A phase 2 trial of abiraterone acetate without glucocorticoids for men with metastatic castration-resistant prostate cancer

BACKGROUND:Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer. METHODS:Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS:A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade ≥3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of ≥50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity. CONCLUSIONS:Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring.Rana R. McKay, Lillian Werner, Susanna J. Jacobus, Alexandra Jones, Elahe A. Mostaghel, Brett T. Marck ... et al

RNA Based Approaches to Profile Oncogenic Pathways From Low Quantity Samples to Drive Precision Oncology Strategies

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling pathways simultaneously and quantitatively with high resolution in tissue samples and circulating tumor cells, specifically with very small specimen quantities. The approach uses mRNA levels of a pathway's direct target genes, selected based on literature for multiple proof points, and used as evidence that a pathway is functionally activated. Using these validated target genes, a Bayesian network model has been built and calibrated on mRNA measurements of samples with known pathway status, which is used next to calculate a pathway activity score on individual test samples. Translation to RT-qPCR assays enables broad clinical diagnostic applications, including small analytes. A large number of cancer samples have been analyzed across a variety of cancer histologies and benchmarked across normal controls. Assays have been used to characterize cell types in the cancer cell microenvironment, including immune cells in which activated and immunotolerant states can be distinguished. Results support the expectation that the assays provide information on cancer driving signaling pathways which is difficult to derive from next generation DNA sequencing analysis. Current clinical oncology applications have been complementary to genomic mutation analysis to improve precision medicine: (1) prediction of response and resistance to various therapies, especially targeted therapy and immunotherapy; (2) assessment and monitoring of therapy efficacy; (3) prediction of invasive cancer cell behavior and prognosis; (4) measurement of circulating tumor cells. Preclinical oncology applications lie in a better understanding of cancer behavior across cancer types, and in development of a pathophysiology-based cancer classification for development of novel therapies and precision medicine

Anti-Tumor Efficacy of Gene Vaccine Expressing PSMA

OBJECTIVE To observe anti-tumor effects of PVAX-PSMA gene vaccine. METHODS The PSMA gene was inserted into a mammalian expression vector, PVAX-1, to construct the DNA vaccine candidate, and was then used to vaccinate C57BL/6 mice. Animals vaccinated with PVAX-1 and NaCl were used as controls. Anti-PSMA antibody was detected in sera of the animals. The proliferation and cytotoxicity of the spleen cells were observed. The immunized mice were inoculated with RM-1 cells. The mice were inoculated with RM-1 cells, and then the mice were immunized. The anti-tumor efficacy of the gene vaccine was evaluated by the ratio of tumor formation, tumor volume, tumor mass before and a er gene vaccination and evaluated by survival rate of the immunized mice.RESULTS High level of anti-PSMA antibody was induced in the PVAX-PSMA group. The splenocytes from PVAX-PSMA group were stimulated to produce strong proliferation responses and significant cytotoxic T-cells (CTL) activity. After the mice were immunized with PVAX-PSMA gene, tumor occurrence was decreased, and the growth velocity of tumor was markedly reduced, resulting in prolonged tumor-free time (P < 0.05).CONCLUSION PVAX-PSMA gene vaccine has significant anti- tumor effects and provides an experimental basis for primary prevention and immunotherapy of prostate cancer

Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen

Thomsen-Friedenreich (TF) antigen, which plays an important role in the regulation of cancer cell proliferation, occurs in ∼90% of all human cancers and precancerous conditions. Although TF antigen has been known for almost 80 yr as a pancarcinoma antigen, the recognition mechanism between TF antigen and target protein has not been structurally characterized. A number of studies indicated that TF disaccharide is a potential ligand of the galactoside-binding galectins. In this work, we identified the TF antigen as a potential ligand of the antitumor galectin AAL (Agrocybe aegerita lectin) through glycan array analysis and reported the crystal structure of AAL complexed with the TF antigen. The structure provides a first look at the recognition mode between AAL and TF antigen, which is unique in a conservative (Glu-water-Arg-water) structural motif-based hydrogen bond network. Structure-based mutagenesis analysis further revealed the residues responsible for recognition specificity and binding affinity. Crystal structures of AAL complexed with two other TF-containing glycans showed that the unique TF recognition mode is kept intact, which may be commonly adopted in some cancer-related galectins. The finding provided the new target and approach for the antitumor drug design and relative strategy based on the AAL-TF recognition mode as a prototype model.—Feng, L., Sun, H., Zhang, Y., Li, D.-F., Wang, D.-C. Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen

Castration-resistant prostate cancer: new science and therapeutic prospects

There is a growing number of new therapies targeting different pathways that will revolutionize patient management strategies in castration-resistant prostate cancer (CRPC) patients. Today there are more clinical trial options for CRPC treatment than ever before, and there are many promising agents in late-stage clinical testing. The hypothesis that CRPC frequently remains driven by a ligand-activated androgen receptor (AR) and that CRPC tissues exhibit substantial residual androgen levels despite gonadotropin-releasing hormone therapy, has led to the evaluation of new oral compounds such as abiraterone and MDV 3100. Their results, coupled with promising recent findings in immunotherapy (eg sipuleucel-T) and with agents targeting angiogenesis (while awaiting the final results of the CALGB trial 90401) will most probably impact the management of patients with CRPC in the near future. Other new promising agents need further development. With our increased understanding of the biology of this disease, further trial design should incorporate improved patient selection so that patient populations are those who may be most likely to benefit from treatment