First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors DOI Creative Commons
Sarina A. Piha‐Paul, Binghe Xu,

Ecaterina E. Dumbrava

et al.

The Oncologist, Journal Year: 2024, Volume and Issue: 29(4), P. e514 - e525

Published: Jan. 31, 2024

Abstract Purpose This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial receptors, Aurora A/B, in patients with advanced solid tumors. Patients Methods received orally daily 28-day cycles. Dose escalation was guided by Bayesian modeling using overdose control. The primary objective to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended for expansion (DRDE). Secondary objectives included pharmacokinetics efficacy. Results Forty-eight were enrolled (dose escalation, n = 40; expansion, 8). MTD not reached; DRDE 12 mg daily. DLTs palmar-plantar erythrodysesthesia syndrome (8 mg, 1) hypertension (15 2). most common treatment-related adverse event (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; 7) or stable disease (SD) ≥ 24 weeks (n 6), including 4/11 (36.4%) FGFR2 mutations/fusions cholangiocarcinoma (PR 3; SD 1), 3/3 (100.0%) hormone receptor (HR)-positive/HER2-negative breast cancer 2; 2/5 (40.0%) triple-negative (TNBC; PR 1; 1/1 castrate-resistant prostate (CRPC; PR). Four (33.3%; HR-positive/HER2-negative cancer, TNBC, cholangiocarcinoma) treated at had PRs. Tinengotinib’s half-life 28-34 hours. Conclusions Tinengotinib well favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative (including TNBC), CRPC. Continued evaluation is warranted II trials.

Language: Английский

Metastasis DOI Creative Commons

Stefanie Gerstberger,

Qingwen Jiang, Karuna Ganesh

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1564 - 1579

Published: April 1, 2023

Language: Английский

Citations

357
Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer DOI Creative Commons
Xue Chen,

Qinfan Yao,

Xinyu Gu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

Citations

214
Cancer cell plasticity during tumor progression, metastasis and response to therapy DOI
Andrea Pérez-González, Kevin Bévant, Cédric Blanpain

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(8), P. 1063 - 1082

Published: Aug. 3, 2023

Language: Английский

Citations

143
Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements DOI Creative Commons
Gautam Sethi, Prangya Rath, Abhishek Chauhan

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(2), P. 712 - 712

Published: Feb. 20, 2023

Due to rising incidence rates of liver cancer and worries about the toxicity current chemotherapeutic medicines, hunt for further alternative methods treat this malignancy has escalated. Compared chemotherapy, quercetin, a flavonoid, is relatively less harmful normal cells regarded as an excellent free-radical scavenger. Apoptotic cell death caused by quercetin been demonstrated many prior studies. It present in fruits, vegetables, herbs. Quercetin targets apoptosis, upregulating Bax, caspase-3, p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2. Additionally, it reported increase STAT3 protein degradation decreasing activation. potential future chemoprevention, based on substantial research its anticancer effects. The review discusses quercetin’s mechanisms action, nanodelivery strategies, other cellular effects cancer.

Language: Английский

Citations

69
Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation DOI Creative Commons

Yuman He,

Zhongzhong Ji,

Yiming Gong

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112033 - 112033

Published: Jan. 31, 2023

Cell plasticity and neuroendocrine differentiation in prostate lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether how metabolic changes contribute this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that or cancer cells possess mostly fragmented mitochondria with low membrane potential rely on glycolysis energy metabolism. We further an important role determinant Numb mitochondrial quality control via binding Parkin facilitating Parkin-mediated mitophagy. Deficiency Numb/Parkin pathway causes a reprogramming featured significant increase production lactate acid, which subsequently leads upregulation histone lactylation transcription neuroendocrine-associated genes. Collectively, Numb/Parkin-directed fitness is key switch promising target through regulation lactylation.

Language: Английский

Citations

68
Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies DOI Creative Commons
Yan-Ruide Li,

Ying Fang,

Zibai Lyu

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 2, 2023

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between microenvironment (TME) is observed, with TME providing supportive niche for CSC survival self-renewal, while CSCs, turn, influence polarization persistence TME, promoting an immunosuppressive state. Consequently, these interactions hinder efficacy current therapies, necessitating exploration novel therapeutic approaches modulate target CSCs. this review, we highlight intricate strategies employed by evade surveillance develop resistance therapies. Furthermore, examine dynamic interplay shedding light on how interaction impacts progression. Moreover, provide overview advanced that specifically which hold promise future clinical translational studies treatment.

Language: Английский

Citations

64
FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions DOI

Masuko Katoh,

Yohann Loriot,

Giovanni Brandi

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(4), P. 312 - 329

Published: Feb. 29, 2024

Language: Английский

Citations

60
Therapeutic resistance to anti-oestrogen therapy in breast cancer DOI
Marie Will, Jackson Liang, Ciara Metcalfe

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(10), P. 673 - 685

Published: July 27, 2023

Language: Английский

Citations

59
The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity DOI
Alastair Davies, Amina Zoubeidi, Himisha Beltran

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(8), P. 1771 - 1788

Published: July 20, 2023

Abstract Lineage plasticity, a process whereby cells change their phenotype to take on different molecular and/or histologic identity, is key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage it predominantly dynamic controlled by transcriptional epigenetic dysregulation. This review explores regulators plasticity interplay with other features malignancy, such as dysregulated metabolism, microenvironment, immune evasion. We also discuss strategies for detection treatment highly plastic tumors. Significance: hallmark critical facilitator oncogenic metastasis, resistance, It essential that mechanisms are elucidated enable development effectively target this phenomenon. In review, we describe cell in highlighting therapeutic approaches may be harnessed patient benefit.

Language: Английский

Citations

50
The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy DOI Creative Commons
Dechao Feng,

Weizhen Zhu,

Jie Wang

et al.

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: April 11, 2024

Abstract In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments the current era, particularly emerging integration of spatiotemporal have enabled a detailed molecular comprehension complex regulation cell fate. The insights obtained from these methodologies anticipated to significantly contribute development personalized medicine. Currently, technology is less frequently utilized for prostate cancer compared with other types tumors. Starting perspective RNA sequencing technology, this review outlined significance (scRNA-seq) research, encompassing preclinical medicine clinical applications. We summarize differences between mouse human as revealed by scRNA-seq studies, well combination multi-omics methods involving highlight key targets diagnosis, treatment, drug resistance characteristics cancer. These studies expected provide novel immunotherapy innovative treatment strategies castration-resistant Furthermore, we explore potential applications stemming technologies review, paving way future research precision

Language: Английский

Citations

25