Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.
SMAC Mimetics; Apoptosis; Inhibitors
Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.
Patients and Methods
Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.
One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).
Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated.
Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m2) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints.
Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%–76%) and 61.4% for arm B (95% CI = 48%–74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7–10.4 months) and 7.6 months for arm B (95% CI = 6.1–8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6–22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death.
GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.
urothelial carcinoma; chemotherapy; gemcitabine; cetuximab; cisplatin
Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity.
Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy- Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed.
A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p=0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm.
Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC.
Cediranib; Dasatinib; Castration resistant prostate cancer; Quality of life; Bone turnover marker
Purpose Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies. Methods Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m2 starting dose was doubled (one patient/dose) until 1.0 mg/m2 based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response. Results Ixazomib was escalated from 0.125 to 2.34 mg/m2 to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m2: grade 3 pruritic rash; 2.34 mg/m2: grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m2. Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8–7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement. Conclusions In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.
Electronic supplementary material
The online version of this article (doi:10.1007/s10637-015-0230-x) contains supplementary material, which is available to authorized users.
20S proteasome; Activating transcription factor 3; Ixazomib; Non-hematologic malignancies; Phase 1 clinical trial (4–6)
To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins.
This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1–5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100 % in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50 %. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken.
Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26 %), nausea (23 %), and vomiting (13 %). Average tmax and T1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3–6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17 %) had stable disease as the best treatment response.
DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2709-8) contains supplementary material, which is available to authorized users.
IAP; Apoptosis; AT-406; DEBIO1143; Cancer; Resistance
Everolimus, an oral inhibitor of mTOR, can augment the efficacy of HER inhibitors in pre-clinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus, and to describe its antitumor activity in the Phase I setting.
In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.
Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis and fatigue. The MTD of the combination was 1250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44% and mean clearance was decreased by 25% when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response (thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months); eleven patients attained stable disease of at least 4 months
Lapatinib and everolimus are well tolerated at doses of 1250 mg and 5 mg po daily, respectively. Stable disease >4 months/PR was achieved in 13 of 78 patients (17%).
everolimus; lapatinib; phase I; mTOR; Her2
This multicenter cooperative group single arm trial assessed the efficacy of a multiagent taxane-based chemotherapy in combination with hormonal therapy in men with metastatic androgen-dependent prostate cancer.
Forty-one patients with newly diagnosed metastatic prostate cancer involving both the axial and appendicular skeletons or viscera were enrolled. Thirty-five were treated with combined androgen blockade and up to 4 cycles of oral estramustine (280 mg orally 3 times per day) and etoposide (50 mg/m2 daily) for 14 days of each 21 day cycle, with paclitaxel (135 mg/m2 IV over 1 hour) on day 2 of each cycle. Chemotherapy was started within 30 days of initiation of hormonal therapy. Patients were followed to determine progression-free survival.
The median progression-free survival for the evaluable population was 13 months (95% CI 10–16 mo) with a median overall survival of 38 months (95% CI 28–49 mo). The main toxicities were myelosuppression with 9 patients with ≥ grade 3 neutropenia, and 1 with grade 4 thrombocytopenia. One patient died with neutropenic infection. Four episodes of thrombosis embolism occurred (3 grade 4, 1 grade 3) with one episode of grade 4 cardiac ischemia.
Administration of chemotherapy to this population is feasible with moderate toxicity. This is a high-risk population with poor prognosis and this study serves as a basis for ongoing phase III trials assessing this approach in metastatic prostate cancer.
Sediment samples collected off the coast of San Diego were analyzed for actinomycete diversity using culture independent techniques. Eight new operational taxonomic units (OTUs) in the Streptomycetaceae were identified as well as new diversity within previously cultured marine OTUs. Sequences belonging to the marine actinomycete genus Salinispora were also detected, despite the fact that this genus has only been reported from more tropical environments. Independent analyses of marine sediments from the Canary Basin (3814 m) and the South Pacific Gyre (5126 and 5699 m) also revealed Salinispora sequences providing further support for the occurrence of this genus in deep-sea sediments. Efforts to culture Salinispora spp. from these samples have yet to be successful. This is the first report of Salinispora spp. from marine sediments >1100m and suggests that the distribution of this genus is broader than previously believed.
A noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole was conducted in men with metastatic prostate cancer.
The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.
Patients and Methods.
We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.
The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.
High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
Itraconazole; Prostate cancer; Angiogenesis; Hedgehog pathway
An ecosystem approach is widely seen as a desirable goal for fisheries management but there is little consensus on what strategies or measures are needed to achieve it. Management strategy evaluation (MSE) is a tool that has been widely used to develop and test single species fisheries management strategies and is now being extended to support ecosystem based fisheries management (EBFM). We describe the application of MSE to investigate alternative strategies for achieving EBFM goals for a complex multispecies fishery in southeastern Australia. The study was undertaken as part of a stakeholder driven process to review and improve the ecological, economic and social performance of the fishery. An integrated management strategy, involving combinations of measures including quotas, gear controls and spatial management, performed best against a wide range of objectives and this strategy was subsequently adopted in the fishery, leading to marked improvements in performance. Although particular to one fishery, the conclusion that an integrated package of measures outperforms single focus measures we argue is likely to apply widely in fisheries that aim to achieve EBFM goals.
This two-arm phase II multicenter trial was designed to assess the efficacy and toxicity of neoadjuvant paclitaxel, gemcitabine, and carboplatin (PCaG) in patients with invasive bladder cancer.
Patients in arm I had either clinical stage T2 with hydronephrosis or T3 bladder cancer. They received 3 cycles of chemotherapy (paclitaxel 200mg/m2 day 1, carboplatin area under the curve (AUC)= 5 day 1, and gemcitabine 800mg/m2 days 1 and 8 of each 21 day cycle). Response was defined as achievement of a pathologic complete response (pT0). Patients on arm II with T4 or lymph node positive disease received up to 6 cycles of PCaG. Response was defined as conversion to surgical resectability.
In arm I, 31 patients were enrolled and 22 were evaluable for response. Seven were pT0 (32% of evaluable patients, 22% by intent to treat). In arm II, 37 patients were enrolled and 29 were evaluable for response with 24 surgically resectable (83% of evaluable and 65% by intent to treat). The most common toxicity was neutropenia with 39 events in arm 1 and 68 in arm 2. There were 7 deaths on study (5 during chemotherapy and 2 post-cystectomy).
Neoadjuvant PCaG resulted in a significant number of responses in both arms but greater than anticipated toxicity. The pT0 rate was modest and overall efficacy difficult to assess due to the toxicity. More studies of novel agents and combinations are needed to improve the efficacy, and reduce the toxicity of neoadjuvant therapy for bladder cancer.
Associations between water sources, socio-demographic characteristics and household drinking water quality are described in a representative sample of six coastal districts of Ghana’s Central Region. Thirty-six enumeration areas (EAs) were randomly chosen from a representative survey of 90 EAs in rural, semi-urban and urban residence strata. In each EA, 24 households were randomly chosen for water quality sampling and socio-demographic interview. Escherichia coli per 100 ml H2O was quantified using the IDEXX Colilert® system and multi-stage regression models estimated cross-sectional associations between water sources, sanitation and socio-demographic factors. Almost three quarters, 74%, of the households have > 2 E. coli /100 ml H2O. Tap water has significantly lower E. coli levels compared with surface or rainwater and well water had the highest levels. Households with a water closet toilet have significantly lower E. coli compared with those using pit latrines or no toilets. Household size is positively associated, and a possessions index is negatively associated, with E. coli. Variations in community and household socio-demographic and behavioural factors are key determinants of drinking water quality. These factors should be included in planning health education associated with investments in water systems.
E. coli; Ghana; household water source; rural urban effects; sanitation; water quality
The crude extract of an Alaskan ethnobotanical plant, Oplopanax horridus, was subjected to counter-current chromatography (CCC), and the selected active regions were evaluated for their synergistic effects with an in vitro model of anti-tubercular efficacy. CCC as a support-free high-resolution separation method was employed to preclude potential irreversible absorption to a solid stationary phase. The microplate Alamar blue assay and the isobole method were used to measure the biological activity and eliminate dose-response dependent errors, respectively. Using the combination of CCC, bioassay and isobole method, significant synergistic effects were observed. Among the entire polarity range, fractions with distribution constant between 0.44 and 0.81 showed the most synergistic enhancement with an increase in potency by 108% for the recombined fractions.
Devil’s Club; Oplopanax horridus; synergy; CCC; isobole method
Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.
We enrolled patients with advanced melanoma, non–small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.
A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006).
Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)
Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC).
Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500mg or 2000mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at six-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers.
Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500mg arm: 1–8; 2000 mg arm: 1–15). At six months, two pts (9%) on the 500mg arm and five pts (23%) on the 2000mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms.
Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.
prostate cancer; metastatic disease; integrins; angiogenesis; cilengitide; bone biomarkers
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogenactivated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.
Integrins mediate invasion and angiogenesis in prostate cancer bone metastases. We conducted a phase II study of Cilengitide, a selective antagonist of αvβ3 and αvβ5 integrins, in non-metastatic castration resistant prostate cancer with rising PSA.
Patients were observed for 4 weeks with PSA monitoring, and then treated with 2,000 mg IV of cilengitide twice weekly until toxicity/progression. PSA, circulating tumor cells (CTCs) and circulating endothelial cells (CECs) were monitored each cycle with imaging performed every 3 cycles. Primary end point was PSA decline by ≥ 50%. Secondary endpoints were safety, PSA slope, time to progression (TTP), overall survival (OS), CTCs, CECs and gene expression.
16 pts were enrolled; 13 were eligible with median age 65.5 years, baseline PSA 8.4 ng/mL and median Gleason sum 7. Median of 3 cycles was administered. Treatment was well tolerated with 2 grade 3 toxicities and no grade 4 toxicities. There were no PSA responses; 11 patients progressed by PSA after 3 cycles. Median TTP was 1.8 months and median OS has not been reached. Median pre- and on-treatment PSA slopes were 1.1 and 1.8 ng/mL/month. Baseline CTCs were detected in 1/9 patients. CTC increased (0 to 1; 2 pts), remained at 0 (2 pts) or decreased (23 to 0; 1 patient) at progression. Baseline median CEC was 26 (0–61) and at progression, 47 (15–148). Low cell counts precluded gene expression studies.
Cilengitide was well tolerated but had no detectable clinical activity. CTCs are of questionable utility in non-metastatic prostate cancer.
EMD 121974; cilengitide; non-metastatic prostate cancer
Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research.
We demonstrate, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 recent autopsies conducted at the University of Michigan, and analyzed the gene expression of these tissues using real time PCR and microarrays.
We present here the discovery of non-ossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to non-osseous metastases from the same patients
This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA and cDNA from tumor samples metastatic to the bone.
Bone marrow; tumor; metastatic prostate cancer
This phase II trial was designed to evaluate the efficacy of vorinostat in chemotherapy pretreated patients with metastatic castrate resistant prostate cancer.
Patients and Methods
Patients with disease progression on one prior chemotherapy, a PSA ≥ 5ng/ml, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the six month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum IL-6 levels.
Twenty-seven eligible patients were accrued. Median number of cycles delivered was 2 (range 1–7). All patients were taken off therapy before six months. The best objective response in the eligible patients was stable disease in 2 (7%) patients. No PSA decline of ≥ 50% was observed. There was one grade 4 adverse event (AE) and 44% of patients experienced grade 3 AEs. Most common AEs were: fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months respectively. Median IL-6 levels (pg/ml) were higher in patients removed from protocol for toxicity vs. progression at all time points, including baseline (5.2 vs 2.1, p=0.02), Day 15-Cycle 1 (9.5 vs 2.2, p=0.01), Day 1-Cycle 2 (9.8 vs 2.2, p=0.01), and end of study (11.0 vs 2.9, p=0.09)
Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL-6 levels and removal from study for toxicities warrants further investigation.
prostate cancer; metastatic; HDAC inhibitors; IL-6; SAHA; vorinostat; Zolinza
Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.
Patients and Methods
Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or ≥ grade 3 nonhematologic toxicity.
Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced ≥ 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone ≥ 30 mg/m2, nine (43%) experienced ≥ 50% PSA declines (95% CI, 22% to 66%).
These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.
We conducted a phase II trial of neoadjuvant paclitaxel, carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 (cT0) rate with paclitaxel, carboplatin and gemcitabine, and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy.
Materials and Methods
Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible. T2+ tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection. Three cycles of paclitaxel, carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection. Patients with cT0 status after paclitaxel, carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance, and those with greater than cT0 status were to undergo immediate cystectomy.
Of 77 patients 74 were assessable, and cT0 status after paclitaxel, carboplatin and gemcitabine was achieved in 34 of 74 patients (46%). Of the 34 patients with cT0 status 10 underwent immediate cystectomy, 6 of whom had persistent cancer. Persistent tumor at transurethral bladder tumor resection was seen in 28 patients (38%) and 21 underwent cystectomy. Thus, 35 of 74 patients underwent cystectomy. With a median followup of 22 months 2-year overall survival was 59% (95% CI 45, 72) and among cT0 cases it was 75% (95% CI 57, 93).
Although neoadjuvant paclitaxel, carboplatin and gemcitabine had a promising 46% cT0 rate, the study failed to meet the primary objective as there was an unacceptably high rate (60%) of persistent cancer at cystectomy in patients presumed to have pT0 status. Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status.
carcinoma; transitional cell; drug therapy
Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.
Semi-volatile organic compounds (SVOCs) in estuarine waters can adversely affect biota but watershed sources can be difficult to identify because these compounds are transient. Natural bacterial assemblages may respond to chronic, episodic exposure to SVOCs through selection of more organotolerant bacterial communities. We measured bacterial production, organotolerance and polycyclic aromatic hydrocarbon (PAH) mineralization in Charleston Harbor and compared surface sediment from stations near a known, permitted SVOC outfall (pulp mill effluent) to that from more pristine stations. Naphthalene additions inhibited an average of 77% of bacterial metabolism in sediments from the more pristine site (Wando River). Production in sediments nearest the outfall was only inhibited an average of 9% and in some cases, was actually stimulated. In general, the stations with the highest rates of bacterial production also were among those with the highest rates of PAH mineralization. This suggests that the capacity to mineralize PAH carbon is a common feature amongst the bacterial assemblage in these estuarine sediments and could account for an average of 5.6% of bacterial carbon demand (in terms of production) in the summer, 3.3% in the spring (April) and only 1.2% in winter (December).
Naphthalene; Organotolerance; Bacterial production; SVOC; PAH mineralization