Biomarker-driven drug repurposing on biologically similar cancers with DNA-repair deficiencies

Similar molecular and genetic aberrations among diseases can lead to the discovery of jointly important treatment options across biologically similar diseases. Oncologists closely looked at several hormone-dependent cancers and identified remarkable pathological and molecular similarities in their DNA repair pathway abnormalities. Although deficiencies in Homologous Recombination (HR) pathway plays a significant role towards cancer progression, there could be other DNA-repair pathway deficiencies that requires careful investigation. In this paper, through a biomarker-driven drug repurposing model, we identified several potential drug candidates for breast and prostate cancer patients with DNA-repair deficiencies based on common specific biomarkers and irrespective of the organ the tumors originated from. Normalized discounted cumulative gain (NDCG) and sensitivity analysis were used to assess the performance of the drug repurposing model. Our results showed that Mitoxantrone and Genistein were among drugs with high therapeutic effects that significantly reverted the gene expression changes caused by the disease (FDR adjusted p-values for prostate cancer =1.225e-4 and 8.195e-8, respectively) for patients with deficiencies in their homologous recombination (HR) pathways. The proposed multi-cancer treatment framework, suitable for patients whose cancers had common specific biomarkers, has the potential to identify promising drug candidates by enriching the study population through the integration of multiple cancers and targeting patients who respond poorly to organ-specific treatments

Non-Stationarities in Extra-Large Scale Massive MIMO

Massive MIMO, a key technology for increasing area spectral efficiency in cellular systems, was developed assuming moderately sized apertures. In this paper, we argue that massive MIMO systems behave differently in large-scale regimes due to spatial non-stationarity. In the large-scale regime, with arrays of around fifty wavelengths, the terminals see the whole array but non-stationarities occur because different regions of the array see different propagation paths. At even larger dimensions, which we call the extra-large scale regime, terminals see a portion of the array and inside the first type of non-stationarities might occur. We show that the non-stationarity properties of the massive MIMO channel changes several important MIMO design aspects. In simulations, we demonstrate how non-stationarity is a curse when neglected but a blessing when embraced in terms of computational load and multi-user transceiver design

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer

Introduction/Background. Nonmetastatic castrate resistant prostate cancer (CRPC) is a challenging disease state. The objective of this study was to evaluate the efficacy and tolerability of bevacizumab in nonmetastatic CRPC patients. Patients. Patients with prostate cancer who developed PSA recurrence after local therapy were included if they had absence of bone or visceral metastases and PSA progression despite androgen deprivation therapy. Methods. Bevacizumab 10 mg/kg intravenously was administered every 14 days until PSA progression, development of metastasis, or unacceptable toxicity. Results. 15 patients were enrolled and treated with bevacizumab for a median duration of 3.1 months. Median baseline PSA was 27 ng/mL, and seven patients had Gleason Score ≥8. Five patients had declined in PSA during the treatment. Median PSA doubling time was prolonged from 4.7 months pretreatment to 6.5 months. Median time to PSA progression and new metastasis were 2.8 and 7.9 months, respectively. There were three grade 3 adverse events (one proteinuria and two hypertension) and one pulmonary embolism. There was no treatment-related mortality. Conclusion. Bevacizumab therapy had minimal impact on the disease course of nonmetastatic CRPC, and investigation of novel strategies is needed

Patient, companion, and oncologist agreement regarding information discussed during triadic oncology clinical interactions

Background Although people with cancer want and need information from their oncologists, patients and oncologists often disagree about what information was discussed during clinical interactions. Most patients have companions present during oncology visits; we investigated whether companions process information more accurately than patients. Specifically, we examined whether patients and companions differed in agreement with oncologists about what was discussed. We also investigated the effect of topic on agreement and patient/companion self‐reported understanding of discussions. Methods Patients with companions were invited to participate on first visits to a cancer center in Detroit, MI. Patients, companions, and oncologists independently completed questionnaires immediately following visits. Participants were asked whether five topics were discussed (diagnosis, prognosis, metastasis, treatment/treatment goals, and side effects) and, if discussed, what oncologists said. Participants were also asked to estimate their own and each other's understanding of discussions. Results A total of 66 patient–companion–oncologist triads participated. Agreement was higher regarding whether topics were discussed than what oncologists said. Agreement did not differ by dyad type. Patients, companions, and oncologists were equally likely to be the source of triadic disagreements. Agreement was high about diagnosis (>90%) but much lower about other topics, particularly side effects. Patients and companions reported greater understanding of discussions than oncologists estimated and more accurately estimated each other's understanding than did oncologists. Conclusions Companions and patients showed similar levels of agreement with oncologists about what they discussed during visits. Interventions are needed to improve communication of information to both patients and companions, especially about particular topics. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96703/1/pon3045.pd

Germline Maintenance Through the Multifaceted Activities of GLH/Vasa in

Vasa homologs are ATP-dependent DEAD-box helicases, multipotency factors, and critical components that specify and protect the germline. They regulate translation, amplify piwi-interacting RNAs (piRNAs), and act as RNA solvents; however, the limited availability of mutagenesis-derived alleles and their wide range of phenotypes have complicated their analysis. Now, with clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), these limitations can be mitigated to determine why protein domains have been lost or retained throughout evolution. Here, we define the functional motifs of GLH-1/Vasa i

Phase II Trial of Docetaxel Chemotherapy in Patients with Incurable Adenocarcinoma of the Esophagus

Background : Chemotherapy remains theprimary mode of treatment for metastaticcarcinoma of the esophagus. The efficacyof various chemotherapeutic regimens hasbeen studied predominantly in patients withsquamous cell carcinoma of the esophagus. In light of the increasing incidence ofadenocarcinoma of the esophagus, studiesevaluating newer chemotherapy agents, suchas docetaxel, in this patient populationare necessary. The objective of this trialwas to determine the complete and partialresponse rate of docetaxel in patients withincurable adenocarcinoma of theesophagus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45210/1/10637_2004_Article_390685.pd

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Abstract Background Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. Methods In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. Results In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. Conclusion IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Trial registration ClinicalTrials.gov Identifier: NCT0038928

Anti-androgenic activity of absorption-enhanced 3, 3\u27-diindolylmethane in prostatectomy patients

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3\u27-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer