Search

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: ARN-509 is a second-generation antiandrogen with antitumor activity in CRPC. Activating mutations in the AR ligand-binding domain (LBD) have been associated with resistance to first- (T877A) and second- (F876L) generation antiandrogens. We evaluated the type and frequency of relevant AR LBD mutations in ARN-509-treated CRPC pts at baseline (BL) and disease progression (PD). Methods: ARN-509-001 was a phase I/II study that evaluated ARN-509 activity in nonmetastatic (M0), chemotherapy-naive, and post-AA CRPC. Of the 97 pts enrolled in phase II at a dose of 240 mg/d, 92 were evaluable for the mutation analysis at BL and 82 at PD. Relevant mutations in circulating tumor DNA were detected using a digital PCR method called BEAMing (Beads, Emulsification, Amplification, and Magnetics) (Richardson AL. Clin Cancer Res. 2012). Results: Median duration of therapy was ∼16 months. One pt in the M0 cohort and one in the chemotherapy-naive cohort had the F876L mutation at BL. Two pts in the chemotherapy-naive cohort and one in the post-AA cohort acquired the AR F876L mutation during treatment. Pts with M0 CRPC did not acquire a mutation (Table 1). Three pts in the post-AA cohort had the T877A mutation at BL; the T877A mutation was not detected in any other cohort at BL. In the post-AA cohort, one pt acquired the T877A mutation during treatment while another lost the mutation (Table). The two pts with detectable F876L at BL developed prostate-specific antigen (PSA) progression at 4 and 6 months, respectively, compared with a median time to PSA progression of 16.4 months in the remainder of pts. Conclusions: Pts with metastatic CRPC who were treated with ARN-509 had a low rate of acquisition of the AR F876L (3/82 = 4%) and AR T877A (1/82 = 1%) mutations. These results suggest that ARN-509 may be continued in the setting of a rising PSA. Larger studies are needed to confirm the prevalence of F876L, T877A, and the conversion rate. | | | AR F876L | AR T877A | |:------------------ | --------- | -------- | -------- | -------- | | | Evaluable | BL | PD | Acquired | BL | PD | Acquired | | | patients | n/N | n/N | | n/N | n/N | | | Total | 92 | 2/92 | 5/82 | 3/82 | 3/92 | 3/82 | 1/82 | | M0 | 49 | 1/49 | 1/47 | 0/47 | 0/50 | 0/47 | 0/47 | | Chemotherapy-naive | 24 | 1/24 | 3/20 | 2/20 | 0/20 | 0/20 | 0/20 | | Post-AA | 19 | 0/19 | 1/15 | 1/15 | 3/19 | 3/15 | 1/15 | Citation Format: Dana E. Rathkopf, Matthew R. Smith, Emmanuel S. Antonarakis, Charles J. Ryan, William R. Berry, Neal D. Shore, Glenn Liu, Celestia Higano, Joshi J. Alumkal, Ralph Hauke, Ronald Tutrone, Mansoor Saleh, Edna Chow Maneval, Shibu Thomas, Deborah Ricci, Margaret K. Yu, Carla J. de Boer, Angela Trinh, Thian Kheoh, Rajesh Bandekar, Howard I. Scher. Androgen receptor (AR) mutations in patients (pts) with castration-resistant prostate cancer (CRPC) with and without prior abiraterone acetate (AA) treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT134. doi:10.1158/1538-7445.AM2015-CT134

Background: ARN-509 is a novel second-generation antiandrogen that binds directly to the ligand-binding domain of the androgen receptor (AR), impairing AR nuclear translocation and DNA binding to the androgen response element. Phase 2 of a multicenter phase 1/2 study evaluates ARN-509 activity in 3 distinct patient populations of men with CRPC: 1) nonmetastatic chemotherapy-naive CRPC; 2) chemotherapy-naïve mCRPC; 3) mCRPC post-AA treatment. Study ARN-509-001 is the first to prospectively examine response to novel second-generation antiandrogens post-AA treatment. We present the results of the post-AA treated cohort, as of July 2013. Methods: All patients had mCRPC with progressive disease based on rising prostate-specific antigen (PSA) and/or imaging. No prior chemotherapy for CRPC was allowed. Patients in the AA-pretreated cohort had to have been treated with AA for at least 6 months. All patients received ARN-509 at the recommended phase 2 dose of 240 mg/d (Rathkopf et al. J Clin Oncol. 2013). The primary end point was PSA response at 12 weeks according to the Prostate Cancer Working Group 2 criteria. Secondary end points included safety, time to PSA progression, and objective response rates. PSA assessments were collected every 4 weeks and tumor imaging was performed every 12 weeks. Results: By July 2013, 21 patients were enrolled and treated in the post-AA cohort. The median age was 67 years (range 48-83). At baseline, 62% of patients had an Eastern Cooperative Oncology Group performance status 0, and 29% had a Gleason score ≥ 8; median PSA was 58.4 ng/mL. Median duration on ARN-509 treatment post AA was 5.6 months (range 1.9-16.7). At 12 weeks, 24% (5/21) of patients had ≥ 50% decline in PSA from baseline. Median time to PSA progression was 16 weeks (95% confidence interval, 12-31 weeks). The best objective response was stable disease in 4 (36%) patients. Patients discontinued the study due to disease progression (n = 13), adverse events (n = 2), consent withdrawn (n = 1), and other reasons (n = 4). The most common treatment-related adverse events were fatigue (n = 11), nausea (n = 5), and diarrhea (n = 3). Conclusions: In men with mCRPC, post-AA treatment, ARN-509 is safe and well tolerated, with modest activity in a subset of patients who develop resistance to AA. Clinical trial information: NCT01171898. Citation Format: Dana E. Rathkopf, Emmanuel S. Antonarakis, Neal D. Shore, Ronald Tutrone, Joshi J. Alumkal, Charles J. Ryan, Mansoor N. Saleh, Ralph J. Hauke, Rajesh Bandekar, Edna Chow Maneval, Carla de Boer, Mary Todd, Margaret K. Yu, Howard I. Scher. ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (AA). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT239. doi:10.1158/1538-7445.AM2014-CT239

Background: Renal cell carcinoma (RCC) is associated with mutation or loss of function of the von Hippel-Lindau gene resulting in hypoxia-inducible factor 1-alpha accumulation and production of growth factors involved in proliferation and angiogenesis. Radical nephrectomy remains the primary treatment option for two thirds of RCC patients who present with tumors confined to the kidney. However, approximately one half of patients will develop metastatic RCC. Treatment of RCC has been hampered by its resistance to most chemotherapy and hormonal therapy, although selected patients have long term remission from high dose of interleukin-2. Despite the recent availability of several active targeted agents in this disease, therapy is not curative. As a result, there is continued demand for improving therapy for metastatic disease to enhance both clinical benefits and patients overall survival. The EGF and IGF-1 pathways have been implicated as potential therapeutic targets in RCC. The objective of this study was to investigate the antitumor response to EGF and IGF inhibitors as a novel combination therapy in metastatic RCC. Methods: RCC cells lines (Caki-1 and Caki-2) were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, 72h, and 96h with different doses of EGFR (AG1478) and/or IGF-1R (AG1024) inhibitors (0-100 µM) given as single agent or in combination therapy. The epithelial cell proliferation was determined by AlamarBlue proliferation assay. Results: Both AG1478 and AG1024, given as single agent, decreased the epithelial cell proliferation of RCC human malignant cell lines (Caki-1 and Caki-2) (p Conclusions: These data suggest that both inhibitors exhibit a synergistic antitumor effect when given as combination therapy. This synergistic benefit exhibits an anti-proliferative and pro-apoptotic effects on RCC cell lines in vitro and warrants further investigation as a potential therapeutic approach for metastatic RCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2011-3602

Introduction and objective: Prostate cancer (CaP) remains a major concern of public health in the United States. Standard treatment already in clinical use has a high curability rate in patients diagnosed with localized and androgen-dependent CaP; however, the progression to hormone refractory CaP is associated with disease relapse and poor prognosis. Hence, it is important to discover a novel strategy to prevent progression of disease whilst minimizing toxicity. One such promising approach is the dietary administration of certain natural compounds such as RBAC, a rice bran carbohydrate extract hydrolyzed by Shiitake mushroom enzymes. Several experimental studies have shown that RBAC in vitro increases both susceptibility and sensitivity of many human malignant cells to undergo apoptosis and to respond to chemotherapeutic drugs. Furthermore, RBAC immunomodulates natural killer (NK) cells in vitro and in vivo and enhances plasma cytokine production and anti-tumor activity in an in vivo mouse model. The aim of this study was to investigate the direct anti-tumor activity of RBAC on CaP cell lines and its impact on cell proliferation, adhesion, and invasion. Methods: A panel of stromal and epithelial cell lines was used [Mesenchymal Stromal Cells (MSC) and CaP epithelial cell lines (PC3 and LNCaP)]. Cell lines were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, and 72h with different doses of RBAC (0-1000 µg/ml). The cell proliferation, adhesion, and invasion assays were determined by Trypan blue and AlamarBlue® proliferation assays, Cytotracker™ adhesion assay, and CytoSelect™ invasion assay, respectively. Results: RBAC significantly decreased the epithelial cell proliferation of MSC, and CaP human malignant cell lines (PC3 and LNCaP) (p Conclusions: These data suggest that RBAC exhibits an anti-proliferative and pro-apoptotic effects on CaP cell lines in vitro and might have therapeutic potential in advanced human CaP. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5662.

Pancreatic cancer (PC) has a dismal five-year survival rate of about 5%. MUC4 mucin is a large glycoprotein aberrantly expressed by PC cells. We have previously shown that MUC4 stabilizes the receptor tyrosine kinase HER-2. Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. It has previously been reported to repress the expression of MUC4 in cultured nasal polyp cells. However, its role in regulating MUC4 expression and PC cell behavior has not been examined. In the present study, we hypothesized that FP represses MUC4 expression in PC cells and thus could be useful in the treatment of PC. An in silico analysis of the MUC4 promoter revealed several glucocorticoid response elements (GREs) upstream of the transcription start site. Further, an analysis of glucocorticoid receptor α isoform (GRα) and MUC4 expression status revealed that PC cells express varying levels of the two genes. Based on MUC4 and GRα status, we chose four PC cell lines- Capan-1 (MUC4+,GRhigh), HPAF/CD18 (MUC4+,GRlow), ASPC-1 (MUC4-,GRhigh) and MiaPaca (MUC4-,GRlow) and examined the effect of FP treatment on MUC4 expression, intracellular signaling and cellular function. We also examined the effects of FP on the growth of subcutaneously implanted Capan-1 cells in SCID mice. FP repressed MUC4 expression in both the MUC4+ cells in a dose and time dependent manner. However, while a nearly 90% reduction of MUC4 was observed in Capan-1 cells within 24 hr, a Thus, we show for the first time that FP represses the transcription of MUC4 oncoprotein while upregulating HER-2 in PC cells, an effect proportional to the expression of GRα by the cells. Significantly, FP treatment decreased the expression of N-cadherin by GRαhigh cells, suggesting a possible role as an inhibitor of metastases in PC. The increased HER-2 together with downregulation of MUC4 could increase the accessibility of HER-2 for therapy with drugs like Trastuzumab and Lapatinib. FP also increased sensitivity to Docetaxel and 5-FU, suggesting its potential utility as a selective chemosensitizing agent in anti-cancer therapy. 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 722.