bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pooled analysis of onapristone extended release (ONA ER) in metastatic cancer patients (pts): A review of liver safety.
Authors: Cottu Paul H. , Jayaram Anuradha , Italiano Antoine , Pacey Simon , Leary Alexandra , Jones Robert J , Campone Mario , Floquet Anne , Berton Rigaud Dominique , Lhomme Catherine , Sablin Marie-Paule , Bexon Alice Susannah , Bonneterre Jacques , Attard Gerhardt , Watkins Paul B 
Published: May 2019

e14647 Background: ONA, a type I progesterone receptor (PR) antagonist, prevents PR activation by disrupting PR dimerization and DNA binding, and inhibits tumor progression. ONA (immediate release) has efficacy comparable to other endocrine therapies in pts with metastatic breast cancer (BC). The only notable toxicity was transient elevation in liver chemistries in some pts. In 2 clinical trials, ONA ER was given to 88 cancer pts who underwent frequent liver chemistry monitoring. Methods: We pooled and reviewed all liver safety data from 2 trials. A hepatologist (PBW) reviewed all pts with either a hepatobiliary SOC AE or who experienced an elevation > ULN of any liver-related laboratory test. Results: Of 88 pts who received ONA ER for a median 8 weeks (3-51), 59% were female, median age 68 (36-89), 99% Caucasian, 28% had liver metastases (mets), 48% bone mets and 17% also took abiraterone (ABI), which has liver toxicity. 54 pts (61%) experienced any ONA ER-related AE. More AEs were seen in ABI pts (67%), those with liver mets (72%) and BC (76%).. In terms of liver-related TEAEs, overall 10% of pts had ALT and 13% AST elevations, while 20% pts with liver mets had raised ALT/AST and 29% of BC pts. Overall 15% pts had G3 TEAEs, compared to 28% pts with liver mets, mostly due to increased GGT (24%), which has unclear clinical impact. There were no discontinuations for LFT elevations. A relationship between the liver events and ONA ER was judged to be unlikely in each subject, except one. This event was detected at day 29 of treatment and consisted of a marked rise in serum GGT and alkaline phosphatase with only a moderate rise in serum ALT (peak – 262). These abnormalities improved quickly after stopping ONA but recurred on reintroduction: these events are not serious by international criteria and the pt was able to continue ONA at a lower dose for 40 weeks without recurrence Conclusions: The safety experience for ONA ER has been reassuring but must continue to be characterized. For new ONA ER studies, weekly liver chemistry monitoring is planned for the first 4 weeks with Q2W monitoring thereafter. The occasional G3 elevations in serum AST, ALT or bilirubin will prompt interruption, but re-starting treatment at a lower dose should be possible for most pts. Clinical trial information: NCT02052128 and NCT02049190.
Effect on tumor growth by TGF-β1/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice.
Authors: Molyneaux Michael , Xu John , Evans David M. , Lu Patrick 
Published: May 2019

e14652 Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.
Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.
Authors: Sammons Sarah , Anderson Grace , Wardell Suzanne , McDonnell Donald P. , Marcom Paul Kelly , Wood Kris 
Published: May 2019

e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-XL causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-XL /BCL-2 inhibitor). Results: Combination BCL-XL (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-XL inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-XL and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-XL.
Prognostic significance of amplifications of stemness genes in primary luminal breast cancer depending on the response to neoadjuvant chemotherapy.
Authors: Kazantseva Polina , Slonimskaya Elena , Litviakov Nicolay , Tsyganov Matvey , Ibragimova Marina 
Published: May 2019

e14655 Background: Neoadjuvant chemotherapy (NAС) is one of the treatment options for breast cancer (BC). However, chemotherapy is known can cause intratumoral changes that increase the risk of metastasis. We have previously found that the appearance of new amplifications in the chromosomal regions harboring stemness genes (3q, 5p, 6p, 7q, 8q, 9p, 9q, 10p, 10q21.1, 13q, 16p, 18Chr, 19p) is associated with the development of hematogenous metastases in 100% of cases. In our study, we evaluated the prognostic significance of amplifications stemness genes in primary BC depending on the NAC response. Methods: The study included 104 patients with stage II-III luminal B (Her2Neu -) breast cancer. All patients received 4-8 courses of NAС followed by surgery and hormone therapy. The follow-up period was 4-10 years. Amplifications in primary tumor DNA were determined using Affymetrix high density microarrays. Metastasis-free survival was estimated using the Kaplan-Meier method. Results: Zero or only 1 amplification was identified in tumor tissue of 42 patients (41%) (group 1). Two or more amplifications were identified in tumor tissue of 60 patients (59%) (group 2). We evaluated metastasis-free survival separately in each group, depending on the NAС response. It was found that in group 1, the median survival time was 122 months in cases with partial or complete regression (PR + pCR, and 63 months in cases with stable disease or disease progression (S + P), p > 0.05. In group 2, the median survival of patients with PR + pCR was not reached, and it was 63 months in patients with S + P, p = 0.025. Conclusions: Achievement of partial or complete regression in breast cancer patients, whose primary tumors displayed 2 or more amplifications of stemness genes, was associated with the increased rates of metastasis-free survival and can be considered as a positive prognostic criterion. However, the response to NAC did not impact survival of patients with 0-1 amplification of stemness genes.
Thyrointegrin αvβ3 nano targeted delivery of chemotherapy into solid tumors and its microenvironment.
Authors: Bharali Dhruba J. , Sudha Thangirala Institute , Godugu Kavitha , Darwish Noureldien H.E , Davis Paul Joseph , Fujioka Kazutoshi Institute , Mousa Shaker A. 
Published: May 2019

e14661 Background: Cancer cells and rapidly dividing endothelial cells relevant to tumors primarily express the αvβ3 integrin. Conjugation of tetraiodothyroacetic acid (tetrac) as diamino-tetrac to a poly (lactic-co-glycolic acid) (PLGA) polymer for the formation of Nano DAT was used to target a specific cell surface receptor on the αvβ3 integrin. PLGA prohibits cell entry and the nano shell could be loaded with a generic cancer chemotherapeutic. Without a payload, Nano DAT has anticancer and anti-angiogenesis properties. Methods: Xenografts of human urinary bladder cancer (263JBV) cells, human breast cancer (SUM149PT) cells, and human pancreatic cancer (SUIT-2) cells were established. Tumor growth and tumor content of cisplatin (263JBV xenografts), doxorubicin (SUM149PT xenografts), or of paclitaxel (SUIT-2 xenografts) were compared in the following daily treatment animal arms of cohorts for 3 weeks: (1) controls, (2) void PLGA Nanoparticle (NPs), (3) chemotherapeutic agent (cisplatin 1 mg/kg, doxorubicin 1 mg/kg, or paclitaxel 0.3 mg/kg), (4) Nano DAT 0.3 mg/kg, and (5) chemotherapeutic agent encapsulated into PLGA NPs and into Nano DAT. Results: Tumors in animals treated with Nano DAT bearing a payload of cisplatin, paclitaxel, or doxorubicin were associated with decreased tumor weight by 50%-60% (P < 0.01) with > 90% loss of cancer cell viability. Mean chemotherapeutic agents content of tumors (ng/gm of tissue) was 5-fold that of tumors from animals treated with chemotherapy, alone, and 3-fold that of tumors exposed to chemotherapy encapsulated into PLGA NPs, measured with an established LC/MS/MS method. Animals receiving cisplatin, alone, developed neurotoxicity (inability to use the hind limbs) in comparison to an animal group treated with Nano DAT bearing a payload of cisplatin, and was confirmed histopathologically. Conclusions: The payload capacity of Nano DAT for cancer chemotherapeutic agents and tumor-specific delivery of cancer chemotherapeutic agents significantly increases bladder, breast and pancreatic cancer content of, respectively, cisplatin and paclitaxel.
Influence of deuterium-depleted water as a nutritive factor on the effectiveness of experimental chemotherapy in aging rats.
Authors: Shikhlyarova Alla I. , Zhukova Galina V. , Dzhimak Stepan S. , Baryshev Mikhail G. , Kit Oleg I. , Goncharova Anna S. , Shirnina Elena A. , Protasova Tatiana P. , Zhadobina Anastasia I. , Bragina Marina I. , Lukbanova Ekaterina A. 
Published: May 2019

e14683 Background: The rates of physical and chemical interactions are associated with water isotopic composition. The ability of deuterium-depleted water (DDW) to influence free radical, metabolic and regulatory processes determines the need to change the drinking diet at aging, tumor growth antitumor chemotherapy (CT). Our purpose was to study the influence of DDW on the state of aging female rats, tumor growth and the CT effectiveness. Methods: The study included 37 aging outbred white female rats (250-280 g) with transplanted sarcoma 45 (S-45) receiving chemotherapy with cyclophosphamide (CF). DDW intake (46±2 ppm, 25-30 mL a day) was started 5 weeks before S-45 transplantation. CF was administered intraperitoneally on day 10 at a dose of 50 mg/kg twice with a 5-day interval. We determined tumor volume by Shrek, deuterium concentrations in the blood plasma (NMR spectrometer JEOL JNM-ECA 400MHz) and inner organs (mass spectrometer DELTAplus H/Device, Finnigan, Germany), estrous cycle stages and types of the nonspecific adaptational reactions of organism by Garkavi-Kvakina-Ukolova (1975). Results: DDW administration before the tumor transplantation significantly balanced the stages of the estrous cycle and increased the incidences of the antistress adaptational reactions development by 1.6 times (p < 0.05); external signs of rejuvenation were observed (changes in hair state and motor activity). After S-45 transplantation, its growth prior to CT was suppressed (tumor volume 0.25±0.07 cm3 vs. 0.47±0.10 cm3 in controls, p < 0.1). DDW increased the effect of CF by 4.8 times by day 15 (0.88±0.67 cm3 vs. 4.22±1.43 cm3 with CF alone, p < 0.05). Concentrations of deuterium in the blood plasma decreased by 33%, in the inner organs (liver, kidney and heart) – by 6-14% (p < 0.05). Conclusions: DDW has an antistress, geroprotective , antitumor and CT-optimizing effect.
Measuring parameters of the cancer ecosystem for cancer ecological staging.
Authors: Cunningham James R. , Rittenbach Jon , Clemens Mitch , Dodd Cheryl , Wilson Ashley , Roberson Kaikuihala 
Published: May 2019

e14684 Background: Cancer progression through clonal evolution and emergent phenotypic heterogeneity is thought to reflect stochastic events such as genetic drift. This divergence over time in the character of a neoplasm might also reflect genetic selection, analogous to other populations in nature, to maximize niche resource utilization. We hypothesized that selection pressures operate in patients with cancer to drive cancer evolution, are clinically identifiable, their influence measurable. Methods: To develop a system for cancer ecology staging, a feasibility study recruited 15 patients with active cancer from any site, with expected survival of more than 6 months and providing informed consent. A set of clinical parameters obtained from a patient questionnaire, physical exam and laboratory testing was used to generate eight separate ecological profiles of tumor microenvironment, chronic inflammation, energy balance, psychosocial stress, GI microbiome, endocrine environment, skeletal remodeling and environmental mutagenesis. A scoring system, based on evidence of positive selection was designed to quantitate the individual profiles. Profile scores were then aggregated using a 2-D radar plot to generate a polygon, an ‘ecogram’, whose area, it is hypothesized, corresponds to the net level of selection pressure influencing tumor evolution. Results: Ecological profiles were obtained from each of 15 patients allowing determination of the ecogram area (EA) bounded by the polygon. EA determinations ranged widely among the 15 patient, from 0-12.7 arbitrary units (au, mean 5.01± 0.80). Ecograms from individual patients demonstrated unique shapes suggesting specificity for individual patient ecology. EA measurements were then used to inform an ecological staging system based on a simplified dichotomization, low/high, of ecosystem resources and threats. Of 15 patients, 6 were considered to have high resources (EA > 5au) available to support tumor evolution. High anti-tumor threat, measured by CD3 lymphocyte immunohistochemical scoring, was detected in 11 patients. Conclusions: An ecological assessment of patients with active cancer appears feasible. Inter-patient variation in ecogram area and morphology suggests there are potential important differences in genetic selection found between patients and should be correlated with survival outcomes in future studies, validation offering a target for ecosystem ‘restoration’.
Feasibility and clinical impact of next-generation sequencing (NGS) in patients with stage IV or recurrent malignancies.
Authors: Covut Fahrettin , Kewan Tariq Zuheir , Thapa Bicky , Haddad Abdo S. , Spiro Timothy Peter , Daw Hamed 
Published: May 2019

e14697 Background: Feasibility and outcomes of routine NGS in patients with stage IV or recurrent malignancies remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 9/2012 and 10/2018 after diagnosis of stage IV or recurrent solid cancer at Cleveland Clinic. Overall survival (OS) was estimated by the Kaplan-Meier method. Logistic and Cox regression analysis were performed to identify predictors of receiving targeted gene therapy (TGT) and OS, respectively. Results: We identified 1699 patients, 825 (49%) were female, 1634 (96%) had stage IV and 65 (4%) had recurrent cancer. At diagnosis of stage IV/recurrent cancer, median age was 61 (range: 18 – 94) and ECOG performance score was 0, 1, and ≥ 2 for 578 (34%), 859 (51%), and 258 (15%) patients, respectively. Most common primary cancers were lung (20%), colorectal (17%), urothelial/prostate (12%), and breast (10%). NGS revealed median of 4 mutated genes (range: 0 – 34), ≥ 1 FDA approved TGT was available in 505 (30%) and 1114 (66%) patients for the same and different primary cancer, respectively. Overall, 219 (13%) patients received 247 lines of TGT for median of 3 months (range: 0.1 – 62) based on NGS results. TGT use was via clinical trials for 49 (22%) and off-label for 83 (38%) patients. Best response was complete/partial response for 63 (29%) and stable disease for 40 (18%) patients. Commonly targeted genes were EGFR (12%), ERBB2/3 (11%), BRAF (10%), BRCA1/2 (8%), and PIK3CA (7%). Median follow-up after diagnosis of stage IV/recurrent cancer was 19 months. Two-year OS for TGT and no TGT cohorts were 70% (95% CI: 64 – 77) and 55% (95% CI: 53 – 58), respectively (p < 0.0001). On multivariable analysis, ECOG ( < 2vs ≥2), systemic therapy between diagnosis of stage IV/recurrent cancer and NGS (≥2 vs < 2 lines), and each 1 increase in number of mutated genes were predictors of receiving TGT (p < 0.05 for all). On multivariable analysis, age (≤65 vs > 65), ECOG ( < 2vs ≥2), stage (recurrent vs IV), and systemic therapy before NGS (≥2 vs < 2 lines) predicted longer OS (p < 0.01 for all). Conclusions: In this large cohort, NGS provided further therapeutic options including clinical trials for approximately 1 out of 10 patients with stage IV or recurrent cancer.
Impact of combined MRP1 inhibition and mutant p53-targeting compound APR-246.
Authors: Ceder Anna Sophia , Eriksson Sofi E. , Cheteh Emarndeena Haji , Bykov Vladimir J.N. , Abrahmsen Lars , Wiman Klas G. 
Published: May 2019

e14712 Background: The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. Mutant p53 protein is often expressed at high levels and accompanied with gain-of-function activities that promote tumor development and resistance towards conventional treatment. APR-246 is a mutant p53-reactivating small molecule undergoing a Phase III clinical study in myelodysplastic syndrome (MDS), and several phase II studies. APR-246 is non-enzymatically converted to its active product methylene quinuclidinone (MQ) which binds to cysteine residues in p53. This stimulates proper folding of p53's DNA-binding core domain, leading to cell death. APR-246 also exhibits pro-oxidant activity as the electrophile MQ binds and inactivates important antioxidants such as glutathione and thioredoxin reductase, which both are essential for cellular defense against oxidative and electrophilic stress. Methods: All results are in vitro experiments by LC-MS as well as experiments in cultured cells, including 14C-APR-246/MQ detection, cell viability measurements, LC-MS analysis, enzyme recycling measurements and Western blotting. Results: We have utilized 14C-labelled APR-246 to investigate the effect of APR-246 and its active moiety MQ in tumor cell cultures upon inhibition of efflux transporter multidrug resistance protein 1 (MRP1) or cystine-glutamate transporter (xCT). Transient downregulation or small molecule inhibitors (MK-571, reversan, sulfasalazin) targeting MRP1 or xCT increased drug content and shifted intra- and extracellular thiol status. Missense mutant TP53-carrying cells exhibited higher sensitivity to APR-246 and combination therapies. MRP1 inhibition showed strong synergy with APR-246 and increased intracellular levels of MQ conjugated to glutathione (GS-MQ). We found that GS-MQ conjugate formation is reversible, and suggest that the intrinsic reversibility of MQ adduct formation is an important aspect of the mechanism of action of APR-246. This reversibility may also in part account for the benign safety profile reported from clinical studies with APR-246. Conclusions: Sensitivity to APR-246 is affected by MRP1 efflux activity and the redox status, reflected in ratios of cysteine/cystine and reduced/oxidized glutathione (GSH/GSSG).