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Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
Huselton, E, Rettig, MP, Campbell, K, Cashen, AF, DiPersio, JF, Gao, F, Jacoby, MA, Pusic, I, Romee, R, Schroeder, MA, et al
Leukemia research. 2021;:106713
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Abstract
Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study.
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Immune characterization of metastatic colorectal cancer patients post reovirus administration.
Parakrama, R, Fogel, E, Chandy, C, Augustine, T, Coffey, M, Tesfa, L, Goel, S, Maitra, R
BMC cancer. 2020;(1):569
Abstract
BACKGROUND KRAS mutations are prevalent in 40-45% of patients with colorectal cancer (CRC) and targeting this gene has remained elusive. Viruses are well known immune sensitizing agents. The therapeutic efficacy of oncolytic reovirus in combination with chemotherapy is examined in a phase 1 study of metastatic CRC. This study evaluates the nature of immune response by determining the cytokine expression pattern in peripheral circulation along with the distribution of antigen presenting cells (APCs) and activated T lymphocytes. Further the study evaluates the alterations in exosomal and cellular microRNA levels along with the effect of reovirus on leukocyte transcriptome. METHODS Reovirus was administered as a 60-min intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3 × 1010. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood prior to reovirus administration and post-reovirus on days 2, 8, and 15. The expression profile of 25 cytokines in plasma was assessed (post PBMC isolation) on an EMD Millipore multiplex Luminex platform. Exosome and cellular levels of miR-29a-3p was determined in pre and post reovirus treated samples. Peripheral blood mononuclear cells were stained with fluorophore labelled antibodies against CD4, CD8, CD56, CD70, and CD123, fixed and evaluated by flow cytometry. The expression of granzyme B was determined on core biopsy of one patient. Finally, Clariom D Assay was used to determine the expression of 847 immune-related genes when compared to pre reovirus treatment by RNA sequencing analysis. A change was considered if the expression level either doubled or halved and the significance was determined at a p value of 0.001. RESULTS Cytokine assay indicated upregulation at day 8 for IL-12p40 (2.95; p = 0.05); day 15 for GM-CSF (3.56; p = 0.009), IFN-y (1.86; p = 0.0004) and IL-12p70 (2.42; p = 0.02). An overall reduction in IL-8, VEGF and RANTES/CCL5 was observed over the 15-day period. Statistically significant reductions were observed at Day 15 for IL-8 (0.457-fold, 53.3% reduction; p = 0.03) and RANTES/CC5 (0.524-fold, 47.6% reduction; p = 0.003). An overall increase in IL-6 was observed, with statistical significance at day 8 (1.98- fold; 98% increase, p = 0.00007). APCs were stimulated within 48 h and activated (CD8+ CD70+) T cells within 168 h as determine by flow cytometry. Sustained reductions in exosomal and cellular levels of miR-29a-3p (a microRNA upregulated in CRC and associated with decreased expression of the tumor suppressor WWOX gene) was documented. Reovirus administration further resulted in increases in KRAS (33x), IFNAR1 (20x), STAT3(5x), and TAP1 (4x) genes after 2 days; FGCR2A (23x) and CD244 (3x) after 8 days; KLRD1 (14x), TAP1 (2x) and CD244(2x) after 15 days. Reductions (> 0.5x) were observed in VEGFA (2x) after 2 days; CXCR2 (2x), ITGAM (3x) after 15 days. CONCLUSIONS Reovirus has profound immunomodulatory properties that span the genomic, protein and immune cell distribution levels. This is the first study with reovirus in cancer patients that demonstrates these multi- layered effects, demonstrating how reovirus can function as an immune stimulant (augmenting the efficacy of immuno-chemo-therapeutic drugs), and an oncolytic agent. Reovirus thus functions bimodally as an oncolytic agent causing lysis of tumor cells, and facilitator of immune-mediated recognition and destruction of tumor cells.
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Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib.
Crona, DJ, Skol, AD, Leppänen, VM, Glubb, DM, Etheridge, AS, Hilliard, E, Peña, CE, Peterson, YK, Klauber-DeMore, N, Alitalo, KK, et al
Cancer research. 2019;(1):231-241
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Abstract
Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. SIGNIFICANCE Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.
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Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.
Goff, LW, Azad, NS, Stein, S, Whisenant, JG, Koyama, T, Vaishampayan, U, Hochster, H, Connolly, R, Weise, A, LoRusso, PM, et al
Investigational new drugs. 2019;(2):315-322
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Abstract
Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m2) and oxaliplatin (85 mg/m2) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m2) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m2 oxaliplatin and 2400 mg/m2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.
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Effects of genistein supplementation on genome‑wide DNA methylation and gene expression in patients with localized prostate cancer.
Bilir, B, Sharma, NV, Lee, J, Hammarstrom, B, Svindland, A, Kucuk, O, Moreno, CS
International journal of oncology. 2017;(1):223-234
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Abstract
Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. We investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy using Illumina HumanMethylation450 and Illumina HumanHT-12 v4 Expression BeadChip Microarrays. The present study was a randomized, placebo-controlled, double-blind clinical trial on Norwegian patients who received 30 mg genistein or placebo capsules daily for 3-6 weeks before prostatectomy. Gene expression changes were validated by quantitative PCR (qPCR). Whole genome methylation and expression profiling identified differentially methylated sites and expressed genes between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation and transcriptional regulation. Enrichment analysis suggested overall reduction in MYC activity and increased PTEN activity in genistein-treated patients. These findings highlight the effects of genistein on global changes in gene expression in prostate cancer and its effects on molecular pathways involved in prostate tumorigenesis.
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An ANOCEF genomic and transcriptomic microarray study of the response to irinotecan and bevacizumab in recurrent glioblastomas.
Laffaire, J, Di Stefano, AL, Chinot, O, Idbaih, A, Gallego Perez-Larraya, J, Marie, Y, Vintonenko, N, Boisselier, B, Farina, P, Delattre, JY, et al
BioMed research international. 2014;:282815
Abstract
BACKGROUND We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence. RESULTS Comparison of the genomic and gene expression profiles of the responders (n = 12) and nonresponders (n = 13) demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates. GBMs assigned to molecular subtype IGS-18 and to classical subtype had a lower response rate than those assigned to other subtypes. In an independent series of 33 patients, neither EGFR amplification nor CDKN2A deletion (which are frequent in IGS-18 and classical GBMs) was significantly associated with the response rate, suggesting that these two alterations are unlikely to explain the lower response rate of these GBMs molecular subtypes. CONCLUSION Despite its limited sample size, the present study suggests that comparing the initial molecular profiles of responders and nonresponders might not be an effective strategy to identify biomarkers of the response to bevacizumab given at recurrence. Yet it suggests that the response rate might differ among GBMs molecular subtypes.
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Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer.
Yi, JH, Do, IG, Jang, J, Kim, ST, Kim, KM, Park, SH, Park, JO, Park, YS, Lim, HY, Kang, WK, et al
Scientific reports. 2014;:7592
Abstract
To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant. Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.
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Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway.
Ji, Q, Liu, X, Fu, X, Zhang, L, Sui, H, Zhou, L, Sun, J, Cai, J, Qin, J, Ren, J, et al
PloS one. 2013;(11):e78700
Abstract
Resveratrol, extracted from Chinese herbal medicine Polygonum cuspidatum, is known to inhibit invasion and metastasis of human colorectal cancer (CRC), in which long non-coding Metastasis Associated Lung Adenocarcinoma Transcript 1 (RNA-MALAT1) also plays an important role. Using MALAT1 lentiviral shRNA and over-expression constructs in CRC derived cell lines, LoVo and HCT116, we demonstrated that the anti-tumor effects of resveratrol on CRC are through inhibiting Wnt/β-catenin signaling, thus the expression of its target genes such as c-Myc, MMP-7, as well as the expression of MALAT1. In detail, resveratrol down-regulates MALAT1, resulting in decreased nuclear localization of β-catenin thus attenuated Wnt/β-catenin signaling, which leads to the inhibition of CRC invasion and metastasis. This finding of ours surely provides important pre-clinical evidence supporting future use of resveratrol in prevention and treatment of CRC.
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A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.
Eustace, A, Mani, N, Span, PN, Irlam, JJ, Taylor, J, Betts, GN, Denley, H, Miller, CJ, Homer, JJ, Rojas, AM, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;(17):4879-88
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Abstract
PURPOSE Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types. EXPERIMENTAL DESIGN Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). RESULTS Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P=0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P=0.90). TLDA-HS did not predict benefit from CON in bladder cancer. CONCLUSION The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial.
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Expression of drug targets in patients treated with sorafenib, carboplatin and paclitaxel.
Jilaveanu, LB, Zhao, F, Zito, CR, Kirkwood, JM, Nathanson, KL, D'Andrea, K, Wilson, M, Rimm, DL, Flaherty, KT, Lee, SJ, et al
PloS one. 2013;(8):e69748
Abstract
INTRODUCTION Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). METHODS Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. RESULTS An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). CONCLUSIONS In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen.