bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of PRL-3 genomic amplification/expression profiles and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers.
Authors: Yamashita Keishi , Watanabe Masahiko 
Published: March 2020

3071 Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase that dephosphorylates molecules involved in cancer invasion and metastasis and subsequently activates either PI3 kinase or Src pathway. PRL-3 was initially identified as a gene that is amplified in metastasis of colorectal cancer. We are thinking much of clinical potential of PRL-3 inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry and genomic status were assessed for PRL-3 in esophageal squamous cell carcinoma (ESCC)(n=88), gastric adenocarcinoma (n=173), and colorectal adenocarcinoma (n=107).RNA interference was used to determine its specific functional roles in GI cancers. Preclinical study using PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4 ESCC and 4 gastric cancer cell lines that were intensely expressed for PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3 expression is associated with lymph node metastasis in primary ESCC (p=0.0012), gastric adenocarcinoma (p<0.0001), and colorectal carcinoma (p<0.0001). In the primary tumors with lymph node metastasis, its expression was recognized in 96, 80, 86%, respectively. (2) If restricted to patients with PRL-3 expression, genomic amplification was found exclusively in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In colorectal cancer, PRL-3 genomic amplification is found in 35% of stage III/IV, but only in 10% of stage II (p=0.002). (3) PRL-3 RNA interference robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and 50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it. Conclusions: PRL-3 inhibitor has a great clinical potential to suppress tumors with metastatic ability, that was represented by lymph node metastasis or recurrent disease of GI cancers.
Effect of MDV3100, a novel androgen receptor signaling inhibitor, on cell proliferation and tumor size in an apocrine breast cancer xenograft model.
Authors: Bernales Sebastián , Guerrero Javier , Gómez Francisco , Alfaro Iván E. , Protter Andrew A 
Published: March 2020

3072 Background: MDV3100, a new androgen receptor (AR) signaling inhibitor, has demonstrated therapeutic effects in men with post-docetaxel prostate cancer (AFFIRM). AR is also expressed in the majority of breast cancers. Molecular profiling of estrogen receptor negative (ER-) breast cancer classifies this disease into basal and molecular apocrine subtypes. Apocrine breast cancer represents ~50% of ER- tumors and is characterized by a steroid response gene signature that includes AR expression. Here we report the effects of MDV3100 on the growth of the ER-/AR+ breast cancer cell line MDA-MB-453 in tissue culture and in an in vivo xenograft mouse model. Methods: MDA-MB-453 cells were maintained in 5% complete or 5% charcoal-stripped serum supplemented with dihydrotestosterone (CSS-DHT). The DHT induced nuclear translocation of AR was determined by subcellular fractionation followed by western blot. AR target gene expression was measured by qPCR. To generate a mouse xenograft model, 5-6 wk old female NOD-SCID-IL2Rgc–/– mice were injected ortotopically with 6x106 MDA-MB-453 cells into the fourth inguinal gland and were administered exogenous DHT (12.5 mg in a 60 day release pellet) or control pellets. When tumor size reached 100 mm3, mice were treated with 10 mg/kg/day MDV3100 or vehicle (0.5% methocel solution) by oral gavage for 33 days. Results: Viability of MDA-MB-453 cells treated with 10 uM MDV3100 was reduced by 10% after 3 days and 27% after 6 days. Treatment with 25 uM MDV3100 reduced cell viability by 27% after 3 days and 36% after 6 days. Similar results were obtained when cells maintained in CSS-DHT were treated with MDV3100. Treatment with MDV3100 blocked DHT-induced nuclear translocation and concordantly reduced the expression of AR-targets fatty acid synthase, prolactin receptor, and gross cystic disease protein-15. In the xenograft model, MDV3100 inhibited tumor growth by 78% as compared to tumors treated with vehicle. Conclusions: MDV3100 reduced cell proliferation in apocrine cell lines. MDV3100 also suppressed exogenous DHT-induced growth of ER-/AR+ tumors in vivo. These results support the evaluation of MDV3100 as a treatment for apocrine tumors.
Translational assessment of the efficacy of CPI-613 against pancreatic cancer in animal models versus patients with stage IV disease.
Authors: Retter Avi S. 
Published: March 2020

3075 Background: CPI-613 is a novel agent that selectively targets the altered mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and autophagia. Results assessing clinical efficacy of CPI-613 translated from animal tumor xenograft models to patients with stage IV pancreatic cancer are presented. Methods: Efficacy of CPI-613 was tested in mice with pancreatic tumor xenografts generated by inoculation of BxPC-3 human pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320 mg/m2), when used in combination with gemcitabine (1,000 mg/m2), was assessed in patients with stage IV pancreatic cancer. Results: In the animal pancreatic tumor xenograft model (n=10/grp), CPI-613 (25 mg/kg, IV, 1x weekly for 4 weeks) suppressed tumor growth by ~100%, when compared to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4 weeks), suppressed tumor growth by only ~50%. Median overall survival in tumor-bearing mice treated with CPI-613 was ~240 days, which was significantly longer than those with gemcitabine or vehicle treatments (~65 and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer (Table), the CPI-613+gemcitabine combination was well-tolerated. In those without prior chemotherapy before participating in the clinical trial (first three patients in the table), the CPI-613+gemcitabine combination prolonged survival that correlated with the dose of CPI-613. Conclusions: CPI-613 exhibits efficacy against pancreatic cancer in animal models, which is translational to patients with stage IV disease. [Table: see text]
A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
Authors: Richter Sue , McWhirter Elaine , Chen Eric Xueyu , Tran Ben , Hotte Sebastien J. , Stathis Anastasios , Hirte Hal W. , Razak Albiruni R.A. , Laughlin Anne , Wang Lisa , Battista Kristina , Stayner Lee-Anne , Ivy S. Percy , Moore Malcolm J. , Oza Amit M. , Siu Lillian L. , Bedard Philippe 
Published: March 2020

3082 Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within <14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease > 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]
Associating retinal drug exposure and retention with the ocular toxicity profiles of Hsp90 inhibitors.
Authors: Zhou Dan , Teofilovici Florentina , Liu Yuan , Ye Josephine , Ying Weiwen , Shin Ogawa Luisa , Inoue Takayo , Lee William , Adjiri-Awere Alfred , Kolodzieyski Lev , Tatsuta Noriaki , Wada Yumiko , Sonderfan Andrew J 
Published: March 2020

3086 Background: In clinical trials certain Hsp90 inhibitors, including AUY922, SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal dysfunction; others, including ganetespib and 17-AAG, have not. Previous animal toxicology experiments have suggested that retinal changes may be linked to photoreceptor degeneration or cell death. Here histopathologic changes and/or exposure profiles of Hsp90 inhibitors with or without clinical reports of ocular toxicity were evaluated to understand the observed differences in toxicity profile between agents in this class. Methods: We reviewed visual symptoms among subjects administered ganetespib, a potent Hsp90 inhibitor currently in phase II trials; evaluated retinal morphology in rats and cyno monkeys given ganetespib; and compared TUNEL-positive photoreceptors and drug exposure profiles in the retina of rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing. Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both drugs induced marked photoreceptor cell death (increased TUNEL-positive cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min remained in the retina). In contrast, and consistent with an absence of clinical visual changes, 17-AAG at the maximum tolerated dose did not elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h post-dose, 94% of 17-AAG had been eliminated from the retina, resulting in a low R/P ratio). Ganetespib given by 1‑hour IV infusion on days 1 and 15 of four 21-day cycles did not cause histopathological changes in the retina of rats or cynos. This finding is consistent with very low rate (~3%) of drug-related visual symptoms observed among over 300 subjects to date that received ganetespib in the clinic. Conclusions: Unlike AUY922 and 17-DMAG, ganetespib is not associated with ocular toxicity in humans, primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit visual disorders when associated with high retina/plasma exposure ratio and lower retinal elimination rate.
Endoxifen for breast cancer: Multiple-dose, dose-escalation study characterizing pharmacokinetics and safety in metastatic breast cancer patients.
Authors: Ahmad Ateeq , Sheikh S. , Nagarkar R. , Singh J. K. , Krishnan S. , Shrivastav S. , Shetty P. , Kale P. , Rane R. C. , Ahmad I. 
Published: March 2020

3089^ Background: Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. To be clinically effective, tamoxifen must be converted to endoxifen by CYP2D6. Direct administration of endoxifen would not be subject to pharmacogenetic variations or drug-drug interactions. Our preclinical studies (Breast Cancer Treat 122, 579-584, 2010) have validated the concept of using endoxifen for the treatment of breast cancer. In human (Clin. Pharmacol. Ther. 88, 814-817, 2010), the single oral doses tested up to 4 mg of endoxifen were safe, well tolerated and bioavailable. Methods: A multiple-dose escalating study was conducted in 3 cohorts and each cohort had 6 patients (18 metastatic breast cancer patients). Endoxifen at 3 dose levels (2, 4, or 8 mg) was given once daily for 28 days. Routine laboratory tests, vital signs and electrocardiograms were measured throughout the study. Blood samples for PK analysis were collected after 28 days post dose. Endoxifen in plasma samples was determined using LC-MS/MS. Results: Endoxifen was found to be safe up to 8.0 mg. At steady state, it displays dose-proportional PK with respect to Cmax and AUC ( see Table below). Conclusions: Multiple daily endoxifen doses of 4.0-8.0 mg resulted in endoxifen exposures that would be sufficient for effective therapy. The favorable safety and multiple-dose PK profile of endoxifen warrants further evaluation of safety and efficacy of endoxifen in breast cancer patients. [Table: see text]
Therapy of human solid tumor xenografts with CD74-targeted milatuzumab-SN-38 immunoconjugates.
Authors: Goldenberg David M. , Cardillo Thomas M. , Sharkey Robert M. , Gold David V. , Govindan Serengulam V. 
Published: March 2020

3091 Background: CD74 is commonly considered to be an antigen present in hematopoietic cancers, but it is also expressed in a number of solid tumors. The humanized anti-CD74 antibody, milatuzumab (hLL1), was previously shown to have exquisite internalization properties, making it an attractive carrier for drug delivery. In this study, we evaluated hLL1 conjugates of a potent topo I inhibitor, SN-38, for treating solid tumors. Methods: Two hLL1-SN-38 conjugates, possessing either a pH-sensitive linker (‘CL2A’ form) or a cathepsin-B-cleavable linker ("CL2E" form), were examined. In vitro analyses were carried out in the A-375 human melanoma cell line, and therapy experiments were performed in female athymic nude mice bearing established s.c. A-375 or s.c. human pancreatic adenocarcinoma (Capan-1) xenografts using specified doses (i.p.) at a twice weekly × 4 wks schedule; animals were sacrificed when tumor volumes (TVs) reached 1 cm3. Results: Both A-375 and Capan-1 cell lines tested positive for CD74 expression by IHC. In vitro, both SN-38 derivatives liberated free drug at the same rate when exposed to cathepsin-B at pH 5, while serum stabilities for CL2A and CL2E forms of the conjugates were ~ 1 d and >10 d, respectively. In the A-375 melanoma cell line, IC50 for the hLL1-SN-38 conjugates of CL2A and CL2E forms were 5 nM and 34 nM, respectively. In the aggressive A-375 s.c. model of melanoma, in nude mice (n =8; TV: 0.23 ± 0.06 cm3) treated with 12.5 mg/kg protein dose (total 1.7 mg/kg SN-38 eq.) of specific or non-specific SN-38 conjugates of CL2A and CL2E forms, only hLL1-CL2A-SN-38 conjugate was efficacious (Log-rank: P<0.009 vs. all controls), with a median survival time of 28 d vs. 10.5 d for untreated. Likewise, in mice bearing Capan-1 xenografts (n = 8-10; TV=0.27 ± 0.05 cm3), two low doses of hLL1-CL2A-SN-38 (12.5 or 5 mg/kg) significantly improved survival in comparison to saline control mice (p<0.035), whereas the CL2E form and a non-specific control demonstrated no efficacy. Conclusions: These results indicate the therapeutic potential of hLL1-CL2A-SN-38 conjugate and the importance of linker chemistry, and encourage additional testing in other CD74-positive solid cancers.
A phase Ib proof-of-concept study of LBH589 (LBH) and everolimus (EVE) in advanced solid tumors enriched for Epstein-Barr virus (EBV)-related cancers.
Authors: Tan Daniel Shao-Weng , Ng Quan Sing , Chong Dawn Qingqing , Lee Guek Eng , Tan Thuan Tong , Chau Noan Minh , Ang Mei-Kim , Zhong Liz , Chowbay Balram , Connolly John , Tan Eng-Huat , Lim Wan-Teck 
Published: March 2020

3098 Background: Histone deacetylase and mTOR inhibition circumvent critical EBV-oncogenic pathways with preclinical studies demonstrating lytic induction in EBV infected cells, as well as immunomodulatory and antiangiogenic effects. Methods: Patients (Pt) with advanced solid tumors enriched for EBV–related cancers were enrolled to determine safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity. LBH was instituted 7-days prior to combination treatment. NPC pt received antiviral prophylaxis of either acyclovir (Ac) or valaciclovir (Vc). Serum EBV DNA levels (EBNA-1) were measured weekly and plasma cytokines profiled using a 31-plex Luminex panel. Results: 15 pt have been treated (M:F 13:2, median age 50, R: 38-63) 10 NPC, 5 non-NPC (colon, RCC, breast, gastric, sarcoma) at 3 dose levels – LBH (3x/wk)-EVE (daily):10-2.5, 10-5, 15-5. Two dose limiting toxicities of G4 (grade) thrombocytopenia were observed at LBH15-RAD5. Significant adverse events (AE) (G≥3) were dysphagia (1) and thrombocytopenia (3). Common AEs (G1/2) included fatigue (80%), anorexia (60%), mucositis (53%), xerostomia (26%), dysphagia (26%). Two minor responses were seen (1 NPC, 1 breast) and 2 pt (1 NPC, 1 RCC) had prolonged stable disease (>16 weeks). Modulation of EBV DNA titres was seen only in NPC pt, with median fold-change from baseline of 10.9 (0.05-174). Pt on Ac prophylaxis (n=5) had significant increases in DNA titres (9-174 fold), while those on Vc (n=4) were less pronounced (0.05-11 fold, p<0.03), with one pt (with minor response) having persistent decline in EBV titres. In a limited pt subset (n=9, 30 timepoints), plasma cytokine profiles were consistent with a T-cell response, specifically, elevated levels of FLT3L, IFN-gamma, IL-13 and IL-17. PK and PBMC target modulation studies are being analysed. Conclusions: LBH-EVE results in induction of EBV DNA titres with an associated host T cell response. MTD is LBH10-EVE5 in Asian pt, majority of whom had NPC. A pre-planned expansion cohort that incorporates multi-parametric functional imaging exploring two schedules of LBH in combination with EVE5 is ongoing.
A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC).
Authors: Deming Dustin A. , Schelman William R. , Lubner Sam Joseph , Mulkerin Daniel , LoConte Noelle K. , Fioravanti Suzanne , Greten Tim , Eickhoff Jens C. , Kolesar Jill , Compton Kathryn , Doyle Laurence A , Wilding George , Duffy Austin G. , Liu Glenn 
Published: March 2020

3103 Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.
Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients.
Authors: Salazar Ramon , Tabernero Josep , Moreno Victor , Nitsche Ulrich , Bachleitner-Hofmann Thomas , Lanza Giovanni , Stork Lisette , Roepman Paul , Simon Iris , Rosenberg Robert 
Published: March 2020

3510 Background: Adjuvant therapy for stage II patients is recommended for patients with high risk features, especially with T4 tumors. Adjuvant therapy is not indicated for patients with MSI-H status who are considered of being at low risk of disease relapse. However, this leaves the majority of patients with an undetermined risk. ColoPrint is an 18-gene expression classifier that identifies early-stage colon cancer patients at higher risk of disease relapse. Methods: ColoPrint was developed using whole genome expression data and was validated in public datasets (n=322) and independent patient cohorts from 5 European hospitals. Tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 70 months) for patients were available and the ColoPrint index was determined using validated diagnostic arrays. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) and the subset of patients who were T3/ MSS (n=227). Results: In the analysis of all stage II patients, ColoPrint classified two-third of stage II patients as being at lower risk. The 3-year Relapse-Free-Survial (RFS) RFS was 91% for Low Risk and 74% for patients at higher risk with a HR of 2.9 (p=0.001). Clinicopathological parameters from the ASCO recommendations (T4, perforation, <12 LN assessed, and/ or high grade) or NCCN guidelines (ASCO factors plus angio-lymphatic invasion) did not predict a differential outcome for high risk patients (p< 0.20). In the subgroup of patients with T3 and MSS phenotype, ColoPrint classified 61% of patients at lower risk with a 3-year RFS of 91% (86-96%) and 39% of patients at higher risk with a 3-year RFS of 73% (63-83%) (p=0.002). No clinical parameter was significantly prognostic in this subgroup. Conclusions: ColoPrint combined with established clinicopathological factors and MSI, significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.