Neoadjuvant Paradigm for Accelerated Drug Development: An Ideal Model in Bladder Cancer

Neoadjuvant cisplatin-based combination chemotherapy for muscle-invasive bladder cancer (MIBC) has been shown to confer a survival advantage in two randomized clinical trials and a meta-analysis. Despite level 1 evidence supporting its benefit, utilization remains dismal with nearly one-half of patients ineligible for cisplatin-based therapy because of renal dysfunction, impaired performance status, and/or coexisting medical problems. This situation highlights the need for the development of novel therapies for the management of MIBC, a disease with a lethal phenotype. The neoadjuvant paradigm in bladder cancer offers many advantages for accelerated drug development. First, there is a greater likelihood of successful therapy at an earlier disease state that may be characterized by less genomic instability compared with the metastatic setting, with an early readout of activity with results determined in months rather than years. Second, pre- and post-treatment tumor tissue collection in patients with MIBC is performed as the standard of care without the need for research-directed biopsies, allowing for the ability to perform important correlative studies and to monitor tumor response to therapy in “real time.” Third, pathological complete response (pT0) predicts for improved outcome in patients with MIBC. Fourth, there is a strong biological rationale with rapidly accumulating evidence for actionable targets in bladder cancer. This review focuses on the neoadjuvant paradigm for accelerated drug development using bladder cancer as the ideal model

Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance

Reactivated androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC). Novel AR targeting drugs abiraterone and enzalutamide have improved survival of CRPC patients. However, resistance to these agents develops and patients ultimately succumb to CRPC. Potential mechanisms of resistance include the following: 1) Expression of AR splice variants such as the AR-V7 isoform which lacks the ligand-binding domain, 2) AR missense mutations in the ligand-binding domain, such as F876L and T877A, and 3) Mutation or overexpression of androgen biosynthetic enzymes or glucocorticoid receptor. Several novel agents may overcome resistance mechanisms. Galeterone acts through multiple mechanisms that include degradation of AR protein and is being evaluated in CRPC patients positive for AR-V7. EPI-001 and related compounds inhibit AR splice variants by targeting the N-terminal transactivation domain of AR. Promising therapies and novel biomarkers, such as AR-V7, may lead to improved outcomes for CRPC patients

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10(11) vp/mL, n = 21; 3 × 10(11) vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer

This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer

Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell–Renal-Cell-Carcinoma: Proof-of-Concept Study

Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone

Comparative Effectiveness of Mitoxantrone Plus Prednisone Versus Prednisone Alone in Metastatic Castrate-Resistant Prostate Cancer After Docetaxel Failure

Mitoxantrone was approved for use in metastatic castrate-resistant prostate cancer (mCRPC) based on pain palliation without observed survival benefit in a small phase III trial in 1996. To re-evaluate for possible survival benefits in a larger contemporary sample and to demonstrate analytic uses of the newly available Project Data Sphere online resource, we used data from control arms of completed clinical trials to compare survival and toxicity among patients with postdocetaxel mCRPC treated with mitoxantrone and prednisone

Arrays of high-aspect ratio microchannels for high-throughput isolation of circulating tumor cells (CTCs)

Microsystem-based technologies are providing new opportunities in the area of in vitro diagnostics due to their ability to provide process automation enabling point-of-care operation. As an example, microsystems used for the isolation and analysis of circulating tumor cells (CTCs) from complex, heterogeneous samples in an automated fashion with improved recoveries and selectivity are providing new opportunities for this important biomarker. Unfortunately, many of the existing microfluidic systems lack the throughput capabilities and/or are too expensive to manufacture to warrant their widespread use in clinical testing scenarios. Here, we describe a disposable, all-polymer, microfluidic system for the high-throughput (HT) isolation of CTCs directly from whole blood inputs. The device employs an array of high aspect ratio (HAR), parallel, sinusoidal microchannels (25 µm × 150 µm; W × D; AR = 6.0) with walls covalently decorated with anti-EpCAM antibodies to provide affinity-based isolation of CTCs. Channel width, which is similar to an average CTC diameter (12–25 µm), plays a critical role in maximizing the probability of cell/wall interactions and allows for achieving high CTC recovery. The extended channel depth allows for increased throughput at the optimized flow velocity (2 mm/s in a microchannel); maximizes cell recovery, and prevents clogging of the microfluidic channels during blood processing. Fluidic addressing of the microchannel array with a minimal device footprint is provided by large cross-sectional area feed and exit channels poised orthogonal to the network of the sinusoidal capillary channels (so-called Z-geometry). Computational modeling was used to confirm uniform addressing of the channels in the isolation bed. Devices with various numbers of parallel microchannels ranging from 50 to 320 have been successfully constructed. Cyclic olefin copolymer (COC) was chosen as the substrate material due to its superior properties during UV-activation of the HAR microchannels surfaces prior to antibody attachment. Operation of the HT-CTC device has been validated by isolation of CTCs directly from blood secured from patients with metastatic prostate cancer. High CTC sample purities (low number of contaminating white blood cells, WBCs) allowed for direct lysis and molecular profiling of isolated CTCs

Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression

ccRCC has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We’ve recently employed the novel positron emission tomography/magnetic resonance (PET/MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

BackgroundThe authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a singleâ arm, openâ label phase 2 study.MethodsEligible patients with platinumâ treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28â day cycles in a 3â stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.ResultsGenomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intentâ toâ treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of â ¤15%). All patients experienced â ¥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (doseâ normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg).ConclusionsTo the authorsâ knowledge, the current study represents the first clinical trial using genomicâ based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.After the genomicâ based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, singleâ agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinumâ refractory disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/1/cncr31817_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/2/cncr31817.pd

Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges