Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 577-577
Author(s):  
Heather M. Moore ◽  
Valentina Boni ◽  
Meritxell Bellet ◽  
Begoña Bermejo De Las Heras ◽  
Maria Gión Cortés ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Target Genes ◽  
Transcriptional Profiling ◽  
Geometric Mean ◽  
Preoperative Treatment ◽  
Dose Selection ◽  
Luminal A ◽  
Biologic Activity ◽  
Estrogen Synthesis ◽  
Wide Range

577 Background: Modulation of ER activity and/or estrogen synthesis is the mainstay therapeutic strategy in ER+ BC treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER degrader (SERD) that achieves robust ER occupancy and is effective regardless of ESR1 mutation status. The first short-term preoperative WOO study (NCT03916744) of giredestrant in ER+/HER2– operable BC was designed for dose selection, while providing an early readout of PD as measured by traditional immunohistochemistry (IHC) and transcriptional profiling by assessing treatment effects in paired tumor tissue pre/posttreatment. We present an interim analysis. Methods: Pts were assigned to 14 days’ preoperative treatment with 10, 30, or 100 mg PO giredestrant QD. Pts had newly diagnosed, stage I–III operable, ER+/HER2– untreated BC ≥1.5 cm in diameter (by ultrasound). Modulation of ER signaling and cell proliferation were assessed using paired formalin-fixed paraffin-embedded tumor specimens collected before and after ̃14 days of study treatment. ER, progesterone receptor (PR), and Ki67 protein levels were analyzed by IHC. Change from baseline in tumor cell proliferation by Ki67 was the primary endpoint. Gene expression analysis was performed using the Illumina TruSeq RNA Access method. Results: From Jul 26, 2019 to Oct 15, 2020, 46/75 biomarker-evaluable pts were enrolled across three dose cohorts (10 mg: n = 15; 30 mg: n = 18; 100 mg: n = 13). Pt demographics and tumor characteristics were similar across cohorts. Baseline PAM50 analysis classified tumors as Luminal A (77%) or B (23%). Giredestrant treatment resulted in robust and indistinguishable PD and biologic activity at all doses. Geometric mean posttreatment proportional reduction of Ki67 was 79% (95% CI: 69–89; 10 mg: 80%; 30 mg: 76%; 100 mg: 80%), and 51% of tumors exhibited complete cell cycle arrest, defined as Ki67 ≤2.7%. Mean posttreatment proportional reductions of ER and PR H-scores were 71% (95% CI: 67–75) and 60% (95% CI: 51–70), respectively. An analysis of a predefined, experimentally derived set of 38 ER target genes (the ‘ER activity signature’), was completed for 42 paired tumor specimens. Forty-one of 42 pts (98%) showed a posttreatment reduction in ER activity with a mean proportional decrease of 79% (95% CI: 70–88). A wide range of baseline ER activity was observed with no correlation to baseline ER or PR H-score, or Ki67. There were no discontinuations due to adverse events (AEs). A single grade 3 serious AE was reported in each cohort (all assessed as unrelated to giredestrant). No grade 4 or 5 AEs were reported. Conclusions: Giredestrant was well tolerated in the preoperative setting in ER+/HER2– operable BC, and PDs were consistent with the 30 mg dose achieving maximal ER inhibition. Clinical trial information: NCT03916744.

scholarly journals Expression of lamina proteins Lamin Dm0 and Kugelkern suppresses stem cell proliferation

2017 ◽  
Author(s):  
Roman Petrovsky ◽  
Jörg Großhans
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Target Genes ◽  
Cell Function ◽  
Nuclear Lamina ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Stem Cell Proliferation ◽  
Wide Range ◽  
Nuclear Stability

AbstractThe nuclear lamina is involved in numerous cellular functions, such as gene expression, nuclear organization, nuclear stability, and cell proliferation. The mechanism underlying the involvement of lamina is often not clear, especially in physiological contexts. Here we investigate how the farnesylated lamina proteins Lamin Dm0 and Kugelkern are linked to proliferation control of intestinal stem cells (ISCs) in adult Drosophila flies by loss-of-function and gain-of-function experiments. We found that ISCs mutant for Lamin Dm0 or Kugelkern proliferate, whereas overexpression of Lamin Dm0 or Kugelkern strongly suppressed proliferation. The anti-proliferative activity is, at least in part, due to suppression of Jak/Stat but not Delta/Notch signalling. Lamin Dm0 expression suppresses Jak/Stat signalling by normalization of about 50% of the Stat target genes in ISCs.Author summaryThe nuclear lamina is a protein meshwork that lies beneath the inner side of the nuclear membrane and interacts with nuclear pores, chromatin and the cytoskeleton. Changes in proteins of the nuclear lamina cause a wide range of diseases which are often not well understood. It is hypothesized that impairment of stem cell function, as a result of lamina changes, might play a key role in some of those diseases. Here we use the well characterized Drosophila midgut as a system to investigate the role of lamina proteins Lamin Dm0 and Kugelkern on stem cell proliferation.

scholarly journals MicroRNAs and angiogenesis: a new era for the management of colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yufei Tang ◽  
Shaoqi Zong ◽  
Hailun Zeng ◽  
Xiaofeng Ruan ◽  
Liting Yao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Noncoding Rna ◽  
Target Genes ◽  
Tumour Progression ◽  
Cell Cycle Checkpoint ◽  
Tumour Angiogenesis ◽  
Small Noncoding Rna ◽  
Wide Range ◽  
Migration Pathways

AbstractMicroRNAs (miRNAs) are a class of small noncoding RNA molecules containing only 20–22 nucleotides. MiRNAs play a role in gene silencing and translation suppression by targeting and binding to mRNA. Proper control of miRNA expression is very important for maintaining a normal physiological environment because miRNAs can affect most cellular pathways, including cell cycle checkpoint, cell proliferation, and apoptosis pathways, and have a wide range of target genes. With these properties, miRNAs can modulate multiple signalling pathways involved in cancer development, such as cell proliferation, apoptosis, and migration pathways. MiRNAs that activate or inhibit the molecular pathway related to tumour angiogenesis are common topics of research. Angiogenesis promotes tumorigenesis and metastasis by providing oxygen and diffusible nutrients and releasing proangiogenic factors and is one of the hallmarks of tumour progression. CRC is one of the most common tumours, and metastasis has always been a difficult issue in its treatment. Although comprehensive treatments, such as surgery, radiotherapy, chemotherapy, and targeted therapy, have prolonged the survival of CRC patients, the overall response is not optimistic. Therefore, there is an urgent need to find new therapeutic targets to improve CRC treatment. In a series of recent reports, miRNAs have been shown to bidirectionally regulate angiogenesis in colorectal cancer. Many miRNAs can directly act on VEGF or inhibit angiogenesis through other pathways (HIF-1a, PI3K/AKT, etc.), while some miRNAs, specifically many exosomal miRNAs, are capable of promoting CRC angiogenesis. Understanding the mechanism of action of miRNAs in angiogenesis is of great significance for finding new targets for the treatment of tumour angiogenesis. Deciphering the exact role of specific miRNAs in angiogenesis is a challenge due to the high complexity of their actions. Here, we describe the latest advances in the understanding of miRNAs and their corresponding targets that play a role in CRC angiogenesis and discuss possible miRNA-based therapeutic strategies.

scholarly journals Ways into Understanding HIF Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 159
Author(s):  
Tina Schönberger ◽  
Joachim Fandrey ◽  
Katrin Prost-Fingerle
Keyword(s):  
Protein Interactions ◽  
Target Genes ◽  
Protein Protein Interactions ◽  
Low Oxygen ◽  
Drug Candidates ◽  
Open Questions ◽  
Wide Range ◽  
Hif Pathway

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

scholarly journals Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 861
Author(s):  
James Hentig ◽  
Kaylee Cloghessy ◽  
Manuela Lahne ◽  
Yoo Jin Jung ◽  
Rebecca A. Petersen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Proliferative Response ◽  
Injury Severity ◽  
Granule Cell Layer ◽  
Dependent Manner ◽  
Adult Zebrafish ◽  
Post Injury ◽  
Blunt Force ◽  
Shh Pathway ◽  
Wide Range

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner.

scholarly journals Profiling the expression of pro-metastatic genes in association with the clinicopathological features of primary breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Seyed-Mohammad Mazloomi ◽  
Mitra Foroutan-Ghaznavi ◽  
Vahid Montazeri ◽  
Gholamreza Tavoosidana ◽  
Ashraf Fakhrjou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Case Series ◽  
Clinicopathological Features ◽  
Cell Junctions ◽  
Homologous Gene ◽  
Axillary Lymph ◽  
Luminal A ◽  
Transcriptional Profiles ◽  
First Time

Abstract Background Metastasis accounts for ninety percent of breast cancer (BrCa) mortality. Cortactin, Ras homologous gene family member A (RhoA), and Rho-associated kinase (ROCK) raise cellular motility in favor of metastasis. Claudins (CLDN) belong to tight junction integrity and are dysregulated in BrCa. Thus far, epidemiologic evidence regarding the association of different pro-metastatic genes with pathological phenotypes of BrCa is largely inconsistent. This study aimed to determine the possible transcriptional models of pro-metastatic genes incorporate in holding the integrity of epithelial cell–cell junctions (CTTN, RhoA, ROCK, CLDN-1, CLDN-2, and CLDN-4), for the first time, in association with clinicopathological features of primary BrCa. Methods In a consecutive case-series design, 206 newly diagnosed non-metastatic eligible BrCa patients with histopathological confirmation (30–65 years) were recruited in Tabriz, Iran (2015–2017). Real-time RT-PCR was used. Then fold changes in the expression of target genes were measured. Results ROCK amplification was associated with the involvement of axillary lymph node metastasis (ALNM; ORadj. = 3.05, 95%CI 1.01–9.18). Consistently, inter-correlations of CTTN-ROCK (β = 0.226, P < 0.05) and RhoA-ROCK (β = 0.311, P < 0.01) were determined among patients diagnosed with ALNM+ BrCa. In addition, the overexpression of CLDN-4 was frequently observed in tumors identified by ALNM+ or grade III (P < 0.05). The overexpression of CTTN, CLDN-1, and CLDN-4 genes was correlated positively with the extent of tumor size. CTTN overexpression was associated with the increased chance of luminal-A positivity vs. non-luminal-A (ORadj. = 1.96, 95%CI 1.02–3.77). ROCK was also expressed in luminal-B BrCa tumors (P < 0.05). The estrogen receptor-dependent transcriptions were extended to the inter-correlations of RhoA-ROCK (β = 0.280, P < 0.01), ROCK-CLDN-2 (β = 0.267, P < 0.05), and CLDN-1-CLDN-4 (β = 0.451, P < 0.001). Conclusions For the first time, our findings suggested that the inter-correlations of CTTN-ROCK and RhoA-ROCK were significant transcriptional profiles determined in association with ALNM involvement; therefore the overexpression of ROCK may serve as a potential molecular marker for lymphatic metastasis. The provided binary transcriptional profiles need more approvals in different clinical features of BrCa metastasis.

scholarly journals New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Daniela P. Foti ◽  
Francesco Paonessa ◽  
Eusebio Chiefari ◽  
Antonio Brunetti
Keyword(s):  
Insulin Receptor ◽  
Target Genes ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Peptide Hormone ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Preclinical Research ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

scholarly journals Id2 Promotes Apoptosis by a Novel Mechanism Independent of Dimerization to Basic Helix-Loop-Helix Factors

1998 ◽  
Vol 18 (9) ◽  
pp. 5435-5444 ◽  
Author(s):  
Monica Florio ◽  
Maria-Clemencia Hernandez ◽  
Hui Yang ◽  
Hui-Kuo Shu ◽  
John L. Cleveland ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Target Genes ◽  
Specific Binding ◽  
Helix Loop Helix ◽  
Cell Death Pathway ◽  
Id Proteins ◽  
Enhanced Expression ◽  
Positive Regulators ◽  
Hlh Transcription Factors

ABSTRACT Members of the helix-loop-helix (HLH) family of Id proteins have demonstrated roles in the regulation of differentiation and cell proliferation. Id proteins inhibit differentiation by HLH-mediated heterodimerization with basic HLH transcription factors. This blocks their sequence-specific binding to DNA and activation of target genes that are often expressed in a tissue-specific manner. Id proteins can also act as positive regulators of cell proliferation. The different mechanisms proposed for Id-mediated promotion of entry into S phase also involve HLH-mediated interactions affecting regulators of the G1/S transition. We have found that Id2 augments apoptosis in both interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells. We could not detect a similar activity for Id3. In contrast to the effects of Id2 on differentiation and cell proliferation, Id2-mediated apoptosis is independent of HLH-mediated dimerization. The ability of Id2 to promote cell death resides in its N-terminal region and is associated with the enhanced expression of a known component of the programmed cell death pathway, the proapoptotic gene BAX.

scholarly journals MisR/MisS Two-Component Regulon in Neisseria meningitidis

2007 ◽  
Vol 76 (2) ◽  
pp. 704-716 ◽  
Author(s):  
Yih-Ling Tzeng ◽  
Charlene M. Kahler ◽  
Xinjian Zhang ◽  
David S. Stephens
Keyword(s):  
Neisseria Meningitidis ◽  
Target Genes ◽  
Inner Core ◽  
Consensus Sequence ◽  
Meningococcal Infection ◽  
Type I ◽  
Mobility Shift ◽  
Iron Assimilation ◽  
Wide Range ◽  
Two Component

ABSTRACT Two-component regulatory systems are involved in processes important for bacterial pathogenesis. Inactivation of the misR/misS system in Neisseria meningitidis results in the loss of phosphorylation of the lipooligosaccharide inner core and causes attenuation in a mouse model of meningococcal infection. One hundred seventeen (78 up-regulated and 39 down-regulated) potential regulatory targets of the MisR/MisS (MisR/S) system were identified by transcriptional profiling of the NMBmisR mutant and the parental wild-type meningococcal strain NMB. The regulatory effect was further confirmed in a subset of target genes by quantitative real-time PCR and β-galactosidase transcriptional fusion reporter assays. The MisR regulon includes genes encoding proteins necessary for protein folding in the bacterial cytoplasm and periplasm, transcriptional regulation, metabolism, iron assimilation, and type I protein transport. Mutation in the MisR/S system caused increased sensitivity to oxidative stress and also resulted in decreased susceptibility to complement-mediated killing by normal human serum. To identify the direct targets of MisR regulation, electrophoretic mobility shift assays were carried out using purified MisR-His6 protein. Among 22 genes examined, misR directly interacted with 14 promoter regions. Six promoters were further investigated by DNase I protection assays, and a MisR-binding consensus sequence was proposed. Thus, the direct regulatory targets of MisR and the minimal regulon of the meningococcal MisR/S two-component signal transduction system were characterized. These data indicate that the MisR/S system influences a wide range of biological functions in N. meningitidis either directly or via intermediate regulators.

Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation domain

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 367-379 ◽  
Author(s):  
W. Du
Keyword(s):  
Cell Proliferation ◽  
Target Genes ◽  
Suppressor Gene ◽  
Genetic Interactions ◽  
Transactivation Domain ◽  
Transcription Activator ◽  
Drosophila Development ◽  
Mitotic Wave ◽  
E2f Transcription Factors ◽  
Null Mutants

In mammals, a large number of proteins including E2F transcription factors have been shown to interact with the tumor suppressor gene product pRB, but it is not clear to what extend the function of pRB is mediated by E2F. In addition, E2F was shown to mediate both transcription activation and repression; it remains to be tested which function of E2F is critical for normal development. Drosophila homologs of the RB and E2F family of proteins RBF and dE2F1 have been identified. The genetic interactions between rbf and de2f1 were analyzed during Drosophila development, and the results presented here showed that RBF is required at multiple stages of development. Unexpectedly, rbf null mutants can develop until late pupae stage when the activity of dE2F1 is reduced, and can develop into viable adults with normal adult appendages in the presence of a de2f1 mutation that retains the DNA binding domain but lacks the transactivation domain. These results indicate that most, if not all, of the function of RBF during development is mediated through E2F. In turn, the genetic interactions shown here also suggest that dE2F1 functions primarily as a transcription activator rather than a co-repressor of RBF during Drosophila development. Analysis of the expression of an E2F target gene PCNA in eye discs showed that the expression of PCNA is activated by dE2F1 in the second mitotic wave and repressed in the morphogenetic furrow and posterior to the second mitotic wave by RBF. Interestingly, reducing the level of RBF restored the normal pattern of cell proliferation in de2f1 mutant eye discs but not the expression of E2F target genes, suggesting that the coordinated transcription of E2F target genes does not significantly affect the pattern of cell proliferation.

Sign in / Sign up

Export Citation Format

Share Document