by resazurin assay. In vitro evaluation of synergism, additivity, or antagonism, against prostate cancer cell lines, was performed by the median effect analysis. The importance of dosage, exposure time, drug ratio, and type of treatment were investigated and compared. Most simultaneous combinations of two drugs with different mechanisms of action or of two topoisomerase II inhibitors resulted in mild antagonism of antiproliferative effects, particularly notorious at high cell death. Imatinib-mitoxantrone and ciprofloxacin-etoposide combinations were exceptions, as they yielded additivity and dose reduction index (DRI) values of 2.6 and 3.5-fold for mitoxantrone and etoposide, respectively. Sequential combinations (ciprofloxacin or imatinib pre-treatment) revealed additive growth inhibition effects, translated in much higher DRI values (from 7.0 to 15.3-fold). Moderate synergism was restricted to sequential ciprofloxacin combinations at high cell death. Ciprofloxacin and imatinib significantly improve growth inhibition activity of standard antineoplastic drugs in a schedule-dependent manner and, therefore, may have an important role as adjuvant therapeutic agents in a clinical setting.

Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer

Prostate cancer is one of the most prevalent cancers in men. Replication-competent oncolytic herpes simplex virus (oHSV) vectors are a powerful antitumor therapy that can exert at least two effects: direct cytocidal activity that selectively kills cancer cells and induction of antitumor immunity. In addition, oHSV vectors can also function as a platform to deliver transgenes of interest. In these studies, we have examined the expression of a xenogeneic homologue of the prostate cancer antigen, prostatic acid phosphatase (PAP), with the goal of enhancing virotherapy against PAP-expressing tumors. PAP has already been used for cancer vaccination in patients with prostate cancer. Here we show that treatment with oHSV bPDelta6 expressing xenogeneic human PAP (hPAP) significantly reduces tumor growth and increases survival of C57/BL6 mice bearing mouse TRAMP-C2 prostate tumors, whereas expression of syngeneic mouse PAP (mPAP) from the same oHSV vector did not enhance antitumor activity. Treatment of mice bearing metastatic TRAMP-C2 lung tumors with oHSV-expressing hPAP resulted in fewer tumor nodules. To our knowledge, this is the first report of oncolytic viruses being used to express xenoantigens. These data lend support to the concept of combining oncolytic and immunogenic therapies as a way to improve therapy of metastatic prostate cancer.

Trends and Racial Differences in the Use of Androgen Deprivation Therapy for Metastatic Prostate Cancer

Trends and Racial Differences in the Use of Androgen Deprivation Therapy for Metastatic Prostate Cancer