Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update.

ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).

DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.

Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and ß-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

PURPOSE: To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS: An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS: The panel considered peer-reviewed reports published in English. RECOMMENDATIONS: The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Diet and Health-related Quality of Life Among Men on Active Surveillance for Early-stage Prostate Cancer: The Men's Eating and Living Study (Cancer and Leukemia Group 70807 [Alliance]).

BACKGROUND: Health-related quality of life (HRQoL) among patients with localized prostate cancer (PC) on active surveillance (AS) and whether it may be improved through lifestyle-focused interventions remain underdefined. OBJECTIVE: To assess longitudinal changes in HRQoL in patients who received and those who did not receive a behavioral intervention that increased vegetable intake. DESIGN, SETTING, AND PARTICIPANTS: A secondary analysis of participants in the Men's Eating and Living (MEAL) study (Cancer and Leukemia Group 70807 [Alliance]), a randomized trial of vegetable consumption in patients on AS, was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient-reported outcomes (PROs) included the Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the Expanded Prostate Cancer Index Composite 26 (EPIC-26), and the Functional Assessment of Cancer Therapy Scale-Prostate (FACT-P). Areas under the curves (AUCs) were used to summarize serial HRQoL. RESULTS AND LIMITATIONS: PROs were completed in 87% (n = 387) of the intention-to-collect population. Baseline characteristics of patients completing HRQoL measures did not differ significantly from the entire study population or between groups. Baseline scores were high for all PROs and remained stable over 24 mo, with no significant differences from baseline at any time point. In adjusted analyses, there were no significant differences in summary AUC measures comparing control with intervention for the total MAX-PC score (p = 0.173); EPIC-26 domains of urinary incontinence (p = 0.210), urinary obstruction (p = 0.062), bowel health (p = 0.607), sexual health (p = 0.398), and vitality (p = 0.363); and total FACT-P scores (p = 0.471). CONCLUSIONS: Among men with localized PC on AS enrolled in a randomized trial, HRQoL was high across multiple domains at baseline, remained high during follow-up, and did not change in response to a behavioral intervention that increased vegetable intake. PATIENT SUMMARY: Patients with localized prostate cancer enrolled on active surveillance experience minimal cancer-associated anxiety, suffer low levels of cancer-associated symptoms, and perceive high physical and emotional well-being.

Validation of the Association of RECIST Changes With Survival in Men With Metastatic Castration-Resistant Prostate Cancer Treated on SWOG Study S0421.

BACKGROUND: Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. PATIENTS AND METHODS: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. RESULTS: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002). CONCLUSION: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.

Patient-reported outcomes for patients with metastatic castration-resistant prostate cancer receiving docetaxel and Atrasentan versus docetaxel and placebo in a randomized phase III clinical trial (SWOG S0421).

Background: SWOG S0421 was a large randomized trial comparing docetaxel/prednisone plus placebo (DPP) to docetaxel/prednisone plus atrasentan over 12 cycles for patients with metastatic castration-resistant prostate cancer (mCRPC). The current report presents the PRO results for this trial, an important secondary endpoint. Methods: The trial specified two primary PRO endpoints. Palliation of worst pain was based on the Brief Pain Inventory (BPI), where a 2 point difference is defined as clinically meaningful. Improvement of functional status was based on the Functional Assessment of Cancer Therapy - Prostate Cancer Trial Outcome Index (FACT-P TOI); a 5-point difference has been defined as clinically meaningful. We compared rates by arm using chi-square tests. Longitudinal analyses using linear mixed models addressed changes by arm over time. Results: Four-hundred eighty-nine patients on each arm were evaluable for PRO endpoint data. There were no differences by arm in clinically meaningful pain palliation (41.7% for DPP vs. 44.0% for DPA, p = .70) or functional status (24.2% for DPP vs. 28.7% for DPA, p = .13). Longitudinal comparisons indicated no differences over time by arm for BPI Worst Pain scores (0.13 points, p = .23). Patients on the DPA arm had improved functional status of 1.78 points on average, a statistically significant (p = .02) but not clinically meaningful difference. Conclusions: The SWOG S0421 PRO data showed little evidence of clinically meaningful differences by arm in either pain palliation or functional status.

The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review.

Renal Cell Carcinoma (RCC) is the most prominent kidney cancer derived from renal tubules and accounts for roughly 85% of all malignant kidney cancer. Every year, over 60,000 new cases are registered, and about 14,000 people die from RCC. The incidence of this has been increasing significantly in the U.S. and other countries. An increased understanding of molecular biology and the genomics of RCC has uncovered several signaling pathways involved in the progression of this cancer. Significant advances in the treatment of RCC have been reported from agents approved by the Food and Drug Administration (FDA) that target these pathways. These agents have become drugs of choice because they demonstrate clinical benefit and increased survival in patients with metastatic disease. However, the patients eventually relapse and develop resistance to these drugs. To improve outcomes and seek approaches for producing long-term durable remission, the search for more effective therapies and preventative strategies are warranted. Treatment of RCC using natural products is one of these strategies to reduce the incidence. However, recent studies have focused on these chemoprevention agents as anti-cancer therapies given they can inhibit tumor cell grow and lack the severe side effects common to synthetic compounds. This review elaborates on the current understanding of natural products and their mechanisms of action as anti-cancer agents. The present review will provide information for possible use of these products alone or in combination with chemotherapy for the prevention and treatment of RCC.

Impact Study: MK-0646 (Dalotuzumab), Insulin Growth Factor 1 Receptor Antibody Combined with Pemetrexed and Cisplatin in Stage IV Metastatic Non-squamous Lung Cancer.

BACKGROUND: Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL. METHODS: Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500 mg/m(2) and C at 75 mg/m(2) IV were given every 3 weeks. D was given at 10 mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PC + D. RESULTS: From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC + D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PC + D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4. CONCLUSION: PC + D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL. TRIAL REGISTRATION: NCT00799240, clinicaltrials.gov.

A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker in patients with extensive small-cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC. METHODS: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6-8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs. RESULTS: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0-3430) and 2 (range 0-526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range -100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival. CONCLUSION: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients' clinical responses to therapy.

Prostate-specific antigen and prostate-specific antigen velocity as threshold indicators in 11C-acetate PET/CTAC scanning for prostate cancer recurrence.

PURPOSE: The aim of this study was to identify which patient characteristics are associated with the highest likelihood of positive findings on 11C-acetate PET/computed tomography attenuation correction (CTAC) (PET/CTAC) scan when imaging for recurrent prostate cancer. METHODS: From 2007 to 2011, 250 11C-acetate PET/CTAC scans were performed at a single institution on patients with prostate cancer recurrence after surgery, brachytherapy, or external beam radiation. Of these patients, 120 met our inclusion criteria. Logistic regression analysis was used to examine the relationship between predictability of positive findings and patients' characteristics, such as prostate-specific antigen (PSA) level at the time of scan, PSA kinetics, Gleason score, staging, and type of treatment before scan. RESULTS: In total, 68.3% of the 120 11C-acetate PET/CTAC scans were positive. The percentage of positive scans and PSA at the time of scanning and PSA velocity (PSAV) had positive correlations. The putative sensitivity and specificity were 86.6% and 65.8%, respectively, when a PSA level greater than 1.24 ng/mL was used as the threshold for scanning. The putative sensitivity and specificity were 74% and 75%, respectively, when a PSAV level greater than 1.32 ng/mL/y was used as the threshold. No significant associations were found between scan positivity and age, PSA doubling time, Gleason score, staging, or type of treatment before scanning. CONCLUSIONS: This retrospective study suggests that threshold models of PSA greater than 1.24 ng/mL or PSAV greater than 1.32 ng/mL per year are independent predictors of positive findings in 11C-acetate PET/CTAC imaging of recurrent prostate cancer.

Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.

PURPOSE: Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. PATIENTS AND METHODS: CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. RESULTS: Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). CONCLUSION: These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.

Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial.

BACKGROUND: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. METHODS: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m(2) every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. FINDINGS: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. INTERPRETATION: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. FUNDED: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200.

BACKGROUND: Glioblastoma multiforme is the most common form of primary brain tumor, often characterized by poor survival. Glioblastoma initiating cells (GICs) regulate self-renewal, differentiation, and tumor initiation properties and are involved in tumor growth, recurrence, and resistance to conventional treatments. The sonic hedgehog (SHH) signaling pathway is essential for normal development and embryonic morphogenesis. The objectives of this study were to examine the molecular mechanisms by which GIC characteristics are regulated by NPV-LDE-225 (Smoothened inhibitor; (2,2'-[[dihydro-2-(4-pyridinyl)-1,3(2H,4H)-pyrimidinediyl]bis(methylene)]bis[N,N-dimethylbenzenamine). METHODS: Cell viability and apoptosis were measured by XTT and annexin V-propidium iodide assay, respectively. Gli translocation and transcriptional activities were measured by immunofluorescence and luciferase assay, respectively. Gene and protein expressions were measured by quantitative real-time PCR and Western blot analyses, respectively. RESULTS AND CONCLUSION: NPV-LDE-225 inhibited cell viability, neurosphere formation, and Gli transcriptional activity and induced apoptosis by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. NPV-LDE-225 increased the expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-R1/DR4, TRAIL-R2/DR5, and Fas and decreased the expression of platelet derived growth factor receptor-α and Bcl2, and these effects were abrogated by Gli1 plus Gli2 short hairpin RNAs. NPV-LDE-225 enhanced the therapeutic potential of FasL and TRAIL by upregulating Fas and DR4/5, respectively. Interestingly, NPV-LDE-225 induced expression of programmed cell death 4 and apoptosis and inhibited cell viability by suppressing micro RNA (miR)-21. Furthermore, NPV-LDE-225 inhibited pluripotency-maintaining factors Nanog, Oct4, Sox2, and cMyc. The inhibition of Bmi1 by NPV-LDE-225 was regulated by induction of miR-128. Finally, NPV-LDE-225 suppressed epithelial-mesenchymal transition by upregulating E-cadherin and inhibiting N-cadherin, Snail, Slug, and Zeb1 through modulating the miR-200 family. Our data highlight the importance of the SHH pathway for self-renewal and early metastasis of GICs.

A second-generation 2-Methoxyestradiol prodrug is effective against Barrett's adenocarcinoma in a mouse xenograft model.

2-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem, we have now synthesized and tested a new prodrug of 2-ME2 that is water-soluble due to a bioreversible hydrophilic group added at the 3-position and that more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anticancer agent for both in vitro and in vivo studies against Barrett esophageal adenocarcinoma (BEAC) and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule network.

Phase II evaluation of early oral estramustine, oral etoposide, and intravenous paclitaxel combined with hormonal therapy in patients with high-risk metastatic prostate adenocarcinoma: Southwest Oncology Group S0032.

OBJECTIVES: To assess the efficacy of a multiagent taxane-based chemotherapy combined with hormonal therapy in men with metastatic androgen-dependent prostate cancer in a multicenter, cooperative group, single-arm trial. METHODS: A total of 41 patients with newly diagnosed metastatic prostate cancer involving both the axial and the appendicular skeletons or viscera were enrolled. Of the 41 patients, 35 were treated with combined androgen blockade and ≤4 cycles of oral estramustine (280 mg orally 3 times daily) and etoposide (50 mg/m(2) daily) for 14 days of each 21-day cycle, with paclitaxel (135 mg/m(2) intravenously within 1 hour) on day 2 of each cycle. Chemotherapy was started within 30 days of the initiation of hormonal therapy. The patients were followed up to determine the progression-free survival. RESULTS: The 35 patients received a total of 126 cycles of chemotherapy, with 30 receiving all 4 cycles. The median progression-free survival for the evaluable population was 13 months (95% confidence interval 10-16), with a median overall survival of 38 months (95% confidence interval 28-49). The main toxicities were myelosuppression, with 9 patients experiencing grade 3 or greater neutropenia and 1 developing grade 4 thrombocytopenia. One patient died of neutropenic infection. Thrombosis embolism occurred 4 times (3 of grade 4 and 1 of grade 3), with 1 episode of grade 4 cardiac ischemia. CONCLUSIONS: The results of our study have shown that the administration of chemotherapy to this population is feasible, with moderate toxicity. Taxane-based chemotherapy did not demonstrate significant efficacy in this high-risk population of patients with a poor prognosis.

Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis.

BACKGROUND: Despite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood. RESULTS: We show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP) cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1. CONCLUSIONS: In conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

Potential role of platelet-derived growth factor receptor inhibition using imatinib in combination with docetaxel in the treatment of recurrent non-small cell lung cancer.

INTRODUCTION: Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. HYPOTHESIS: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC). METHODS: A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m/wk intravenously × 3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months. RESULTS: Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months. CONCLUSION: Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed.

Tumor cell-derived PDGF-B potentiates mouse mesenchymal stem cells-pericytes transition and recruitment through an interaction with NRP-1.

BACKGROUND: New blood vessel formation, or angiogenic switch, is an essential event in the development of solid tumors and their metastatic growth. Tumor blood vessel formation and remodeling is a complex and multi-step processes. The differentiation and recruitment of mural cells including vascular smooth muscle cells and pericytes are essential steps in tumor angiogenesis. However, the role of tumor cells in differentiation and recruitment of mural cells has not yet been fully elucidated. This study focuses on the role of human tumor cells in governing the differentiation of mouse mesenchymal stem cells (MSCs) to pericytes and their recruitment in the tumor angiogenesis process. RESULTS: We show that C3H/10T1/2 mouse embryonic mesenchymal stem cells, under the influence of different tumor cell-derived conditioned media, differentiate into mature pericytes. These differentiated pericytes, in turn, are recruited to bind with capillary-like networks formed by endothelial cells on the matrigel under in vitro conditions and recruited to bind with blood vessels on gel-foam under in vivo conditions. The degree of recruitment of pericytes into in vitro neo-angiogenesis is tumor cell phenotype specific. Interestingly, invasive cells recruit less pericytes as compared to non-invasive cells. We identified tumor cell-secreted platelet-derived growth factor-B (PDGF-B) as a crucial factor controlling the differentiation and recruitment processes through an interaction with neuropilin-1 (NRP-1) in mesenchymal stem cells. CONCLUSION: These new insights into the roles of tumor cell-secreted PDGF-B-NRP-1 signaling in MSCs-fate determination may help to develop new antiangiogenic strategies to prevent the tumor growth and metastasis and result in more effective cancer therapies.