Faculty Bibliography

A dendrimer-based building block for theranostics was designed. The multifunctional dendrimer is polyamide-based and contains nine azide termini, nine amine termini, and fifty-four terminal acid groups. Orthogonal functionalization of the multifunctional dendrimer with a near-infrared (NIR) cyanine dye afforded the final dendrimer that shows fluorescence in the NIR region and no toxicity toward T98G human cells. The synthetic strategy described here might be promising for fabricating the next generation of materials for theranostics

BACKGROUND: Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six patients treatment-naive advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE: Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION: Clinical Trials.gov NCT00119249

BACKGROUND: The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). METHODS: Patients with stage III-IV OFPC initiated treatment within 12weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175mg/m(2)) and carboplatin (AUC 6) every 3weeks for up to 6 cycles, plus oral erlotinib 150mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10). RESULTS: The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC

BACKGROUND: Although adolescent major depressive disorder (MDD) is acknowledged to be a heterogeneous disorder, no studies have reported on biological correlates of its clinical subgroups. This study addresses this issue by examining whether adolescent MDD with and without melancholic features (M-MDD and NonM-MDD) have distinct biological features in the kynurenine pathway (KP). The KP is initiated by pro-inflammatory cytokines via induction of the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN). KYN is further metabolized into neurotoxins linked to neuronal dysfunction in MDD. Hypotheses were that, compared to healthy controls and to NonM-MDD adolescents, adolescents with M-MDD would exhibit: (i) increased activation of the KP [i.e., increased KYN and KYN/TRP (reflecting IDO activity)]; (ii) greater neurotoxic loads [i.e., increased 3-hydroxyanthranilic acid (3-HAA, neurotoxin) and 3-HAA/KYN (reflecting production of neurotoxins)]; and (iii) decreased TRP. We also examined relationships between severity of MDD and KP metabolites. METHODS: Subjects were 20 adolescents with M-MDD, 30 adolescents with NonM-MDD, and 22 healthy adolescents. MDD episode duration had to be >or= 6 weeks and Children's Depression Rating Scale-Revised (CDRS-R) scores were >or= 36. Blood samples were collected at AM after an overnight fast and analyzed using high-performance liquid chromatography. Group contrasts relied on analysis of covariance based on ranks, adjusted for age, gender, and CDRS-R scores. Analyses were repeated excluding medicated patients. Fisher's protected least significant difference was used for multiple comparisons. RESULTS: As hypothesized, KYN/TRP ratios were elevated and TRP concentrations were reduced in adolescents with M-MDD compared to NonM-MDD adolescents (p = .001 and .006, respectively) and to healthy controls (p = .008 and .022, respectively). These findings remained significant when medicated patients were excluded from the analyses. Significant correlations were obtained exclusively in the M-MDD group between KYN and 3-HAA/KYN and CDRS-R. CONCLUSIONS: Findings support the notion that adolescent M-MDD may represent a biologically distinct clinical syndrome

ABSTRACT: BACKGROUND: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age=58, mean thickness=2.09 mm, stage I=136, stage II=41, stage III=32, median follow-up=54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. RESULTS: HU177 sera concentrations ranged from 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p=0.04) and with increasing mortality (p=0.01). The association with overall survival remained statistically significant after controlling for thickness and histologic subtype in a multivariate model (p=0.035). CONCLUSIONS: Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care

BACKGROUND: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group. METHODS: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected. RESULTS: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively. CONCLUSIONS: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow

PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mug/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved

Background: TRC093 is a humanized monoclonal antibody that specificallybinds cleaved collagen and has been shown to inhibit angiogenesisand tumor growth in preclinical studies. TRC093 is currentlybeing evaluated in a phase I clinical study for the treatment of metastatic human tumors (Gordon et al. EJC Supp 6, abs #414, pp130, 2008). Interestingly, one of the patients in this studywith granulosa cell carcinoma of the ovary with progressivedisease had a mixed response in the liver after 2 months of treatment. Given these encouraging results, we began to examinethe biological relevance of the cryptic epitope recognized byTRC093 in ovarian carcinoma and whether a soluble form of thiscryptic collagen epitope may represent a clinically useful markerfor patients at risk for ovarian and breast cancer. To thisend, we have adapted an ELISA assay for the detection of theshed collagen cryptic epitope that is defined by this antibodyto examine a patient population at risk for ovarian and breastcancer. Methods: To begin to assess the relevance of the cryptic collagenepitope recognized by TRC093 in ovarian tumor growth, humanSKOV3 ovarian carcinoma cells were injected subcutaneously intonude mice. Six days later when detectable tumors were observed,mice were treated (i.p.) 3x per week with TRC093 over a doserange up to 250 mug/injection for a period of 28 days.To assess the relevance of a shed soluble form of the crypticcollagen epitope in a patient population at risk for ovarianand breast cancer, serum samples from a group of high-risk womenvolunteers prospectively enrolled at the NYU School of Medicinewere analyzed for TRC093 epitope concentration by ELISA as previouslydescribed (Ng et al., Clin Can Res, 14:6253). Results: TRC093 significantly (p< 0.05) inhibited SKOV3 tumorgrowth at 100 mug and 250 mug/injection as comparedto control. These findings suggest that theTRC093 cryptic collagenepitope may represent a relevant therapeutic target for ovariancarcinoma. In a group of 23 high-risk women identified withrespect to their clinical status, a mean mu SEM of 42.9mu 9.8 mug/ml was determined for the patients withovarian/ breast cancer history compared with a mean of 15.3mu 2.9 mug/ml for normal women in this study population(p = 0.0254). Conclusions: The TRC093 shed serum epitope can distinguish betweena high-risk population of women with breast or ovarian cancerand normal clinical status. We are expanding the sample sizewith more ovarian surgical patients. The xenograft studies providefurther support for the potential use of the SKOV3 human ovariancarcinoma model to examine the effect of TRC093 in combinationwith cisplatin and or bevacizumab. The TRC093 epitope may representa key therapeutic target in ovarian cancer