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INTRODUCTION AND OBJECTIVES:VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance. In xenograft mouse models of tax...

Understanding the mechanisms by which castration-resistant prostate cancer (CRPC) progresses provides an opportunity to identify novel therapeutic strategies to treat this disease. This understanding has led to approaches to attack prostate cancer's androgen axis in unique ways. This review will examine the classes of novel therapies for androgen axis blockade in CRPC, with a particular focus on the unique characteristics of drugs in various stages of clinical development.The success of abiraterone and enzalutamide has stimulated multiple investigations into novel approaches to attack the androgen-signaling pathway. Drugs under development include cytochrome P17 inhibitors with 17,20-lyase specificity, androgen receptor antagonists that are active against mutated and constitutively active splice variant forms of the protein, androgen receptor degraders, and bromodomain/bromodomain extra-terminal inhibitors that prevent chromatin binding of activated receptors. The clinical development of several of these experimental agents is reviewed.Given the unique mechanisms of action for drugs in development, and the possibility that the novel agents may be active in the setting of common resistance mechanisms, treatment options for patients are likely to expand greatly in the coming years. Future studies should prioritize combinations of agents with unique mechanisms of action to optimize outcomes for patients, and should rely on precision-medicine approaches to target known molecular alterations.

The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.

Marco Bianchi*, Alberto Briganti, Milan, Italy; Jeffrey R. Karnes, Rochester, MN; Giorgio Gandaglia, Nicola Fossati, Milan, Italy; Martin Spahn, Bern, Switzerland; Paolo Gontero, Turin, Italy; Lorenzo Tosco, Leuven, Belgium; Burkhard Kneitz, Wurzburg, Germany; Felix Chun, Hamburg, Germany; Emanuele Zaffuto, Milan, Italy; Dirk De Ridder, Leuven, Belgium; Maxine Sun, Montreal, Canada; Markus Graefen, Hamburg, Germany; Giansilvio Marchioro, Novara, Italy; Detlef Frohneberg, Karlsruhe, Germany; Bertrand Guilloneau, New York, NY; Simone Giona, Turin, Italy; Rafael Sanchez-Salas, Xavier Cathelineau, Paris, France; Pierre Karakiewicz, Montreal, Canada; Hein Van Poppel, Leuven, Belgium; Francesco Montorsi, Milan, Italy; Steven Joniau, Leuven, Belgium

The recent Food and Drug Administration approval of sipuleucel-T for metastatic castration-resistant prostate cancer and of the anticytotoxic T-lymphocyte antigen 4 antibody (Ipilimumab) for metastatic melanoma has led to a renewed interest in immunotherapy for prostate and other cancers. Ipilimumab has entered phase III testing for prostate cancer, as has a viral-based anti-prostate-specific antigen vaccine (ProstVac-VF). Complementing these phase III studies are a number of innovative phase II studies, aimed at bringing immunotherapy forward in the setting of less advanced disease, as well as a number of interesting trials combining immunotherapy with conventional therapy for prostate cancer.Although a number of immunotherapy trials have been initiated, few mature results are available at the current time. These data are likely to mature in the setting of an increasingly complex treatment paradigm in which multiple hormonal and novel agents are available.Immunotherapy for prostate cancer represents an attractive treatment approach, with the currently available agent sipuleucel-T providing a significant survival benefit without appreciable toxicity. Novel approaches to improve the efficacy of this and other immune-active agents are currently under evaluation.

Considerable progress has been made in prostate cancer immunotherapy over the last year, and two agents have completed phase III testing. This review will discuss the most promising immune-directed strategies in development for prostate cancer, outlining interventions that mitigate tumor-induced tolerance and highlighting several combination immunotherapy approaches.A pivotal phase III study using Sipuleucel-T, an autologous prostatic acid phosphatase (PAP)-loaded dendritic cell immunotherapy, in men with metastatic castration-resistant prostate cancer (CRPC) demonstrated a survival advantage over placebo. By contrast, two phase III studies of GVAX, an allogeneic tumor cell vaccine, in a similar patient population failed to show a survival benefit of GVAX or GVAX/docetaxel over standard docetaxel/prednisone. Other strategies currently in clinical development include the ProstVac poxviral vaccine, a PAP-encoding DNA vaccine, and immune checkpoint inhibitory approaches.Although Sipuleucel-T may receive FDA approval for patients with metastatic CRPC, challenges remain in identifying immunotherapy strategies that overcome immune tolerance, especially when disease burden is substantial. An emerging paradigm focuses on using immunotherapy together with checkpoint antagonists or in combination with conventional therapies in patients with early-stage disease. Such approaches are likely to yield optimal results, but must carefully be explored in well designed phase II studies before moving forward.

The taxanes (paclitaxel and docetaxel) are antimicrotubule agents used in the treatment of breast and ovarian cancers. Taxanes promote regression of collagen-induced arthritis in both animal models and humans by inhibiting proliferating synoviocytes. We report a case of rheumatoid arthritis suppressed by the administration of docetaxel-based chemotherapy. In October 2006, a 66-year-old woman presented to the hospital with symptoms in multiple joints that began 4 weeks after she had completed chemotherapy for ovarian cancer. She complained of pain, swelling, and stiffness in her hands and wrists bilaterally, as well as in her right elbow, left shoulder, and bilateral knees and ankles. She noted morning stiffness lasting approximately 2 hours and diminished grip strength. In June 2006, the patient had been diagnosed with ovarian carcinoma and had been treated with surgery, followed by adjuvant chemotherapy with docetaxel (60 mg/m2) and carboplatin dosed every 3 weeks for 4 cycles. Chemotherapy had ended in September 2006. The patient reported that her articular symptoms first began 6 months before her diagnosis of cancer, and had progressively worsened. Strangely, both her pain and stiffness had improved dramatically for the duration of her chemotherapy treatments, only to reappear again 4 weeks after the final cycle of chemotherapy. At presentation, she had swelling and tenderness in the metacarpophalangeal, proximal interphalangeal, and carpometacarpal joints bilaterally, as well as in multiple other joints. Laboratory studies showed a normocytic anemia, an erythrocyte sedimentation rate of 84 mm/h, and a C-reactive protein of 31 mg/L. Plain radiographs of the hands demonstrated symmetrical synovial thickening and joint space swelling involving the wrists and small joints of the hands. Rheumatoid factor was 673 IU/mL (normal