bluuebunny/crossref_metadata_2025_split huggingface dataset:
The multidirectional effects of some comorbid disorders on the malignant process and tumor-bearing organism in the experiment.
Authors: Zhukova Galina V. , Shikhlyarova Alla I. , Goncharova Anna S. , Tkachev Sergey Yu. , Protasova Tatiana P. , Triandafilidi Elena I. , Bykadorova Oksana V. , Shevchenko Alexey N. , Filatova Elena V. , Khomutenko Irina A. , Shashkina Larisa Yu. , Kit Oleg I. 
Published: May 2020

e15616 Background: The question of the effects of comorbid diseases on oncogenesis has been little studied else. The increase in the frequency of dorsopathies and arthritis with age determines the important of the question about their influence on malignant process. The aim of the research was to study the features of the tumor growth and animal's condition under chronic neurogenic and inflammatory pain. Methods: In experiments on 54 white unbred male rats of 280-390 g, with transplantable Guerin's carcinoma (сG), two experimental models of chronic pain were used - unilateral sciatic nerve ligation (SNL) according to G.J. Bennet (neurogenic pain) and injections of formalin (Fm) into the ankle joint of the back paw (inflammatory pain). Formalin injection is known to be used to form both acute and chronic pain. The dynamics of tumors size, level of motor activity (MAL) in open field test, hematological parameters (by the blood analyzer «Exigo EOS vet», Sweden), adaptation status (AS) by Selye-Garkavi-Kvakina and also the lifespan of the animals (LS) were evaluated. Results: Unlike the unidirectional negative influence of chronic pain known in tumor-bearing animals in the cases of bilateral SNL, two opposite effects were observed with unilateral SNL and the formalin injection. Along with accelerated tumor growth in some animals (up to 62%), increase of LS of more than a third of the rats of the main groups by 3-30% in comparative with maximal LS in the control group was noted. In these cases, often the death of animals occurred with the larger tumors than in the control groups. In the cases of unilateral SNL, a relation between changes in the characteristics of the AS and the LS was noted. In the cases of Fm injections, animals with diverse LS differed in the features of the inflammatory reaction and the dynamics of the MAL. The prognostic value of shifts of the MAL in chronic inflammatory pain and tumor growth is assumed. Conclusions: A nonlinear relationship between the processes caused by chronic pain, oncogenesis, and individual characteristics of systemic regulation was shown. The question about the mechanisms of adaptation to the malignant process, promoting the body's viability in large tumors in conditions of chronic neurogenic and inflammatory pain is of interest.
Bstrongximab-MMAE, a novel antibody-drug-conjugate for metastatic gastric and pancreatic cancers.
Authors: Schopperle William Michael 
Published: May 2020

e15620 Background: As of today, there are no current beneficial clinical therapeutic cancer treatments for advance metastatic gastric or pancreatic cancers. A new approach to finding effective and meaningful drugs to treat these cancers is based an emerging hypothesis that cancer is a reprogramming disease and its origin and development is due to retrograde-like malignant cells with primitive and embryonic characteristics which are responsible for the dissemination of the disease and the almost universal clinical response of tumor resistance when treated with standard current therapies. Methods: A pluripotent human germ cell tumor cell line, TERA-1, was used to isolate and purify embryonic antigens which where used to immunized mice and, with standard B-cell hybridoma technology, to generate monoclonal antibodies. Antibodies were screened by ELISA and SDS-PAGE Western blotting to identify antibodies specific to gastric and pancreatic cancers but not to normal tissues. A second assay was used to screen the potential of the antibodies to function as antibody-drug-conjugate therapeutics against cancer. Results: A lead therapeutic antibody, Bstrongomab, was identified in the antibody screens: it is positive for gastric and pancreatic cancers but does not react with normal tissues. Bstrongomab is an IgG1 monoclonal antibody which has high affinity and specificity to the embryonic target TRA-1-60. TRA-1-60 is a carbohydrate molecule which is highly expressed in normal embryonic stem cells and not expressed in normal tissues but is re-expressed in gastric and pancreatic cancers. Immunohistochemical tissue staining studies show TRA-1-60 is expressed in gastric and pancreatic cancers. Recent published scientific reports confirm this finding. A human/mouse therapeutic version of Bstrongomab was developed - Bstrongximab - and used to generate a novel therapeutic antibody-drug-conjugate with Bstongximab and the toxic payload MMAE (Monomethyl auristatin E). Pre-clinical i n-vitro and in-vivo studies show Bstrongximab-MMAE is a potent drug for gastric and pancreatic cancers. Conclusions: Bstrongximab is a novel IgG1 human/mouse chimeric therapeutic antibody that targets TRA-1-60, a novel and yet to be tried cancer target that is highly expressed in gastric and pancreatic cancers but not in normal tissues. Bstrongximab-MMAE has the potential to be a first-in-class cancer therapeutic that provides real and meaningful benefits to patients with metastatic gastric and pancreatic cancers.
A precision medicine tool “Knowledge Frames” to explain poor results of STING agonist trials.
Authors: Blunt Al , Messerschmidt Gerald L. , Gyorffy Steve 
Published: May 2020

e15632 Background: STING activating cyclic-di-nucleotides result in the production of interferons, activating immune cells. We show that “Precision Medicine Knowledge Frames” (PMKF) are analyses inherently involving 2 processes: Frame 1 – Bench Science - biochemical functions of the experimental product, and Frame 2 - Human Organism Level - actions from product biochemical effects to tumor cell killing. Methods: STING agonists meet this PMK frame1 and activate STING (step 1) effectively. Activated STING binds TBK1 (step 2), then phosphorylates IRF3 (step 3), enters the nucleus (step 4), dimerizes (step 5) and binds specific regions of the DNA (step 6) for interferon transcription (step 7), which are secreted (step 8). Frame 2, the Human Organism Level - final common pathway requires many additional actions: Interferon must interact with immune cells (step 9) [within tumor or peripheral locations]. Very warm or hot tumors [contain functional immune cells] actively allow trafficking (homing) to the tumor (step 10) and infiltrating the tumor microenvironment (step 11). An activated immune cell can kill the tumor cell(s) (step 12). Cold tumors may not allow homing (step 10) to the tumor and/or infiltration (step 11) of the microenvironment. Results: PMKF modeling was applied to STING administration public data. Lack of efficacy was predicted if one of the critical pathway steps to tumor cell death are dysfunctional. Early steps (Frame 1) to interferon production and excretion into the environment occur within normal cells (antigen presenting cells) predictably. However, in the setting of malignancy, Frame 2 steps are often aberrant at the Organism Level. Cold tumors do not allow immune cell homing (step 10) and inhibit tumor infiltration (Step 11), tumor cell localization and killing of the tumor cell (step 12). Conclusions: STING Agonist are cutting edge therapies that perform PMKF Frame 1 well and increase interferon production. Application of the PMKF - Frame 2 demonstrate poor clinical activity may be explained by poor immune cell homing, infiltration and functional killing within the cold tumor microenvironment (dysfunctional steps 10, 11 and 12). Population selection may improve these results.
Preclinical evaluation of WXSH0011, a selective small molecule dual inhibitor of FGFR/c-Met.
Authors: Chen Zhengxia , Dai Meibi , Sun Deheng , Xia Yuanfeng , Zhang Yang , Chan Chi-Chung , Li Jian , Chen Shuhui 
Published: May 2020

e15641 Background: FGFRs (fibroblast growth factor receptors) are a family of receptor tyrosine kinases. c-Met is a receptor tyrosine kinase with a high-affinity ligand, hepatocyte growth factor/scatter factor (HGF/SF). Aberrations in the FGFR pathway are associated with a variety of human cancers. c-Met and HGF have been implicated in carcinogenesis and metastatic tumor progression because of their ability to enhance angiogenesis, cancer cell proliferation, migration, and invasion. WXSH0011 is an orally bioavailable novel potent and selective FGFR/c-Met dual kinase inhibitor, which displayed significant antitumor activity in preclinical models of solid cancer with FGFRs/c-Met overexpression. Preclinical studies demonstrated that WXSH0011 has potential to be effective in solid cancer, such as HCC and Gastric. Methods: Kinase inhibiting activity of WXSH0011 was determined with FGFRs/ c-Met kinase assays. Cellular anti-proliferative activity was evaluated with FGFR overexpressed NCl-H1581, SNU-16, RT112/84, Hep3B, c-Met overexpressed MHCC97H, EBC-1 cell line and FGFR, c-Met both overexpressed PDC cell line (LI-03-0141 (HCC) and ST-02-0063 (Gastric) PDC). The antitumor activity of WXSH0011 was evaluated in vivo cell derived-xenograft (CDX) models of Gastric Cancer SNU-16 and HCC Hep3B. Results: WXSH0011 displayed potent kinase inhibiting activity for FGFR1/2/3/4 and c-Met/ with IC50 0.19 nM/0.21 nM/1.15 nM/1.49 nM /15.9 nM, respectively. WXSH0011 inhibited cell proliferation in FGFR overexpressed NCl-H1581, SNU-16, RT112/84, Hep3B with IC50 10 nM, 3 nM, 2 nM, 63 nM, c-Met overexpressed MHCC97H and EBC-1 cell line with IC50 0.832 µM, 0.52 µM, FGFR, c-Met dual overexpressed LI-03-0141 (HCC) and ST-02-0063 (Gastric) PDC with IC50 0.19 µM, 0.08 µM. Kinome panel screening revealed that WXSH0011 demonstrated good overall kinase selectivity. WXSH0011 showed antitumor efficacy in gastric cancer SNU-16 (TGI = 100% @5 mpk, BID), as well as in the liver cancer Hep3B model (TGI = 86.92% @20 mpk, QD). Conclusions: We have identified a novel selective and potent dual FGFR/c-Met inhibitor WXSH0011. Preclinical studies shows antitumor efficacy of WXSH0011 in gastric and liver cancer models. It is currently at IND submission stage.
Delivery of all-trans-retinoic-acid (ATRA) in liposomes modulated MDSCs and T-cell activities in the tumor microenvironment.
Authors: Xu Yuhong , Zheng Anjie , Jin Shanshan , Chen Xiaolong 
Published: May 2020

e15644 Background: All-Trans-Retinoid-Acid (ATRA) is a naturally occurring vitamin A metabolite that participates in many biological processes. Beside its highly potent effect of promoting terminal differentiation of acute promyelocytic leukemia blasts into mature granulocytes, there have been many other studies suggesting its activity on the myeloid derived suppressor cells (MDSCs) and tumor specific CD8+ T cells in animal models as well as using clinical samples. But the use of ATRA as an immune-oncological agent in solid tumor therapy has been limited by the very poor solubility of the compound, its fast metabolism, and very limited exposure achieved after oral administration. Methods: We prepared a new dosage form by encapsulating ATRA inside PEGylated liposomes. The liposomes were shown to accumulate inside solid tumor tissues and deliver more ATRA with longer duration. Results: The effect and dose response of the liposomal ATRA on CT26 murine tumor growth were examined, as well as specific molecular signatures concerning tumor infiltrating myeloid cells. Notably, there was significant higher expression of CD86 and lower expression of PD-L1. These myeloid cells had very low inhibitory effect on ex vivo activated T cells, while on the other hand could promote specific antigen presentation to amplify CD8+ T cells. Furthermore, the liposomal ATRA was also shown to synergize with anti-PD-1 treatment to result in more CD8 T cell distribution in the tumor tissues. Conclusions: These data may suggest an exciting opportunity for targeting MDSCs using liposomal ATRA for combination with T cell based therapeutics in cancer immunotherapy.
Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: Learnings from a survey of approved drugs.
Authors: Mittapalli Rajendar K , Yin Donghua , Beaupre Darrin M. , Palaparthy Rameshraja 
Published: May 2020

e15648 Background: The ideal starting dose (SD) for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low SD combined with small dose increments could lead to a lengthy dose escalation (DE) and could expose patients unnecessarily to sub-therapeutic dosing. Over the past decade, the SD selection for oncology FIP trials was predominantly based on ICH S9 Guidance. This work attempts to assess the performance of current approaches in SD selection and DE methods for small molecule oncology drugs (SMOD), with an aim to identify potential opportunities for more efficient FIP DE methods and to minimize patients receiving sub-therapeutic dosing. Methods: A systematic review of the FIP trials of USFDA approved SMODs from 2010 to early 2019 was performed. The data sources included the FDA “USPI”, relevant “Summary basis of approval” documents, and published articles. The review focused on FIP trial data including the SD, DE design, the number of cohorts to the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D), and the number of subjects in each cohort. These data were analyzed to evaluate the efficiency and appropriateness of current approaches for FIP SD selection and DE. Results: Of 53 SMODs approved between 2010 and early 2019, ~ 65% were kinase inhibitors and ~74% were approved for solid tumor indications. All SMODs appeared to follow ICH S9 Guidance for SD selection and none of SMODs had more than doubling for dose increments in the escalation. The median MTD to SD ratio was 8 (1 to 125). A majority (57%) of the trials used a 3+3 design for DE and had a median of 4 cohorts (0 to 11) to reach MTD or RP2D from the SD. About 30% of the FIP trials had ≥ 6 DE to reach the MTD or RP2D, and in this subset, greater than 55% of the trial participants received subtherapeutic dosing. Conclusions: The ICH S9 Guidance-based SD and the DE methods for SMODs have generally performed well in most cases; the SD was well tolerated and the MTD or RP2D were achieved with reasonable efficiency. However, for a portion of SMODs the SD appeared to be too low or the DE was too conservative, suggesting opportunities for improvement to minimize the number of patients dosed at sub-therapeutic doses.
FIH phase I dose escalation study of FN1501, an investigational FLT-3 inhibitor with multiple targets in patients with relapsed or refractory solid tumors and acute myeloid leukemia.
Authors: Richardson Gary Edward , Vaishampayan Ulka N. , Bozon Viviana , Hui Ai-Min , Williamson Stephen K. 
Published: May 2020

e15656 Background: FN1501 inhibits various tyrosine kinases as CDK4/6, KIT, PDGFR, ALK and RET proteins, particularly potent on FLT3 and EGFR2. A Ph1 FIH trial for patients (pts) with solid tumors and Acute Myeloid Leukemia (AML) is on-going1. Preclinical data showed that FN1501 inhibits the phosphorylation of FLT3 and its downstream kinase STAT5 in human acute leukemia cell lines, arrests the cell cycle inducing apoptosis and inhibits growth and proliferation of leukemia cells. It has anti-proliferation activity against other leukemia cell lines bearing FLT3 mutations, and lymphoma cell lines2, 3. Methods: 26 pts with advanced solid tumors or AML enrolled in the escalation phase and received IV FN1501 on days 1, 3, 5, 8, 10 and 12 on 21-day cycles. Primary objectives are safety and MTD, secondary objectives include preliminary activity, PK and PD. Plasma PK were assessed at different timepoints pre and post dose in C1 and C2. Results: As of 6FEB20, 26 pts have been treated in 7 ascending doses of 2.5mg, 5mg, 10mg, 15mg, 22.5mg, 30mg and 40mg. A 54 mg dose cohort is on-going. No DLTs, no SAEs or deaths associated to FN1501 have been reported. 12 pts (46%) had one grade 3 or higher TEAE and 7 pts (27%) had dose interruptions due to a TEAE. Administration of FN1501 to pts with metastatic solid tumors has resulted in anti-tumor activity. 9 pts had durable stable disease across 4 doses in renal, endometrial, ovarian, gastric, appendix and thymic malignancies. One pt with serous endometrial carcinoma achieved a cPR after 2 cycles at 40mg with a 47% tumor size reduction (target lesions). As of 26Oct19 preliminary PK data showed a t1/2 of approximately 12.7-19.0 hours post-dose. Mean Cmax and AUC increased proportionally with dose and Clearance is consistent among all doses. Conclusions: This on-going Ph1trial of FN1501 is providing evidence of dose or exposure effects as a single agent in patients with solid tumors. Since FN1501 targets multiple kinases on addition to FLT3, antitumor activity beyond AML is also being observed, suggesting that the potent inhibitory effects of other tyrosine kinases, including EGFR2 may be playing a role in the regulation of cellular functions, cell growth, differentiation and angiogenesis effects. FN1501 has been well tolerated and AEs are manageable. Genomic alterations investigations are underway to identify candidate biomarkers useful for predicting sensitivity to the multiple FN1501 tyrosine kinases. Further development of FN1501 is warranted. Clinical trial information: NCT03690154.
An integrative molecular framework to predict homologous recombination deficiency.
Authors: Bell Joshua SK , Venkat Aarti , Parsons Jerod , Igartua Catherine , Leibowitz Benjamin D. , Tell Robert , White Kevin 
Published: May 2020

e15664 Background: Homologous recombination deficiency (HRD) is the primary biomarker for sensitivity to PARP inhibitors, but identifying the genetic and transcriptomic characteristics that fully capture all HRD patients has remained difficult. For example, DNA-based approaches are limited to patients with pathogenic mutations and loss of heterozygosity (LOH) events, and can fail to properly classify patients with variants of unknown significance. To capture more dynamic cellular processes that arise immediately upon induction of HRD through silencing or loss of BRCA 1/2, a more integrated approach that includes both RNA and DNA based models is necessary. Methods: Using DNA sequencing we developed a genome-wide LOH score that combines pathogenic mutation status and LOH at the BRCA1/2 loci, and the proportion of bases sequenced in the Tempus xT panel that undergo LOH. We also developed three independent RNA-based models to predict BRCA deficiency: 1) An elastic net transcriptome model to predict DNA-based HRD scores derived from exome and SNP array data for each tumor type represented in TCGA; 2) A logistic model to detect BRCA1 promoter hypermethylation from the transcriptome in TCGA data; 3) A model that leveraged the mSigDB annotated gene sets to conduct single sample gene set enrichment analysis (ssGSEA) on Tempus-sequenced patients, selecting over a hundred gene sets that were predictive of BRCA-deficiency. These 4 features were combined to develop a stacked, linear-regression model to distinguish BRCA-intact from BRCA-deficient patients. Results: We found that the genome-wide LOH score alone is predictive of BRCA deficiency. However, our integrated model was highly accurate at distinguishing between BRCA-intact and BRCA-deficient patients and outperformed any single RNA- or DNA-based model. Using this model, we identified many patients that are likely to respond to PARP inhibitors that would have been overlooked using RNA or DNA-based inferences alone. Conclusions: Our approach highlights the strength of integrating diverse molecular features to refine diagnosis and enable oncologists to deliver the most effective therapies to patients.
The landscape of muti-PIK3CA variations of 10,000 Chinese solid-tumor patients.
Authors: Gu Weiguang , Zhou Chengzhi , Shen Zhuojian , Huang Jian , Qiao Chang , Hu Jinwei , Wang Weifeng , Yao Ming , Wang Kai 
Published: May 2020

e15670 Background: PI3K/mTOR signaling pathway plays a central role in cancer biology. Our study aimed to explore the characteristics of multiple PIK3CA variations in the Chinese patient with solid tumors. Methods: Formalin fixed, paraffin embedded (FFPE) tumor samples and matched peripheral blood from 10,194 Chinese solid tumor patients were collected for next-generation sequencing based 450 genes panel assay. The testing was carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China. Genomic alterations including SNV, short and long Indel, CNV, Fusion/Rearrangement were assessed. Microsatellite stable (MSS) status and TMB (tumor mutational burden) were also acquired by an NGS algorithm. Results: A total of 672 (6%) patients were identified harboring PIK3CA mutations, 93 (13.8%) of them had multiple PIK3CA mutations. Patients with multiple PIK3CA mutations included 51 females and 42 males with a mean age of 56 years old. Tumors with multiple PIK3CA mutations were composed of stage I (N = 14), II (N = 22), III (N = 18), IV (N = 25) and 14 without staging information. Cervical, breast, gastric and colorectal cancers were top ranked multiple-PIK3CA-mutant tumors (21%, 17%, 15%, 12% and 6%, respectively). TMB-H (≥10 mut/Mb) was significantly higher in multiple-PIK3CA-mutant tumors than that in single-PIK3CA-mutant tumors (60% vs 32%, P < 0.001). The MSS status was similar between multiple- and single-PIK3CA-mutant tumors (14% vs 11%). The most common PIK3CA alterations in both multiple- and single-PIK3CA-mutant tumors were E545 (36% vs 28%), H1047 (19% vs 24%) and E542 (16% vs 13%). Noticeably, the frequency of R88 (16% vs 3%, P < 0.0001), E726 (10% vs 0.8%, P < 0.0001), E453 (10% vs 1%, P < 0.0001), and M1043 (9% vs 0.8%, P < 0.0001) mutations were significantly higher in multiple-PIK3CA-mutant tumors than that in single-PIK3CA-mutant tumors. The top 3 most frequent PIK3CA dual mutation combinations were E545K+E726K, H1047R+E726K and E545K+R88Q. Among the co-mutated genes, copy numbers of ERBB2 were less altered in multiple-PIK3CA-mutant tumors than single-PIK3CA-mutant tumors (1% vs 6%, p < 0.05). Conclusions: This study, for the first time, revealed that approximately 13% PIK3CA positive Chinese solid tumor pts harboring multiple PIK3CA mutations. Several novel dual-PIK3CA-mutations were detected and multiple-PIK3CA-mutant pts more likely had high TMB, which may guide potential immunotherapy or PI3K-targeted therapy for multiple PIK3CA Chinese solid tumor patients.