Talactoferrin alfa is an anti-cancer agent with activity in renal cell cancer (RCC) patients and a novel immunomodulatory mechanism of action

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14648-14648
Author(s):  
A. Varadhachary ◽  
M. Spadaro ◽  
J. Engelmayer ◽  
P. Blezinger ◽  
T. Valli ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Cell Cancer ◽  
Single Agent ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Cd8 Cells ◽  
Anti Cancer ◽  
Cancer Activity

14648 Background: Talactoferrin alfa (talactoferrin) is a novel, orally administered immunomodulatory protein with demonstrated anti-cancer activity in preclinical experiments. Methods: Talactoferrin’s safety and efficacy in cancer patients was evaluated in a Phase I/II trial. Patients with metastatic disease who had failed standard therapy were treated with single-agent oral talactoferrin. Tumors were measured by CT scan using RECIST criteria. Talactoferrin’s mechanism of action was evaluated in preclinical experiments in tumor-bearing immunocompetent BALB/c and knockout mice. Cytokine levels were measured by ELISA. Cellular changes were measured by FACS analysis and immunofluorescence. Results: Seven patients with metastatic RCC who had failed previous systemic therapy were treated with oral, single-agent talactoferrin. Talactoferrin was safe and very well tolerated without a single drug-related SAE. All seven patients achieved at least Stable Disease, with one patient showing a deep and sustained partial response (71% shrinkage by RECIST two years after start of therapy). There was an apparent increase in median PFS to 7.3 months, with two patients still progression free after two years. Median OS has not yet been reached. In experiments conducted to define its anti-cancer mechanism, orally administered talactoferrin was found to act at the gut and the Gut Associated Lymphoid Tissue (GALT). Talactoferrin induced the chemotaxis of immune cells to intestinal Peyer’s Patches in mice, initiating an immunostimulatory cascade in the GALT and activating both innate and adaptive immunity. We observed significantly increased numbers of Dendritic Cells, NK-T cells and CD8+ T-lymphocytes in small intestinal Peyer’s patches, a systemic increase in Natural Killer (NK) and Cytotoxic T-lymphocyte (CTL) activity, activation of tumor draining lymph nodes, and cellular infiltration of distant tumors. The critical role of NK-T and CD8+ cells was demonstrated in knockout and depletion experiments. Conclusions: Talactoferrin, a first-in-class molecule with apparent clinical anti-cancer activity in RCC, acts through a novel immunomodulatory mechanism of action. [Table: see text]

scholarly journals Rapid G protein-regulated activation event involved in lymphocyte binding to high endothelial venules.

1993 ◽  
Vol 178 (1) ◽  
pp. 367-372 ◽  
Author(s):  
R F Bargatze ◽  
E C Butcher
Keyword(s):  
G Protein ◽  
Pertussis Toxin ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Inhibitory Effect ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
High Endothelial Venules ◽  
Activation Event

The homing of blood borne lymphocytes into lymph nodes and Peyer's patches is mediated in part by recognition and binding to specialized high endothelial venules (HEV). Here we demonstrate that a rapid pertussis toxin-sensitive lymphocyte activation event can participate in lymphocyte recognition of HEV. In situ video microscopic analyses of lymphocyte interactions with HEV in exteriorized mouse Peyer's patches reveal that pertussis toxin has no effect on an initial "rolling" displayed by many lymphocytes, but inhibits an activation-dependent "sticking" event required for lymphocyte arrest. This is the first demonstration that physiologic lymphocyte-endothelial interactions can involve sequential rolling, activation, and activation-dependent arrest, previously shown only for neutrophils. The inhibitory effect of the toxin is dependent on its G protein-modifying ADP-ribosyltransferase activity and can be reversed by phorbol myristic acetate, which bypasses cell surface receptors to trigger activation-dependent adhesion. Lymphocyte sticking can occur within 1-3 s after initiation of rolling. We conclude that a rapid receptor-mediated activation event involving G protein signaling can trigger stable lymphocyte attachment to HEV in vivo, and may play a critical role in regulating lymphocyte homing.

scholarly journals Mechanism of action of the third generation benzopyrans and evaluation of their broad anti-cancer activity in vitro and in vivo

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Alexander J. Stevenson ◽  
Eleanor I. Ager ◽  
Martina A. Proctor ◽  
Dubravka Škalamera ◽  
Andrew Heaton ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Third Generation ◽  
The Third ◽  
Anti Cancer ◽  
Cancer Activity

scholarly journals DDIS-01. THE ANTIBODY-DRUG CONJUGATE ABT-414 DEMONSTRATES SINGLE-AGENT ANTI-CANCER ACTIVITY ACROSS A PANEL OF GBM PATIENT-DERIVED XENOGRAFTS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi69-vi69 ◽  
Author(s):  
Bianca Marin ◽  
Ann Mladek ◽  
Danielle Burgenske ◽  
Lihong He ◽  
Zeng Hu ◽  
...  
Keyword(s):  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Anti Cancer ◽  
Cancer Activity ◽  
Antibody Drug

Adding oral talactoferrin to first-line NSCLC chemotherapy safely enhanced efficacy in a randomized trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7095-7095 ◽  
Author(s):  
Y. Wang ◽  
D. Raghunadharao ◽  
G. Raman ◽  
D. Doval ◽  
S. Advani ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Strong Association ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind ◽  
Significant Difference ◽  
Anti Cancer ◽  
Evaluable Population ◽  
Cancer Activity

7095 Background: Talactoferrin alfa (TLF) is an oral immunomodulatory protein with a novel mechanism. TLF showed preclinical anti-cancer activity alone and in combination with chemotherapy. In Phase I/II trials, TLF was safe with apparent single-agent anti-cancer activity in non-small cell lung cancer (NSCLC). Methods: 110 chemo-naive patients with advanced or metastatic NSCLC were randomized (1:1) in a multi-center trial to carboplatin/paclitaxel (C/P) therapy plus either TLF or placebo. Starting the day after C/P (C:AUC 5 mg/mL/min; P:175 mg/m2) in chemo-cycles 1, 3 and 5, oral TLF (1.5 g BID) or placebo was administered in 35-day cycles for up to three cycles or until progression. Primary endpoint was Confirmed Response Rate (RR; PR+CR) by CT using RECIST. Secondary endpoints included Progression Free Survival (PFS) and Overall Survival (OS). Results: Baseline patient and disease characteristics were comparable in both groups. All 110 patients were included in the Intent To Treat (ITT) population. 100 patients with at least one CT scan after starting treatment were prospectively defined as the Evaluable population. Adding oral TLF to C/P enhanced efficacy on all endpoints examined including RR, PFS and OS. Confirmed RR in the 100 evaluable patients significantly increased from 29% to 47% (P = 0.05). Confirmed RR in the 110 ITT patients improved from 27% to 42% (P = 0.08). Median PFS in both evaluable and ITT patients improved by 2.8 months (67%). Median OS improved by 31% and 18% in evaluable and ITT patients, respectively. A landmark analysis comparing survival in patients with and without a PR showed a significant difference (P < 0.01), suggesting a strong association between RR and survival. TLF appeared to be very safe and well tolerated with no drug-related SAEs. Fewer AEs were observed in the TLF arm than in the placebo arm, 346 and 432 AEs, respectively (P = 0.0023). The number of Grade 3/4 AEs was also lower in the TLF arm, 60 versus 91 (P = 0.0144). Conclusions: Adding oral TLF to standard C/P chemotherapy in NSCLC was safe and increased efficacy in a randomized, multi-center, double-blind, placebo-controlled trial, with apparent improvements in RR, PFS and OS. Results with TLF compare favorably to other anti-cancer agents. Oral TLF will be further evaluated in a Phase III trial. [Table: see text]

Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3030-3030
Author(s):  
Sarah Patricia Blagden ◽  
Jennifer Bré ◽  
Peter Mullen ◽  
Chathunissa Gnanaranjan ◽  
Essam Ahmed Ghazaly ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Single Agent ◽  
Nucleotide Metabolism ◽  
Clinical Activity ◽  
Phase Ib ◽  
Platinum Resistant ◽  
Anti Cancer ◽  
Platinum Agent ◽  
Cancer Activity

3030 Background: The inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. This, in combination with platinum-induced DNA-damage, is key to promoting anti-cancer activity in a variety of tumors, including ovarian, biliary tract, lung, breast and bladder. NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog. NUC-1031 has shown broad clinical activity across multiple solid tumors as both a single agent and in combination with platinum agents. We show potential synergism between NUC-1031 and a platinum agent in advanced ovarian (OC) and biliary tract (BTC) cancers. Methods: PRO-002 was a phase Ib study; 25 patients (pts) with recurrent OC who had exhausted all other therapy options received NUC-1031 + carboplatin. 17 pts were considered platinum resistant (10) or platinum refractory (7). ABC-08 is a phase Ib study, 14 pts with advanced BTC treated in the first-line setting with NUC-1031 + cisplatin. Results: In PRO-002, strong efficacy signals were observed in non-platinum-responsive patients. Of the 17 response-evaluable platinum-resistant or refractory pts, 5 partial responses (PRs) and 11 stable diseases (SDs) were achieved, resulting in an ORR of 29% and a DCR of 94%. NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue. Encouraging response rates were also observed in ABC-08 compared to historical standard of care (ABC-02). One CR (7%), 6 PRs (43%) and 1 SD (7%) were observed, resulting in an ORR of 50%. NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs. Complementary in vitro evidence suggests that the beneficial interaction occurs whereby platinum treatment sensitizes cells to NUC-1031. Conclusions: Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population. Future studies utilizing both NUC-1031 plus a platinum agent will further elucidate the potential of this therapeutic combination.

P–284 Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
C Lange ◽  
A Machad. Weber ◽  
R Schmidt ◽  
C Schroeder ◽  
T Strowitzki ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Protein Expression ◽  
Mechanism Of Action ◽  
In Vitro Study ◽  
Metformin Treatment ◽  
Target Proteins ◽  
Proteomic Approach ◽  
Anti Cancer ◽  
Cancer Activity

Abstract Study question The aim of the study was to identify new target proteins/pathways that are affected by metformin treatment in endometrial cancer cells in a proteomic approach. Summary answer The expression of 1,300 different proteins were investigated, of which 80 proteins with the most prominent changes were presented and some discussed in detail. What is known already The incidence of endometrial cancer (EC) has increased over the past years. Metabolic diseases such as obesity, type II diabetes mellitus (T2DM), and associated conditions (i.e. polycystic ovary syndrome (PCOS), insulin resistance) lead to elevated levels of circulating estrogens, which promote EC development and progression. Metformin, an insulin-sensitizing biguanide drug, commonly used in the treatment of T2DM, especially in obese patients, displayed anti-cancer effects in various cancer types, including EC. Different proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin’s anti-cancer activity is still not completely understood. Study design, size, duration In the present in vitro study, EC cells were cultured in 5.5 mmol/L glucose medium (supplemented with 10 nmol/L ß-estradiol (E2)) and treated with metformin (0.5 mmol/L), insulin (100 ng/mL), or remained untreated for 7 d. The expression of 1,300 different proteins was detected in cellular extracts in an affinity proteomic approach and compared between the treatment groups in order to identify potential target proteins and pathways that contribute to the anti-cancer effects of metformin. Participants/materials, setting, methods The study was carried out with the EC cell line HEC–1A that represents a postmenopausal model with low E2 sensitivity. Proteins were extracted, quantified with the BCA assay, and protein expression was analyzed using the scioDiscover antibody microarray. Differences in protein abundance between samples were presented as log2-fold changes (log2FC) with significance for samples that displayed |log2FC| ≥ 0.5 and adjusted p ≤ 0.05. Pathway analysis was carried out with the STRING and DAVID databases. Main results and the role of chance The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. Results for the 80 most affected proteins were presented and the consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential target proteins and pathways affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug’s anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia. Limitations, reasons for caution The results were obtained from an in vitro study with human cancer cell lines, and thus cannot be easily extrapolated to patients. Wider implications of the findings: In the context of a hyperinsulinemic environment, further proteins might be of interest, i.e. AMFR, CCND2, CD63, ERBB3, EZR, GFAP, IRF4, PI3, PLCG2, SORL1, VEGFA, VTCN1, SPP1, and TM9SF2. Here, a metformin-induced insulin-sensitization might be able to counteract unfavorable effects on protein expression profile that have been induced by hyperinsulinemia. Trial registration number Not applicable

scholarly journals Critical Role of Dendritic Cells in T Cell Retention in the Interfollicular Region of Peyer’s Patches

2013 ◽  
Vol 191 (2) ◽  
pp. 942-948 ◽  
Author(s):  
Takashi Obata ◽  
Naoko Shibata ◽  
Yoshiyuki Goto ◽  
Izumi Ishikawa ◽  
Shintaro Sato ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Critical Role ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Cell Retention

scholarly journals α4 integrin plays a critical role in early stages of T lymphocyte migration in Peyer's patches of rats

1996 ◽  
Vol 8 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Yoshikazu Tsuzuki ◽  
Soichiro Miura ◽  
Makoto Suematsu ◽  
Iwao Kurose ◽  
Takeharu Shigematsu ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Critical Role ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Lymphocyte Migration ◽  
Early Stages

scholarly journals Maf is a regulator of differentiation for gut immune epithelial cell Microfold cell (M cell)

2021 ◽  
Author(s):  
Joel Johnson George ◽  
Fabio Tadeu Arrojo Martins ◽  
Laura Martin-Diaz ◽  
Keijo Viiri
Keyword(s):  
Transcription Factors ◽  
Critical Role ◽  
Single Layer ◽  
Cell Development ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
M Cells ◽  
M Cell ◽  
Development And Differentiation ◽  
Antigen Presenting

Microfold cells (M cells) are a specialized subset of epithelial intestinal cells responsible for immunosurveillance of the gastrointestinal tract. M cells are located in the Peyer's patches and are crucial for monitoring and the transcytosis of antigens, microorganisms, and pathogens via their mature receptor GP2. A mature M cell with Gp2 receptor aids in the uptake of antigens, which are passed through the single layer of epithelium and presented to underlying antigen-presenting cells and processed further down-stream with B cells, T cells, and dendritic cells. Recent studies revealed several transcription factors and ligands responsible for the development and differentiation of mature M cells however, an exhaustive list of factors remains to be elucidated. Our recent work on the epigenetic regulation of M cell development found 12 critical transcription factors that were controlled by the polycomb recessive complex 2. Musculoaponeurotic fibrosarcoma transcription factor (Maf) was identified as a gene regulated by the polycomb repressive complex (PRC2) during the development of M cells. In this paper, we explore Maf's critical role in M cell differentiation and maturation. Maf falls under the purview of RANKL signaling, is localized in the Peyer's patches of the intestine, and is expressed by M cells. Given that, complete knockout of the Maf gene leads to a lethal phenotype, organoids isolated from Maf knockout mice and treated with RANKL exhibited impaired M cell development and a significant decrease in Gp2 expression. These findings reveal that Maf is an important regulator for M cell development and differentiation.

scholarly journals Stress Granules in the Anti-Cancer Medications Mechanism of Action: A Systematic Scoping Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Mohammad Reza Asadi ◽  
Marziyeh Sadat Moslehian ◽  
Hani Sabaie ◽  
Marziye Poornabi ◽  
Elham Ghasemi ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Scoping Review ◽  
Critical Role ◽  
Cell Formation ◽  
Methodological Framework ◽  
Health It ◽  
Translation Process ◽  
Current Systematic Review ◽  
Anti Cancer ◽  
The Impact

Stress granule (SG) formation is a well-known cellular mechanism for minimizing stress-related damage and increasing cell survival. In addition to playing a critical role in the stress response, SGs have emerged as critical mediators in human health. It seems logical that SGs play a key role in cancer cell formation, development, and metastasis. Recent studies have shown that many SG components contribute to the anti-cancer medications’ responses through tumor-associated signaling pathways and other mechanisms. SG proteins are known for their involvement in the translation process, control of mRNA stability, and capacity to function in both the cytoplasm and nucleus. The current systematic review aimed to include all research on the impact of SGs on the mechanism of action of anti-cancer medications and was conducted using a six-stage methodological framework and the PRISMA guideline. Prior to October 2021, a systematic search of seven databases for eligible articles was performed. Following the review of the publications, the collected data were subjected to quantitative and qualitative analysis. Notably, Bortezomib, Sorafenib, Oxaliplatin, 5-fluorouracil, Cisplatin, and Doxorubicin accounted for the majority of the medications examined in the studies. Overall, this systematic scoping review attempts to demonstrate and give a complete overview of the function of SGs in the mechanism of action of anti-cancer medications by evaluating all research.

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