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In the last decade, many life-prolonging therapeutic options have emerged for metastatic castration-resistant prostate cancer (mCRPC). The recent VISION trial is the first to demonstrate a survival benefit of Lutetium-177[ 177 Lu]Lu-PSMA-617 in post-chemotherapy mCRPC. This journal club reviews the VISION trial in the context of the earlier TheraP trial of [ 177 Lu]Lu-PSMA-617 in mCRPC post docetaxel and androgen pathway inhibition, to provide direction for the real-world application of [ 177 Lu]Lu-PSMA-617. Treatment in the control groups differed significantly between both trials and may have influenced outcomes: TheraP mandated cabazitaxel whereas VISION's design could not allow it. In both trials, [ 177 Lu]Lu-PSMA-617 had a good safety profile, with common adverse events being fatigue, nausea, dry mouth, marrow suppression and diarrhea. Given its efficacy and favorable safety even in heavily pre-treated patients, [ 177 Lu]Lu-PSMA-617 provides hope to mCRPC patients and may be applied to earlier disease stages in future investigations.

As precision oncology evolves toward developing more targeted therapies, sequencing has moved to the forefront of treatment decision-making. Whole genome sequencing (WGS) has emerged as a technology capable of identifying candidates for rare and targeted treatments. Yet, because the tumor is constantly evolving during relapse and therapy resistance, the frequency with which WGS should be performed to identify potential new therapies for progressing patients remains unknown. A recent study in Nature Medicine by Van de Haar et al. observed a remarkably stable driver gene mutational profile among 250 biopsy pairs from 231 patients undergoing standard of care treatments during the biopsy interval. Their findings suggest that the actionable metastatic cancer genome is relatively stable over time and that a single WGS provides a complete view of the treatment opportunities available to most metastatic cancer patients.

The vast majority of the human proteome is yet to be functionally characterized thus hindering ongoing investigations on potential drug resistance mechanisms and advanced treatment options. Chemical proteomics is a powerful solution for enzyme profiling and the development of next generation cancer therapeutics previously deemed undruggable by small molecules. Within this field, activity-based protein profiling (ABPP) is a specialized technology capable of discriminating enzyme interactions that occur within complex, biological environments. In a recent publication by Lovell et al, the kallikrein-related peptidase (KLK) family of serine proteases that is highly implicated in the progression of prostate cancer (PCa) was subject to ABPP to elucidate enzymatic activities in the presence of enzalutamide. This is the first report of ABPP in PCa and of activity-based chemical probes selective for individual KLKs. Further, the study reveals androgen receptor-dependent activity among KLK proteins, particularly in mediating the invasion of the bone microenvironment.

Ibrutinib (Imbruvica®, 2013) is a Bruton's tyrosine kinase (BTK) inhibitor approved for multiple B-cell malignancies and cGVHD. Its treatment is associated with increased risk of cardiac adverse events. Atrial fibrillation is a common cause of therapy discontinuation and interruptions, which have been correlated with shorter progression-free survival in chronic lymphocyte leukemia (CLL) patients. Recently, Xiao et al. identified that ibrutinib-mediated atrial fibrillation is likely due to off-target CSK inhibition. Given promising in vitro and in vivo evidence of maintained biological activity in CLL at lower-than-labeled ibrutinib doses, this elucidated mechanism substantiates the case to investigate alternative dosing schedules. The potential to minimize ibrutinib's off-target effects while conserving response warrants further discussion and investigation of optimal ibrutinib dosing.

The PROfound trial highlights that there is a benefit in testing genes involved in homologous recombination (HR) and forms the rationale for testing in all patients with metastatic, castration-resistant prostate cancer (mCRPC). This trial also demostrates that olaparib improves progression free survival (PFS), objective response rate (ORR), and time to pain progression in patients who harbor alterations in BRCA1, BRCA2 , and ATM . These are groundbreaking findings - this is the first trial that demonstrates the efficacy of olaparib versus standard therapy in a genomically-selected patient population with metastatic prostate cancer. Although this trial does not demonstrate improvements in overall survival (OS), we believe that this may be an underestimation based on trial-design. Future studies of olaparib are likely to yield further promising results.

The Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a randomized phase III trial that evaluated the outcomes of men with metastatic prostate cancer who received castration with or without docetaxel. Patients from this trial were genotyped in a recent study to detect HSD3B1 variance and to determine 2-y freedom from castration-resistant prostate cancer as well as overall survival. The results of this study identified HSD3B1 as a possible biomarker that can be used to predict response to therapy in patients with metastatic disease.

ERA 223, a phase III, international, multicenter, double-blind study published in Lancet Oncology , was the first randomized controlled trial to investigate combined radium-223 (Ra-223) and abiraterone acetate plus prednisone or prednisolone (AAP) therapy. The data from ERA 223 demonstrated no increase in efficacy for this combination over AAP alone, and instead identified a significant safety concern due to the higher risk of fracture in the co-treatment group. The surprising results of this trial likely stem from the compounding osteoporotic effects of the different treatments, particularly the addition of prednisone, and supplementing therapy regimens with osteoprotective agents may aid in mitigating this safety risk.

Introduction : Transporters comprising the blood-brain barrier complicate delivery of many therapeutics to the central nervous system. The present study ascertained whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. Methods : Wild-type and Mdr1a/Mdr1b (-/-) mice were treated with botryllamide G and lapatinib ("doublet therapy"), and while a separate cohort of wild-type mice was treated with botryllamide, tariquidar and lapatinib ("triplet therapy"). Results : Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the in vitro IC 50 of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In Mdr1a/Mdr1b (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 h*ng/mL vs 4007 h*ng/mL; P = .031), but not plasma exposure ( P = .15). No significant differences were observed after 24 h. Lapatinib brain exposure was greater through 1 h when wild-type mice were administered triplet therapy (298 h*pg/mg vs 120 h*pg/mg; P < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 h*pg/mg vs 4461hr*ng/mL; P < .001) and did not alter the brain:plasma ratio. Conclusions : In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking Abcb1 , although the combination of botryllamide G and tariquidar increases brain exposure in wild-type mice only briefly (1 h). Additional research is needed to find analogs of this compound that have better pharmacokinetics and pharmacodynamic effects on ABCG2 inhibition.

Surgical intervention is a common treatment modality for localized cancer. Post-operative analysis involves evaluation of surgical margins to assess whether all malignant tissue has been resected because positive surgical margins lead to a greater likelihood of recurrence. Secondary treatments are utilized to minimize the negative effects of positive surgical margins. Recently, in Science Translational Medicine, Zhang et al describe a new mass spectroscopic technique that could potentially decrease the likelihood of positive surgical margins. Their nondestructive in vivo tissue sampling leads to a highly accurate and rapid cancer diagnosis with great precision between healthy and malignant tissue. This new tool has the potential to improve surgical margins and accelerate cancer diagnostics by analyzing biomolecular signatures of various tissues and diseases.

Numerous growth-inducing signaling pathways have been implicated in the development of metastatic castrate-resistant prostate cancer, but their cross-talk with androgen receptor functions remains poorly understood. A recent study published in Science Signaling by Chen et al. 1 has identified a novel androgen-mediated signaling axis driven by loss of SPDEF and gain of TGFBI to facilitate metastasis, which may explain the acquisition of resistance to androgen deprivation therapy. These findings suggest that therapeutic inhibition of androgen signaling may inadvertently promote castrate resistance by inhibiting tumor suppressive functions of the androgen receptor.

A recent publication in Science demonstrates the ability of prostate cancer cells to switch lineages from one that is dependent on androgen signaling to a cell type that is not. Known as lineage plasticity, this phenomenon is driven by the transcription factor SOX2 in RB1 and TP53-deficient prostate cancer. SOX2 is a potential prognostic marker and therapeutic target in castration resistant prostate cancer.

Recent trends in cancer therapy have begun emphasizing the use of precision medicine, especially genetic tools, in the evaluation of malignancies and decision-making. Prostate cancer is a malignancy where the benefits and utility of screening and early treatment are still heavily controversial. A recent paper in the New England Journal of Medicine found that patients with metastatic prostate cancer presented germline mutations in DNA-repair genes at a significantly higher incidence than those with localized prostate cancer. These findings indicate the need for further research in this field as genetic differences between metastatic and localized prostate cancer could have great clinical value.

A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.

The standard treatments of localized prostate cancer include surgical resection and/or radiotherapy. Recently in 2016, Zhao et al. described a tool to predict which patients will most likely gain from postoperative radiotherapy. Such a method can personalize treatment plan by maximizing benefit but minimizing harm.

Docetaxel is the current first line therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is no standard number of docetaxel cycles given to patients. In their post hoc analysis of the Mainsail study, de Morrée et al. show that the number of docetaxel cycles administered to a patient is a significant factor contributing to overall survival. These findings warrant further investigation into the standardization of the number of docetaxel cycles administered.

The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p <0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma.

The Hippo-YAP signaling pathway has been established as a crucial regulator of tissue growth and tumorigenesis but the mechanism for transcriptional control remains unclear. In their study, Galli et al. show that YAP/TAZ binding is restricted to a small number of gene enhancers and that YAP/TAZ regulates transcriptional elongation by recruiting the Mediator complex.

Currently there are no molecular biomarkers used to help guide treatment selection for those patients with castration-resistant prostate cancer. A recent study published in JAMA Oncology (Antonarakis et al.) presents evidence supporting the potential use of androgen receptor splice variant 7 as a biomarker for optimal treatment selection in this population.

Overcoming drug resistance in castrate resistant prostate cancer requires improved understanding of mechanisms by which resistance occurs, as well as new treatment options. A recent study published in Nature (Li et al. 2015) examines the mechanism of abiraterone activity, and reveals the bioactivity of a breakdown product with exciting repercussions for therapy regimes.

Identification of genetic alterations in Metastatic Castration Resistant Prostate Cancer (mCRPC) may provide scientists and clinicians with a list of new targets for drug research and development. Recently published in Cell, Robinson et al. present the first look at genetic data from mCRPC lesions gathered over multiple years and from many institutions.

Prior to 2011, only 2 systemic treatments were approved for the treatment of melanoma and these had limited efficacy. In the past 4 years, 6 novel agents have received FDA approval. Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway: the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib. These have been developed in parallel with a class of immunologic mediators often referred to as "immune checkpoint inhibitors." These recent studies represent a marked acceleration of progress in the treatment of metastatic melanoma. While it was hoped that combining BRAF and MEK inhibitors would significantly mitigate drug resistance, such combinations have yielded only modestly better results than monotherapy. However, these combinations were successful in reducing the development of cutaneous squamous cell carcinomas and keratocanthomas. Therefore, combination therapies are clearly warranted. Thus far there are only limited data addressing the value of combinations of immunotherapeutic agents: a phase 1 trial of concurrent nivolumab plus ipilimumab suggested enhanced activity that may not depend on BRAF mutation status. Despite the attention and publicity given to the progress achieved in the therapy of melanoma, the majority of patients with metastatic disease still have a poor prognosis. Even novel combination regiments of BRAF and MEK inhibitors achieve complete response in only 13% of patients and a median PFS of 11.4 months in all patients. Better therapies remain desperately needed, especially for the 30-40% of patients with wild-type BRAF, for whom BRAF/MAPK inhibition offers no benefit. In the latter benefit is expected from emerging immunotherapies either singly or in combinations. The extent to which immunotherapies will add to regimens targeting BRAF remains to be determined.

The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). Enzalutamide is a potent AR antagonist that was initially approved in 2012 for men with CRPC who had previously failed chemotherapy treatment with docetaxel. Herein, we reviewed 2 key manuscripts that have recently appeared in the New England Journal of Medicine regarding enzalutamide. The PREVAIL Phase 3 trial was designed to evaluate enzalutamide before chemotherapy in men with CRPC. The study illustrated that 65% of patients receiving enzalutamide had radiographic-progression free survival. There was a significant risk reduction of radiographic progression or death, compared with the placebo group. The enzalutamide group's median overall survival was 32.4 months vs. 30.2 months in the placebo group.

A new bigenic mouse model, engineered with the overexpression of PSGR and the knockout of PTEN, has been used to study the relationship between 2 genes and disease progression. A study in Oncogene (Rodriguez et al.) has shown that these 2 genetic polymorphisms synergistically promote the development of prostate cancer.

Indolent Non-Hodgkin Lymphomas (iNHL) are typically B-cell malignancies and are incurable with current standard approaches. Thus, there is a demand for novel agents specific for this group of disorders. In a phase II study published by Gopal et al. in the New England Journal of Medicine, idelalisib, a small molecule inhibitor of PI3Kδ that was FDA approved in July of 2014, was shown to be effective when combined with rituximab in patients who cannot tolerate chemotherapy and as last line therapy in patients with iNHL refractory to 2 prior systemic therapies. Idelalisib demonstrated tolerable diarrhea, fatigue, nausea, pyrexia, and cough. While this novel agent is a clinically significant addition to the iNHL arsenal, further research is needed to determine its most appropriate place in iNHL therapy.

Following FDA approval of sipuleucel-T in 2010 for metastatic castration resistant prostate cancer (mCRPC), several studies have described the effect of sipuleucel-T on peripheral immune responses. Retrospective associations have also been made with immune responses and survival. A recently published study by Fong et al. was the first to characterize the immune response of sipuleucel-T in the tumor microenvironment. The findings of this study have been hypothesis generating, yet it remains unclear whether the peri-tumor immune response described is predictive of survival. Increasing evidence suggests that radiographic or PSA progression does not accurately reflect survival with sipuleucel-T and other immunotherapies. Finding an immune biomarker which can accurately reflect clinical benefit and validating it prospectively offers the potential for a predictive indicator of response in an area where none currently exists.

The VEGF-A binding monoclonal antibody bevacizumab is a widely prescribed angiogenesis inhibitor and indicated for many types of cancer. As shown by three randomized phase 3 trials recently published in the New England Journal of Medicine, novel indications for this drug are still being explored. In the RTOG 0825 and AVAglio trials the effect of bevacizumab addition to standard therapy in newly diagnosed glioblastoma (radiotherapy plus temozolomide) was investigated, while in GOG 240 the combination of platinum-based chemotherapy plus bevacizumab was explored in advanced cervical cancer. In RTOG 0825, addition of bevacizumab to standard therapy did not result in survival benefit, and moreover, quality of life was more deteriorated in the bevacizumab arm. In AVAglio, however, progression-free survival (PFS) was significantly increased in the bevacizumab group and these patients also experienced a longer deterioration-free survival. These conflicting results do not fully support the incorporation of bevacizumab in the first-line treatment of glioblastoma. In contrast, in GOG 240 the bevacizumab group (including paclitaxel plus topotecan or paclitaxel) experienced a significant longer PFS and overall survival, and quality of life was not negatively affected in these patients. Thus, these results favor the use of bevacizumab in the treatment of advanced cervical cancer.

Gene fusions involving ETS transcription factors (predominantly ERG and ETV1) and PTEN deletions are prevalent in the prostate cancer genome. This report describes a novel mouse model that overexpresses ERG and lacks PTEN with the majority of mice developing prostate tumors by 6 mo. Biological mechanisms suggest increased/altered binding of the male hormone receptor in the genome. This model will be useful in pre-clinical evaluation of new drugs targeting these common prostate cancer genomic alterations.

Burkitt lymphoma is an aggressive form of non-Hodgkin lymphoma that has a short doubling time, thus intense short-cycle chemotherapy has been thought to be essential. A recent NCI-sponsored clinical trial investigated DA-EPOCH-R given to 19 HIV-negative patients and a short course regimen (SC-EPOCH-RR) given to 11 HIV-positive patients in hopes of maintaining the efficacy of the regimen while decreasing the typical side effects from the intensive short-cycle chemotherapy. Low intensity EPOCH-R based therapy achieved excellent rates of efficacy despite a significant difference in the median cumulative dose between the DA-EPOCH-R and SC-EPOCH-RR cohorts. Furthermore, both cohorts experienced mainly grade 1 and grade 2 toxicities, with SC-EPOCH-RR cohort patients experiencing less adverse events than DA-EPOCH-R cohort patients. This recent clinical investigation suggests the most important therapeutic principle is not the intensity but rather the length of exposure time above an effective threshold concentration. Since short, intense bolus doses are the standard therapy for Burkitt lymphoma, these findings are clinically relevant and significant.

Lenalidomide is an immunomodulatory agent (IMiD) that has activity in hematologic cancer (e.g., multiple myeloma). The immunomodulatory and apoptotic properties are readily apparent in therapy. However, the exact mechanism of action has been difficult to quantify until recently when it was shown that another IMiD, thalidomide, binds to an E3 ubiquitin ligase complex constituent, CRBN. The article by Kronke et al. demonstrates that, by binding to CRBN and altering its selectivity, lenalidomide potentiates the ubiquitination and proteolysis of 2 specific proteins, IKZF1 and IKZF3. An article in the same issue, by Lu et al., supports these observations. IKZF1 and IKZF3 are transcription factors that are necessary for multiple myeloma, and repression of these transcription factors is a likely mechanism for lenalidomide activity in this disease.

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.

The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. Its transcriptional activity has previously been studied in cell lines. A group at the University of Cambridge recently outlined the AR transcriptional program in tissue samples, with an emphasis on castration-resistant tumors. AR binding sites, gene-expression changes (in xenografts), and potential transcription factor interactions were notably different from those observed in cultured cells. These discrepancies suggest a distinct signaling network for the AR in vivo and serve as a reminder that results from in vitro models should be checked against clinical realities.

The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). However, durable responses to these therapies have been limited and there is a need to identify additional therapeutic targets within the AR-signaling network. Recently a group at University of Michigan Medical School outlined the potential for BET bromodomain protein inhibitors as a novel epigenetic approach to treatment of CRPC. In prostate cancer cell lines, BET bromodomain inhibitor, JQ1, was shown to induce apoptosis and down-regulate AR-regulated gene transcription. Bromodomain and the extra-terminal (BET) subfamily of human bromodomain proteins, with a focus on BRD4, were shown to play a major role in AR signaling and interact with AR via bromodomain (BD) 1/2. JQ1 inhibits this BRD4-AR bond, resulting in removal of RNA polymerase II from AR target genes, causing reduced AR gene transcription and subsequent diminished AR signaling. JQ1 lead to a significant reduction in tumor volume and weight in VCaP xenograft mice.

In a study recently published in Science, Magnon et al. show that both the sympathetic and parasympathetic components of the autonomic nervous system play an integral part in the development and dissemination of prostate cancer (PCa). Inhibition of the sympathetic nervous system (SNS) and disruption of the adrenergic receptors, specifically Ardβ 2, resulted in the prevention of primary PCa tumor development in mice. The authors found that inhibition of the SNS is only successful in preventing murine tumor development if completed early enough, and the parasympathetic nervous system (PNS) predominates in later stages of PCa. Inhibition of the PNS by way of the cholinergic receptor, muscarinic 1 (Chrm1), caused mice to develop less metastases to the pelvic lymph nodes, intestines, and bones. A PCa progression scheme has been outlined where initial tumor engraftment is controlled by the SNS but then becomes less prominent than the PNS, which promotes metastasis. The investigators showed the dependence of the autonomic nervous system on development of PCa and present opportunities for prevention; further studies are needed to confirm these results in humans.

There is a need to identify better biomarkers to monitor diseases and/or assess therapeutic responses. For those with cancer, one can identify DNA fragments that contain somatic mutations originating in the tumor DNA in plasma or serum. There have been several early studies suggesting that advances in sequencing technologies will allow identification of somatic genomic alterations that can be used to monitor tumor dynamics. Dawson et.al. investigated circulating cell-free DNA carrying tumor specific alterations in patients with breast cancer. The authors compared CT imaging from 30 women with metastatic breast cancer receiving treatment, using two assays for circulating tumor DNA, CA 15-3, and CTCs. Taken the two methods together circulating tumor DNA was detected in 29 or 30 women (97%) and 115 of 141 plasma samples (82%). Circulating tumor DNA levels showed a greater dynamic range and greater correlation with changes in tumor burden than did CA 15-3 or CTC. The relatively small study showed that circulating tumor DNA has a superior sensitivity to other circulating biomarkers and a dynamic range that correlates with tumor burden.

Identification of the mechanisms that drive progression of metastatic castration-resistant prostate cancer (CRPC) has fostered interest since early androgen studies in the 1940s. Little knowledge has surfaced about the role mutations play in prostate cancer development. A group at the Michigan Center for Translation Pathology studied exomes of lethal, metastatic CRPC and documented the overall mutation rates. In classifying these mutations, the monoclonal cause of CRPC was recognized. Nine identified genes showed significant mutations. Six of these genes had previously been reported as mutated in prostate cancer. The analysis also found significantly mutated androgen receptor (AR) cofactors and linked proteins, including FOXA1 and MLL2. Another finding concerned an aberration in CHD1. Prostate cancers with deletions or mutations in CHD1 showed a strong correlation with ETS gene family fusion negative prostate cancers (96%). In profiling these exomes, this group provides an original method to identify deletions and mutations that drive CRPC progression.

Innate or acquired resistance to chemotherapy presents an important and predictable challenge in cancer therapy. Malignant tumors consist of both neoplastic and benign cells such as stromal fibroblasts, which can influence the tumor's response to cytotoxic therapy. In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. Such findings outline a mechanism by which cytotoxic therapies given in cyclical doses can actually augment later treatment resistance and may open the door to new areas of research and to the development of new therapeutic targets that block the DNA damage response program.

There has been increasing recognition that organic anion transporter proteins (OATPs) play an important role in the biology of various cancers. De novo expression of OATPs has been identified in breast, colon, pancreatic, gastric and prostate cancer cells, among others. In patients with prostate cancer, polymorphisms encoding decreased functioning OATP1B3 were associated with a longer time to progression on androgen deprivation therapy and a longer overall survival which is likely caused by reduced tumoral testosterone uptake. Because of these findings, therapeutic inhibition targeting OATP1B3 has been proposed. However, any enthusiasm for inhibiting OATP1Bs therapeutically has been tempered by reservations about potential consequences. For instance, inhibitors could interfere with several normal physiological processes mediated by OATP1B3 (i.e., bile acid reuptake, bilirubin uptake, etc) or cause potential, as-yet unknown, drug interactions by barring hepatic uptake, subsequent metabolism and elimination.

Numerous epidemiological studies have suggested dietary factors may alter the risk of prostate cancer. Punnen and colleagues have conducted a case-control study focused on aggressive prostate cancer (N = 982), where not only details on meat consumption were collected, but also meat preparation was captured. A multivariate logistic regression model was used to assess the association between meat consumption, grilled meat consumption, doneness level, mutagens and aggressive prostate cancer. High consumption of processed meat, including ground beef, was associated with aggressive prostate cancer. Ground beef showed the strongest association (overall risk, OR = 2.30, 95% confidence interval, CI: 1.39-3.81; P-trend = 0.002). Well-done meat conferred a higher risk of aggressive prostate cancer. Interestingly, the consumption of rare or less cooked meat was not associated with an increased risk of prostate cancer. When the investigators evaluated the estimated meat mutagens produced by cooking at high temperatures, they identified an increased risk with MelQx and DiMelQx, OR = 1.69 95% CI: 1.08-2.64, P-trend = 0.02 and OR = 1.53 95% CI: 1.00-2.35, P-trend = 0.005, respectively.

The clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway has recently been met with numerous phase III failures that showed modest survival benefits. Understanding the resistance mechanisms of antiangiogenic therapy is essential to overcoming the limited effectiveness of VEGF-pathway inhibitors. A recent study published in the Proceedings of the National Academy of Sciences provides a novel explanation to the treatment limitations of angiogenesis inhibitors and suggests a potential strategy to improve the clinical utility of these agents.

Androgen deprivation therapy is the frontline treatment for metastatic prostate cancer; however, because the majority of cases of advanced prostate cancer progress to castration-resistant prostate cancer (CRPC), there is a considerable need to better understand the synthesis of intratumoral concentrations of the androgen receptor (AR) agonist, 5α-dihydrotestosterone (DHT) in CRPC. In a recent article in the Proceedings of the National Academy of Sciences, Chang et al. show that, contrary to widely held assumptions, the dominant pathway to DHT synthesis does not involve testosterone as a precursor to DHT, but instead involves the conversion of Δ ( 4) -androstenedione (AD) to 5α-dione (AD→5α-dione→DHT) by the steroid-5α-reductase isoenzyme 1 (SRD5A1). The authors show that it is this alternative pathway that drives the progression of CRPC, and they confirm these findings in six established human prostate cancer cell lines as well as in the metastatic tumors from two patients with CRPC. Such findings open the door to new areas of research and to the development of new therapeutic targets in CRPC.

Pathologic fractures, spinal compression, and pain take a great toll on the healthcare costs and well-being of men with prostate cancer metastatic to the bone. For almost 10 years, the only drug proven to prevent these skeletal-related adverse events was the bisphosphonate zoledronic acid. In a study published by Fizazi et al. in The Lancet, the monoclonal antibody to RANKL, denosumab, is shown to be superior to zoledronic acid in the prevention of these events. The only notable adverse event more frequent in either arm was increased hypocalcemia in the denosumab arm. There was a greater frequency of osteonecrosis of the jaw in the denosumab treatment group that did not reach statistical significance, but is of great concern. While further analysis is needed to determine the value of denosumab in preventing adverse events and improving quality of life, this new therapy is a significant addition to the treatment of men living with metastatic prostate cancer.

This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

The autocrine motility factor receptor or glycoprotein-78 (gp78) and C-terminus of Hsp70-interacting protein (CHIP) are E3-ligases required for ubiquitination of cytochrome P450s of the 3A subfamily (CYP3A) in endoplasmic reticulum-associated degradation (ERAD). The CYP isozyme 3A4 (CYP3A4) is responsible for the metabolism of the majority of xenobiotics including anticancer agents. Much variability in clinical response to chemotherapy is observed and it has been suggested that variability in CYP3A4 expression could be a factor. The study reviewed in this journal club comments on the importance of further characterizing gp78 and CHIP as relevant proteins in ERAD of CYP3A4. This study demonstrated how both gp78 and CHIP play direct roles in reducing CYP3A4 protein content as well as CYP3A4 ubiquitination. Interestingly, when gp78 and CHIP were knocked down by siRNAs directed towards each protein, the stabilized CYP3A4 remained functional. This has implications for drug-drug interactions for agents metabolized by CYP3A4, which can influence drug exposure levels. This is relevant because most anticancer agents have very narrow therapeutic windows, thus even slight changes in CYP3A4 levels could alter the exposure of that drug and result in either insufficient efficacy or toxicity. Future studies must explore genetic variability in the ERAD pathway and identify new factors that influence CYP3A ERAD in order to better characterize how CYP3A variability affects anticancer drug pharmacology.

Prostate cancer is the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Globally, more than 900,000 new cases of prostate cancer will be diagnosed in 2010 and more than 260,000 will, unfortunately, die from the disease. In the US, an estimated 217,000 new cases of prostate cancer and 32,000 deaths are expected this year. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the gland, treatment options are limited. For this population of patients, androgen suppression is the cornerstone of initial therapy. Furthermore, progression to castration resistant prostate cancer (CRPC) is inevitable. The current front-line treatment for patients with CRPC is the chemotherapeutic agent docetaxel (administered every 3 weeks). Until now, it is the only agent that has been shown to prolong survival in CRPC. The approval trial for docetaxel found a median overall survival of 19.2 months for patients receiving docetaxel plus prednisone compared to 16.3 months for patients receiving mitoxantrone plus prednisone (p=0.0094). Mitoxantrone plus prednisone is often utilized for its palliative benefits, but two randomized trials failed to demonstrate a survival advantage.

Previous attempts to link prostate cancer progression to genetic alterations have been unsuccessful, and consequently, there is still no reliable predictor of prognosis for men with this disease. A recent study by Taylor et al., published in Cancer Cell, assesses copy number alterations, mutations, and transcriptomes in 218 tumors and 12 prostate cancer cell lines and xenografts. Their analysis identifies frequencies of ERG alterations, 8p loss and 8q gain similar to previous findings. It also reveals novel genetic factors in prostate cancer progression, including the androgen receptor coactivator, NCOA2, which serves as an oncogene in about 11% of tumors, and a deletion at chromosome 3p14, which was associated with TMPRSS-ERG fusion. The copy number alteration data demonstrates six distinct subgroups of prostate cancer with considerable variation in time to biochemical relapse. Classification of prostate cancer into these genetic subgroups may help clinicians predict the likelihood of disease progression in newly diagnosed men, ultimately guiding treatment decisions and therapy development.

Romidepsin is a histone deacetylase inhibitor (HDI), approved by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Although various mechanisms have been proposed for the activity of HDIs, including induction of genes controlling cell cycle, acetylation of cytoplasmic proteins and direct induction of apoptosis, the mechanism underlying activity of romidepsin and other HDIs in CTCL is not known. Romidepsin induces long-lasting responses. The side-effect profile is similar to that of other HDIs, causing fatigue, nausea and thrombocytopenia. Management of the CTCL population requires vigilence to prevent infection with skin contaminants, and monitoring of potassium and magnesium, electrolytes found to be low in a large proportion of patients. Electrocardiographic (ECG) changes are common but are not associated with myocardial damage. When molecular end points were evaluated in 61 patients enrolled on a Phase II trial with romidepsin, response was associated with persistence of acetylated histone H3, suggesting that drug exposure is important in effective therapy with romidepsin. Future studies will endeavor to identify combination strategies to increase the efficacy both in resistant CTCL and in solid tumors and to identify biomarkers of response that will allow selection of patients most likely to benefit from the therapy.

Radiation therapy is a potentially curative, important treatment option in localized prostate cancer. However, at 8 years after radiation therapy, even in the best risk subset of patients, approximately 10% of patients will experience clinical disease recurrence. The identification of molecular markers of treatment success or failure may allow for the development of strategies to further improve treatment outcomes. Herein, we investigated five molecular markers of DNA repair. 513 patients with castrate-resistant prostate cancer (CRPC), including 284 patients who received radiotherapy, 229 patients without radiotherapy and 152 healthy individuals were genotyped for five polymorphisms in DNA excision repair genes:ERCC1 N118N (500C>T), XPD K751Q (2282A>C), XRCC1 R194W (685C>T), XRCC1 R399Q (1301G>A) and PARP1 V762A(2446T>C). The distribution of genetic polymorphisms in the patients with CRPC and in healthy controls was compared,and the association between the polymorphisms and overall survival was investigated. The polymorphisms evaluated did not show differences between the patient group and the healthy controls, nor did they show a trend toward an association with survival. However, in the radiation treated subgroup, the median survival time was associated with the XRCC1 haplotype. The median survival time was 11.75 years for patients with the R399Q AA /R194W CC haplotype,12.17 years for patients with the R399Q AG/R194W CC haplotype, 6.665 years for patients with the R399Q AG/R194WCT haplotype, and 6.21 years for patients with the R399Q GG/R194W CT haplotype (p = 0.034). This association was not found when all patients were investigated. We conclude that the genetic polymorphisms in XRCC1 may affect the outcome in patients who received radiotherapy for localized prostate cancer.

Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.(1) Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,(2) in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After 2 weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854 vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo.