☆ 4.7 Review

Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

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Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents

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Summary: The PI3K/PKB/mTOR signaling pathway has a well-known biochemical role in cell-cycle regulation. It becomes overactive during the development of cancer, promoting cell proliferation and inhibiting apoptosis. Therefore, targeting this pathway has become important in the treatment of various malignant tumors. Selective inhibitors have been identified, but drugs that target multiple proteins within the pathway have shown higher efficacy and limited drug resistance, making them promising anticancer agents. This survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signaling pathway as potential pharmacological treatments for cancer.

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Summary: This Review describes the structure, function, regulation, and disease roles of clinically relevant PIKs outside of class I PI3Ks, as well as the development of potent and specific small-molecule inhibitors. Phosphoinositide kinases are master regulators of cellular processes and their dysregulation has been implicated in various human diseases. Recent years have seen increased interest in targeting phosphoinositide kinases beyond class I PI3Ks, leading to the clinical development of selective inhibitors. This comprehensive analysis provides an overview of the current understanding and progress in the development of phosphoinositide kinase inhibitors.

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Comparative Proteomic and Transcriptomic Analysis of the Impact of Androgen Stimulation and Darolutamide Inhibition

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Summary: Mass spectrometry-based proteomic analysis of VCaP prostate cancer cells treated with androgen and the AR signaling inhibitor darolutamide showed a general agreement with transcriptomic responses. However, there were discrepancies in the magnitude of changes induced in gene expression levels and protein levels, indicating post-transcriptional regulation mechanisms.

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Wenqing Jia et al.

Summary: The PI3K/AKT/mTOR signaling pathway plays a crucial role in cellular processes such as cell growth, proliferation, and metabolism. Abnormal activation of PI3K alpha, one of the isoforms of PI3K, is frequently observed in cancer, especially breast cancer, and is associated with malignant behaviors of cancer cells. Alpelisib is the only approved PI3K alpha inhibitor for breast cancer treatment, and several others are being evaluated in clinical trials.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023)

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Article Hematology

A randomized, placebo-controlled phase 3 trial of the PI3K8 inhibitor leniolisib for activated PI3K8 syndrome

V. Koneti Rao et al.

Summary: Activated phosphoinositide 3-kinase delta (PI3K delta) syndrome (APDS) is a genetic disorder that results in immune dysregulation and deficiency. In a clinical trial, leniolisib, a selective PI3K delta inhibitor, was found to improve lymphadenopathy and increase the percentage of naive B cells in patients with APDS, demonstrating a positive impact on their immune system. Overall, leniolisib was well tolerated with minimal adverse events.

BLOOD (2023)

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Article Oncology

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer

Giuseppe Curigliano et al.

Summary: This study evaluated the efficacy and safety of gedatolisib in combination with other anti-tumour agents in advanced solid tumours. The results showed that the combination therapy of gedatolisib and cisplatin had good clinical activity and acceptable tolerability profile in patients with triple-negative breast cancer, both in first-line and second/third-line settings.

BRITISH JOURNAL OF CANCER (2023)

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Susan J. Keam

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Summary: The IPATunity130 Cohort B study investigated the use of ipatasertib-paclitaxel in HR+ breast cancer patients with PI3K pathway mutations. The results showed that adding ipatasertib to paclitaxel did not improve efficacy in these patients.

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A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer

Corinne Maurice-Dror et al.

Summary: EPI-506 is a novel drug targeting the N-terminal domain of the androgen receptor, showing potential in overcoming resistance mechanisms. The phase 1 trial established its safety but was terminated early due to poor oral bioavailability. Next generation compounds are being developed with improved properties.

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JOURNAL OF BIOLOGICAL CHEMISTRY (2022)

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Article Cell Biology

AR imposes different effects on ZFHX3 transcription depending on androgen status in prostate cancer cells

Xing Fu et al.

Summary: Androgen receptor (AR) and the ZFHX3 transcription factor both play important roles in prostate development. AR drives prostatic carcinogenesis, while ZFHX3 acts as a tumor suppressor. The study found that ZFHX3 transcription is upregulated by androgen via AR binding, and that ZFHX3 downregulation is associated with poor patient survival in prostate cancer.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2022)

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Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Lina Merkens et al.

Summary: Prostate cancer is a hormone-driven disease and targeted therapies against androgen receptor (AR) signaling have been widely used. However, some patients eventually develop castration-resistant disease. Aggressive variant prostate cancer (AVPC) with neuroendocrine differentiation has emerged and its growth is independent of the AR pathway. Understanding the molecular mechanisms contributing to transdifferentiation is crucial for improving diagnosis and treatment strategies.

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Summary: In this study, we reported a potent AKT degrader MS21 and its structure-activity relationship (SAR) studies. Additionally, we discovered another VHL-recruiting AKT degrader MS143 with similar efficacy as MS21, as well as a novel CRBN-recruiting PROTAC MS5033. These compounds effectively degraded AKT by hijacking the ubiquitin-proteasome system and showed significant inhibition of cell growth in multiple cancer cell lines. Furthermore, they exhibited good plasma exposure levels in mice and were suitable for in vivo studies.

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Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer

Xueliang Gao et al.

Summary: Research findings suggest that blocking p110 beta can slow down the progression of castration-resistant prostate cancer and reduce tumor growth. Combining p110 beta with other inhibitors shows potential for treating CRPC.

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Review Biotechnology & Applied Microbiology

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Summary: Targeted protein degradation (TPD) is a new therapeutic modality that can tackle disease-causing proteins which are difficult to target with conventional small molecules. PROTAC molecules, utilizing the ubiquitin-proteasome system to degrade target proteins, has achieved clinical proof-of-concept and attracted significant industry activity. Future directions include identifying target classes suitable for TPD, expanding the use of ubiquitin ligases for precision medicine, and extending the modality beyond oncology.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer

Matthew R. Smith et al.

Summary: Darolutamide, in combination with androgen-deprivation therapy and docetaxel, significantly increased overall survival among patients with metastatic hormone-sensitive prostate cancer compared to placebo plus androgen-deprivation therapy and docetaxel. The addition of darolutamide also led to improvement in secondary end points without notable differences in adverse events.

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Bart Vanhaesebroeck et al.

Summary: PIK3CA is a frequently activated kinase gene in solid tumors. This study shows that the PI3Kα inhibitors taselisib and inavolisib can induce degradation of mutant p110α protein in breast cancer cells that are positive for HER2 RTK, thereby limiting feedback-mediated drug resistance and potentially widening the therapeutic range of PI3Kα inhibition.

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Overview of the Development and Use of Akt Inhibitors in Prostate Cancer

Anis Gasmi et al.

Summary: Deregulation of the PI3K-Akt-mTOR pathway is crucial in the development and progression of various cancers. In prostate cancer, PTEN loss of function is believed to be the main driver. Despite the challenges in developing selective Akt inhibitors, recent phase II and III clinical trials have shown promising outcomes with Ipatasertib and Capivasertib in combination with androgen deprivation therapies for patients with metastatic castration-resistant prostate cancer and PTEN loss. Ongoing trials are currently evaluating different combinations of Akt inhibitors at different stages of prostate cancer.

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Article Biochemistry & Molecular Biology

Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase

Haili Wang et al.

Summary: PI3K kinase plays a crucial role in cellular processes, and its overexpression is associated with various cancers. PROTAC technology, using the ubiquitin-proteasome system, can degrade target proteins. This study successfully connected a highly active PI3K inhibitor to VHL ligand and developed PROTAC molecules targeting PI3K kinase.

BIOORGANIC & MEDICINAL CHEMISTRY (2022)

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Article Medicine, General & Internal

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

Blossom Mak et al.

Summary: This study assessed the association between circulating lipids, somatic genetic aberrations, and clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). The results revealed that certain genetic aberrations were associated with elevated circulating sphingolipids, and patients with both genetic and lipid abnormalities had worse prognosis. These findings may have implications for the selection of metabolic therapies.

BMC MEDICINE (2022)

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Meeting Abstract Oncology

Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER plus metastatic breast cancer

Rachel Layman et al.

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Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer

Ilsa M. Coleman et al.

Summary: This study classified metastatic castration-resistant prostate cancers (mCRPC) into LumA, LumB, and Basal subtypes using the PAM50 breast cancer classification algorithm and investigated their association with treatment outcomes. The study found that the LumA subtype was enriched in TGFss and... pathways.

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Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer

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Summary: In patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on abiraterone treatment, the combination of samotolisib/enzalutamide showed tolerable side effects and significantly improved progression-free survival (PFS), especially in patients with intact PTEN and no androgen receptor splice variant 7.

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Review Oncology

Molecular mechanisms of neuroendocrine differentiation in prostate cancer progression

Yuchen Xie et al.

Summary: This review focuses on the molecular characteristics and relevant genes and molecular mechanisms that contribute to the transformation of neuroendocrine differentiation in prostate cancer, aiming to discover new methods for accurate diagnosis and targeted therapy.

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The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings

Ryann E. Shor et al.

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MOLECULAR ONCOLOGY (2022)

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FKBP51 and FKBP52 regulate androgen receptor dimerization and proliferation in prostate cancer cells

Keisuke Maeda et al.

Summary: FKBP51 and FKBP52 are key regulators of prostate cancer cell growth, with the inhibition of AR dimer formation serving as a promising treatment strategy for prostate cancer.

MOLECULAR ONCOLOGY (2022)

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Review Pharmacology & Pharmacy

Axelrod Symposium Protein Kinases in Tune- Special Section-Minireview

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Article Biochemistry & Molecular Biology

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Tanja Limberger et al.

Summary: This study reveals the functional consequences of truncation mutations of the KMT2C gene in prostate cancer, showing that these mutations drive proliferation and formation of PIN. Loss of both KMT2C and PTEN in prostate cancer leads to loss of senescence, metastatic dissemination, and reduced life expectancy. The study highlights the prognostic significance of KMT2C mutation status and suggests MYC signalling axis inhibition as a potential treatment option for patients with KMT2C truncations and poor prognosis.

MOLECULAR CANCER (2022)

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Review Endocrinology & Metabolism

PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications

Atish D. Choudhury

Summary: Despite significant advances in molecular characterization and therapeutic targeting, prostate cancer remains a major cause of cancer death in the US. The PI3K/AKT/mTOR signaling pathway is commonly altered in prostate cancer, with clinical trials of pathway inhibitors demonstrating modest activity. Challenges include toxicities from noncancerous tissue signaling and the need for rational combinations and biomarker selection to optimize therapeutic benefit.

PROSTATE (2022)

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Article Biochemistry & Molecular Biology

Topological dynamics of an intrinsically disordered N-terminal domain of the human androgen receptor

Vahid Sheikhhassani et al.

Summary: Researchers used molecular dynamics simulations and circuit topology analysis to determine the tertiary structure of the N-terminal domain (AR-NTD) of the human androgen receptor. They found that the AR-NTD adopts highly dynamic conformations and consists of two identifiable regions with distinct topology and dynamics. The study reveals a competition between the N-terminal and C-terminal regions for binding to the DNA-binding domain of the receptor, as well as the structural mechanisms of action of the AR inhibitor EPI-001.

PROTEIN SCIENCE (2022)

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Article Multidisciplinary Sciences

Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

Fanying Tang et al.

Summary: This study classified CRPC into different subtypes using ATAC-seq, RNA-seq, and DNA sequencing. The identified subtypes include AR-dependent, neuroendocrine, Wnt-dependent, and stem cell-like subtypes driven by AP-1 transcription factors. Transcriptomic signatures were used for patient classification, and SCL was found to be the second most common subtype of CRPC.

SCIENCE (2022)

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Article Oncology

RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy

Kyung W. Song et al.

Summary: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action by degrading mutant p110a protein, leading to more potent inhibition of mutant PI3K pathway signaling and cell viability, and better maintenance of prolonged pathway suppression.

CANCER DISCOVERY (2022)

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Article Oncology

Molecular mechanisms underlying the development of neuroendocrine prostate cancer

Shiqin Liu et al.

Summary: Prostate cancer is a common cancer in men in the United States and often leads to cancer-related deaths. Androgen deprivation therapy is the standard treatment for advanced prostate cancer, but some patients develop castration-resistant prostate cancer and even neuroendocrine prostate cancer. Neuroendocrine prostate cancer is characterized by the expression of neuroendocrine markers and the absence of androgen receptor, and is often associated with aggressive tumors, therapy resistance, and poor clinical outcomes.

SEMINARS IN CANCER BIOLOGY (2022)

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Article Multidisciplinary Sciences

Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR-V7 splice variant chromatin binding and transcriptional activities

Paul Basil et al.

Summary: The constitutively active androgen receptor splice variant AR-V7 is involved in resistance to androgen deprivation therapy in CRPC. This study compares the activities of AR and AR-V7 using cell lines with matched expression levels. The two isoforms have both shared and distinct transcriptomes and cistromes, with AR-V7 showing unique binding sites.

SCIENTIFIC REPORTS (2022)

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Article Cell Biology

The mTOR chromatin-bound interactome in prostate cancer

Catherine R. Dufour et al.

Summary: An increasing number of studies support the direct role of nuclear mTOR in gene regulation and chromatin structure. However, the limited knowledge of chromatin-bound mTOR partners restricts our understanding of how nuclear mTOR controls transcription. This study comprehensively maps the mTOR chromatin-bound interactome in prostate cancer cellular models and identifies a 67-protein interaction network enriched with chromatin modifiers, transcription factors, and SUMOylation machinery. SUMO2/3 and nuclear pore protein NUP210 are among the strongest interactors, while the androgen receptor (AR) is the dominant androgen-inducible mTOR partner. Further investigation reveals the role of NUP210 in mTOR nuclear trafficking, the functional transcriptional module formed by mTOR, AR, and the nucleosome remodeling and deacetylase (NuRD) complex, and the androgen-dependent mTOR-SUMO2/3 promoter-enhancer association.

CELL REPORTS (2022)

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Article Oncology

Androgen receptor reprogramming demarcates prognostic, context-dependent gene sets in primary and metastatic prostate cancer

Tesa Severson et al.

Summary: The androgen receptor (AR) plays a fundamental role in prostate pathophysiology and its reprogrammed binding to DNA contributes to prostate tumorigenesis and disease progression. This study identifies genes regulated by AR in different histological contexts and demonstrates the clinical significance of their expression in prostate cancer patients. The research highlights the importance of integrating context-dependent epigenetic data into genetic analyses.

CLINICAL EPIGENETICS (2022)

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Article Oncology

PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives

Iwona Hus et al.

Summary: The development of small agents targeting the B-cell receptor (BCR) pathway has greatly improved the treatment of chronic lymphocytic leukemia (CLL). Selective inhibitors of PI3K delta, such as idelalisib and duvelisib, have been approved for CLL treatment. Umbralisib, a selective inhibitor of PI3K delta and CK1 epsilon, has shown promising results in combination regimens in clinical trials for CLL treatment.

CANCERS (2022)

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Article Oncology

Proteomic and Transcriptomic Profiling Reveals Mitochondrial Oxidative Phosphorylation as Therapeutic Vulnerability in Androgen Receptor Pathway Active Prostate Tumors

Caroline Xue et al.

Summary: Metastatic prostate cancer is a leading cause of male cancer deaths and has limited treatment options. The lack of preclinical models for advanced stage prostate cancer is a major barrier to understanding aggressive subtypes. In this study, we used LuCaP patient-derived xenograft models to represent the genomic and phenotypic features of human disease. Through comprehensive transcriptomic and proteomic profiling, we identified molecular markers associated with androgen receptor-positive and androgen receptor-null castration-resistant prostate cancers. Our findings suggest activation of specific pathways in these subtypes and highlight the importance of integrating transcriptomic and proteomic approaches in preclinical models for understanding poorly understood signaling pathways in metastatic prostate cancer.

CANCERS (2022)

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Review Oncology

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Yan Peng et al.

Summary: Cancer is a global public health issue that hinders the improvement of life expectancy worldwide. Current therapeutic options are insufficient, necessitating targeted treatments. Understanding the association between the PI3K/AKT/mTOR pathway and tumorigenesis, as well as the development of therapies targeting this pathway, is crucial for clinical decision-making.

FRONTIERS IN ONCOLOGY (2022)

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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer

Tianyan Wang et al.

Summary: This study identifies the role of PIP5K1α in promoting the growth and invasion of castration-resistant prostate cancer. The study also reveals the importance of the N-terminal domain of PIP5K1α and its function as an upstream regulator of androgen receptor and its target genes.

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A phase II study of MK-2206, an AKT inhibitor, in uterine serous carcinoma

Elizabeth H. Stover et al.

Summary: MK-2206 showed limited activity in uterine serous carcinoma (USC), although some patients achieved sustained progression-free intervals. Further investigations are needed to identify features associated with treatment response.

GYNECOLOGIC ONCOLOGY REPORTS (2022)

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Article Chemistry, Medicinal

Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα

Emily J. Hanan et al.

Summary: This study optimized a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3K alpha that also induce selective degradation of the mutant p110 alpha protein. Structure-based design led to potent inhibitors with over 300-fold selectivity and further optimization of pharmacokinetic properties resulted in excellent in vivo efficacy. Clinical candidate GDC-0077 (inavolisib) is now being evaluated in a Phase III clinical trial for treating patients with PIK3CA-mutant breast cancer.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Biochemistry & Molecular Biology

Alternations of gene expression in PI3K and AR pathways and DNA methylation features contribute to metastasis of prostate cancer

Yue Zhao et al.

Summary: PCa tumors exhibit distinct gene expression profiles associated with AR and PI3K-AKT pathways, influencing disease outcome. PSA is a better predictor of PFS than Gleason score, and PCa progression is more likely to occur after the third year. Epigenetic markers have predictive value for PFS, but CpG sites showed lower predictive value in OS and PFS compared to CpG corresponding genes.

CELLULAR AND MOLECULAR LIFE SCIENCES (2022)

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Article Oncology

The Impact of PIK3R1 Mutations and Insulin-PI3K-Glycolytic Pathway Regulation in Prostate Cancer

Goutam Chakraborty et al.

Summary: This study found a significant enrichment of PIK3R1 alterations in metastatic prostate cancer and showed that these alterations may be associated with worse clinical outcomes. Knockdown of PIK3R1 led to increased cell proliferation and AKT activity in prostate cancer cell lines, and PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors in cell lines and organoids. Additionally, PIK3R1-altered prostate tumors showed increased glucose uptake in PET imaging. These findings highlight the importance of PIK3R1 alterations in regulating the insulin-PI3K-glycolytic pathway in metastatic prostate cancer.

CLINICAL CANCER RESEARCH (2022)

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Article Chemistry, Medicinal

Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader

Cheng-Liang Zhu et al.

Summary: This study successfully synthesized an AKT degrader B4, which efficiently degrades AKT protein and exhibits significant efficacy in anti-proliferation and inhibiting signaling pathways.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Urology & Nephrology

Overall Survival Update for Patients with Metastatic Castration-resistant Prostate Cancer Treated with Capivasertib and Docetaxel in the Phase 2 ProCAID Clinical Trial

Simon J. Crabb et al.

Summary: The addition of capivasertib to docetaxel may extend overall survival in patients with metastatic castration-resistant prostate cancer. Subgroup analysis suggests that the benefit is maintained in patients previously treated with androgen receptor-targeted agents.

EUROPEAN UROLOGY (2022)

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Review Biochemistry & Molecular Biology

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Ekaterina Nevedomskaya et al.

Summary: Cancer arises from alterations at various cellular levels, and omics technologies have provided valuable insights into the molecular pathways involved in cancer development. In the case of prostate cancer, comprehensive omics analyses have deepened our understanding and offered hope for personalized treatments.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Oncology

First-in-human global multi-center study of RLY-2608, a pan-mutant and isoform-selective PI3Kα inhibitor, as a single agent in patients with advanced solid tumors and in combination with fulvestrant in patients with advanced breast cancer.

Cesar Augusto Perez et al.

JOURNAL OF CLINICAL ONCOLOGY (2022)

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Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial

Sacha J. Howell et al.

Summary: This study demonstrates that the addition of Capivasertib to fulvestrant improves progression-free survival and overall survival in women with aromatase inhibitor-resistant advanced breast cancer. The expanded genetic testing panel suggests that Capivasertib predominantly benefits patients with alterations in the PI3K/AKT/PTEN pathway.

LANCET ONCOLOGY (2022)

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Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial

John M. Pagel et al.

Summary: This study evaluated the safety and antitumour activity of zandelisib, a PI3K delta inhibitor, in patients with relapsed or refractory B-cell malignancy. The results showed that zandelisib was safe when administered continuously or intermittently, and demonstrated similar antitumour activity across different doses. These findings support the ongoing global phase 2 and phase 3 trials.

LANCET ONCOLOGY (2022)

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Article Multidisciplinary Sciences

Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Cameron Herberts et al.

Summary: This study performed whole-genome sequencing of plasma and synchronous metastases in patients with aggressive prostate cancer, revealing multiple dominant populations in ctDNA and shifts in mutational processes. They found that AR augmentation is the dominant genomic driver of acquired treatment resistance.

NATURE (2022)

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Review Cell Biology

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

Yanhua Chen et al.

Summary: Prostate cancer is a hormone-dependent malignancy that is treated by targeting the androgen receptor signaling pathway. Recent advances in second-generation AR antagonists have improved the survival of patients with prostate cancer, but challenges of incomplete treatment response and development of resistance remain.

CELL DEATH & DISEASE (2022)

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Review Endocrinology & Metabolism

The Role of Epigenetic Change in Therapy-Induced Neuroendocrine Prostate Cancer Lineage Plasticity

William K. Storck et al.

Summary: The androgen receptor (AR) signaling pathway plays a critical role in the growth and differentiation of prostate cancer cells. Androgen deprivation therapy is the main treatment for metastatic prostate cancer, but resistance to AR signaling inhibitors is common. Lineage plasticity, specifically the switch to an alternate differentiation program, is a recently identified resistance mechanism. This review discusses the role of AR pathway loss and activation of a neuronal differentiation program in lineage plasticity, and explores new epigenetic therapeutic strategies to reverse this process.

FRONTIERS IN ENDOCRINOLOGY (2022)

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Article Oncology

Annual report to the nation on the status of cancer, part 1: National cancer statistics

Kathleen A. Cronin et al.

Summary: This study provides an annual update on cancer occurrence and trends in the United States from 2001 to 2018. Overall, cancer death rates have been declining, particularly for lung cancer and melanoma. However, the incidence rates for some common cancers have been increasing, possibly due to changes in risk factors, screening practices, and diagnostic methods. It is important to address the racial/ethnic disparities in cancer incidence and mortality, and the data from this study can inform prevention, early detection, and treatment efforts.

CANCER (2022)

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Article Oncology

Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study

Naoki Kotani et al.

Summary: This study evaluated the efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, in patients with metastatic castration-resistant prostate cancer. The results showed a significant correlation between ipatasertib exposure and improved survival, as well as an increased risk of adverse events with ipatasertib treatment and/or increased exposure. Despite variability in exposure, patients receiving ipatasertib treatment may continue to benefit from this therapy.

CANCER CHEMOTHERAPY AND PHARMACOLOGY (2022)

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Article Oncology

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Martin Sjostrom et al.

Summary: This study integrates whole-genome 5hmC, DNA, 5mC, and transcriptome sequencing to investigate prostate cancer. The results show that 5hmC marks activation of cancer drivers and downstream targets, and reveal altered cell states throughout the disease course. Additionally, 5hmC sequencing of cell-free DNA proves useful as a prognostic biomarker for identifying an aggressive subtype of prostate cancer.

CANCER RESEARCH (2022)

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Article Oncology

Intrinsic Molecular Subtypes of Metastatic Castration-Resistant Prostate Cancer

Eric Feng et al.

Summary: In this study, the researchers identified the intrinsic molecular subtypes of metastatic castration-resistant prostate cancer (mCRPC) and assessed their molecular and clinical correlates using a large cohort with gene expression data. The results showed the heterogeneity of mCRPC beyond currently accepted molecular phenotypes, emphasizing the need for transcriptome-wide profiling in future studies to understand the impact of these differences on treatment responses and outcomes.

CLINICAL CANCER RESEARCH (2022)

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Article Oncology

Advances in the development of a targeted N-Terminal Domain androgen receptor (AR) degrader (ANITAC) for the treatment of prostate cancer

N.H. Hong et al.

EUROPEAN JOURNAL OF CANCER (2022)

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Article Oncology

A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations

Jordi Rodon et al.

Summary: The study aims to test a new oral medication TAS-117 for patients with solid tumors harboring germline PTEN mutations, exploring its potential treatment for rare forms of cancer.

FUTURE ONCOLOGY (2022)

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Review Biochemistry & Molecular Biology

Overview of Research into mTOR Inhibitors

Beibei Mao et al.

Summary: The mammalian target of rapamycin (mTOR) is a crucial protein kinase involved in various cellular processes. Inhibitors of mTOR have shown antiviral, anti-inflammatory, and antiproliferative effects and have been applied in the research of different diseases.

MOLECULES (2022)

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Article Biochemistry & Molecular Biology

Targeting androgen receptor phase separation to overcome antiandrogen resistance

Jingjing Xie et al.

Summary: Liquid-liquid phase separation is identified as a new mechanism of drug resistance, effectively inhibiting proliferation and tumor growth of prostate cancer cells by disrupting AR condensates.

NATURE CHEMICAL BIOLOGY (2022)

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Article Biochemistry & Molecular Biology

Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression

Yanmin Guo et al.

Summary: This study reveals the involvement of PTEN M1-ubiquitination in the regulation of AKT signaling and prostate cancer progression. The researchers identified specific ubiquitination sites on PTEN and showed that the M1-ubiquitination level correlates with clinical outcomes in prostate cancer patients. Additionally, they discovered that HOIP, a component of the LUBAC complex, plays a role in enhancing AKT signaling in a PTEN-dependent manner.

ONCOGENE (2022)

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Article Urology & Nephrology

Testosterone and the Androgen Receptor

Thomas Gerald et al.

Summary: Testosterone and its steroid metabolite hormones play a crucial role in the development of male sexual characteristics and function, as well as in maintaining homeostasis in multiple organ systems. Researchers have made significant progress in understanding its production, mechanism of action, and metabolism, as well as its implications in normal physiological and pathological processes.

UROLOGIC CLINICS OF NORTH AMERICA (2022)

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Review Endocrinology & Metabolism

Lysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer

Bharti Jaiswal et al.

Summary: This review summarizes recent research advances in understanding the role of lysine acetyltransferases (KATs) in regulating androgen receptor (AR) activity at the level of post-translational modifications in normal prostate physiology and prostate cancer (PCa) development. Targeting these enzymes may have therapeutic potential for AR-related pathology in combination with hormonal therapy.

FRONTIERS IN ENDOCRINOLOGY (2022)

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Review Medicine, General & Internal

Drivers of Radioresistance in Prostate Cancer

Liam King et al.

Summary: Prostate cancer is the second most commonly diagnosed cancer worldwide, and the development of radioresistance is a major challenge in treatment. Understanding the biological mechanisms behind radioresistance is crucial for developing effective therapies.

JOURNAL OF CLINICAL MEDICINE (2022)

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Review Oncology

New Directions in the Therapy of Glioblastoma

Katarzyna Szklener et al.

Summary: This article discusses the therapeutic targets and novel targeted therapies for glioblastoma, as well as the treatment efficacy of various antitumor drugs and their impact on patients.

CANCERS (2022)

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Review Oncology

To bind or not to bind: Cistromic reprogramming in prostate cancer

Michelle Shen et al.

Summary: The cistrome of key regulatory factors in prostate cancer, including the androgen receptor (AR) and other transcription factors, is substantially reprogrammed during disease progression. The SWI/SNF complex and the chromatin-modifying helicase CHD1 also play important roles in this process.

FRONTIERS IN ONCOLOGY (2022)

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Review Oncology

Targeting phase separation on enhancers induced by transcription factor complex formations as a new strategy for treating drug-resistant cancers

Ken-Ichi Takayama et al.

Summary: The limited treatment options for drug-resistant cancers have led to the search for alternative targets. Recent studies have shown that transcription factors undergo liquid-liquid phase separation (LLPS) and play key roles in cancer progression and drug resistance. This article summarizes the latest evidence on LLPS formation on enhancers as a potential therapeutic target in advanced cancers.

FRONTIERS IN ONCOLOGY (2022)

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Article Oncology

Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2

Maryam Labaf et al.

Summary: This study examines the acute effects of overexpressed androgen receptor (AR) on its cistrome and transcriptome in a prostate cancer (PCa) model. The results show that overexpression of AR leads to redistribution of AR chromatin binding and activation of a distinct transcription program, including DNA damage repair pathways. The study also predicts the involvement of EZH2 in this AR reprogramming and identifies a subset of AR/EZH2 co-targeting genes that are overexpressed in castration-resistant PCa and associated with worse patient outcomes.

FRONTIERS IN ONCOLOGY (2022)

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Article Pharmacology & Pharmacy

Drug-Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer

Dhruvitkumar S. Sutaria et al.

Summary: This study evaluated the pharmacokinetics, safety, and tolerability of Ipatasertib and Daholutamide in patients with metastatic castration-resistant prostate cancer. The results showed a mild reduction in the exposure of Ipatasertib when administered in combination with Daholutamide, which was not clinically significant. Additionally, the combination therapy was well-tolerated with minimal side effects in patients.

PHARMACEUTICS (2022)

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Review Oncology

AMPK's double-faced role in advanced stages of prostate cancer

Faeze Gharibpoor et al.

Summary: Prostate cancer is the second leading cause of cancer deaths in men, and there are limited drug options for advanced stages of the disease. 5'-AMP-activated protein kinase (AMPK) plays a significant role in the metabolism of prostate cancer and has the potential to be a treatment option. However, its exact role in cancer cell survival or death remains unknown. This study reviews the pathways by which AMPK may contribute to advanced stages of prostate cancer, drug resistance, and metastasis. Additionally, the study mentions drugs developed to target AMPK for the treatment of advanced prostate cancer.

CLINICAL & TRANSLATIONAL ONCOLOGY (2022)

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Review Biochemistry & Molecular Biology

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

Yundong He et al.

Summary: This review summarizes the targeted agents and their mechanisms for treating prostate cancer (PCa), as well as discusses their limitations and future directions.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2022)

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Article Oncology

Durable Clinical Activity to the AKT Inhibitor Ipatasertib in a Heavily Pretreated Patient With an AKT1 E17K Mutant Metastatic Breast Cancer

Sminu Bose et al.

CLINICAL BREAST CANCER (2021)

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Article Pathology

High throughput assessment of biomarkers in tissue microarrays using artificial intelligence: PTEN loss as a proof-of-principle in multi-center prostate cancer cohorts

Stephanie A. Harmon et al.

Summary: The study aimed to develop an AI system for automated detection and localization of PTEN loss in prostate cancer tissue samples, demonstrating high accuracy and efficiency of this method.

MODERN PATHOLOGY (2021)

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Article

The INPP4B paradox: Like PTEN, but different

Sabryn A. Hamila et al.

Advances in Biological Regulation (2021)

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Article Cell Biology

Knockout of Akt1/2 suppresses the metastasis of human prostate cancer cells CWR22rv1 in vitro and in vivo

Bing Su et al.

Summary: This study created prostate cancer cells with double knockout of Akt1 and Akt2 genes to investigate their role in metastasis, finding that their knockout significantly reduced metastasis by interfering with AR nuclear translocation through regulating FOXO proteins. These findings suggest that downstream regulatory factors in the AKT and AR interaction network play a crucial role in prostate cancer metastasis and could be potential targets for treatment.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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Review Oncology

Phosphorylation and Driver Mutations in PI3Kα and PTEN Autoinhibition

Ruth Nussinov et al.

Summary: PI3K and PTEN are crucial proteins in cancer, with opposing actions regulating cell signaling. Phosphorylation and dephosphorylation by these proteins control cell cycle progression. Driver mutations can destabilize protein interfaces, leading to oncogenic activation.

MOLECULAR CANCER RESEARCH (2021)

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Article Oncology

The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models

Clara Lemos et al.

Summary: The study identified a novel and potent AMPK inhibitor, BAY-3827, which displayed strong anti-proliferative effects in androgen-dependent prostate cancer cell lines. Analysis of gene expression and chromatin immunoprecipitation revealed the impact of AMPK signaling in cancer, particularly in prostate cancer models.

CELLULAR ONCOLOGY (2021)

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Review Biochemistry & Molecular Biology

Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

Thanakorn Pungsrinont et al.

Summary: Androgen deprivation therapy and androgen receptor-targeted therapy are effective in treating prostate cancer initially, but tumors may develop resistance mechanisms through alternative pathways, such as the PI3K-AKT-mTOR pathway. This resistance leads to a decrease in the efficacy of ADT and AR antagonists over time.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Review Biochemistry & Molecular Biology

FOXO3a and Its Regulators in Prostate Cancer

Dominika Ewa Habrowska-Gorczynska et al.

Summary: FOXO3a is a crucial transcription factor involved in cellular responses to stress and damage, with potential implications in cancer treatment. Its deregulation in cancer cells is associated with tumorigenesis, highlighting its role as a tumor suppressor, while also presenting opportunities for targeted therapies using common anti-cancer drugs.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Biochemistry & Molecular Biology

Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling

Laurence M. Gagne et al.

Summary: Metabolic dysfunction plays a crucial role in tumorigenesis, with mTOR serving as a key regulator of metabolic pathways promoting cancer cell proliferation and survival. Phosphorylation of Tyr 289 of DEPTOR is identified as a novel molecular switch that regulates both mTOR complex 1 and mTOR complex 2 activity.

JOURNAL OF BIOLOGICAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders

Xufen Yu et al.

Summary: AKT, a critical node in the PI3K/AKT/m-TOR signaling pathway, is strongly correlated with cancer. Two novel and potent AKT degraders were identified, showing the ability to induce AKT protein degradation and inhibit cancer cell proliferation.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Oncology

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung et al.

Summary: The global cancer burden in 2020 saw an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths. Female breast cancer surpassed lung cancer as the most commonly diagnosed cancer, while lung cancer remained the leading cause of cancer death. These trends are expected to rise in 2040, with transitioning countries experiencing a larger increase compared to transitioned countries due to demographic changes and risk factors associated with globalization and a growing economy. Efforts to improve cancer prevention measures and provision of cancer care in transitioning countries will be crucial for global cancer control.

CA-A CANCER JOURNAL FOR CLINICIANS (2021)

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Review Biochemistry & Molecular Biology

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Michael L. Mohler et al.

Summary: Traditional endocrine therapy for prostate cancer focuses on androgen receptor signaling suppression, but in castration-resistant prostate cancer patients, AR axis remains active. Recent evidence suggests targeting noncanonical direct binding sites on AR may provide a new approach to inhibit the AR axis.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Medicine, Research & Experimental

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT

Tao Shen et al.

Summary: The study revealed that MAPK4 promotes prostate cancer growth and castration resistance by activating GATA2/AR and AKT pathways. Activation of both GATA2/AR and AKT is necessary for MAPK4 tumor-promoting activity.

JOURNAL OF CLINICAL INVESTIGATION (2021)

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Review Oncology

Research update on the anticancer effects of buparlisib

Jinshan Xing et al.

Summary: Buparlisib is a potent and selective PI3K inhibitor that inhibits four isomers of PI3K, playing a role in inhibiting cell proliferation, promoting apoptosis, and blocking angiogenesis through antagonizing the PI3K/AKT pathway. It has demonstrated clinical efficacy in solid tumors and hematological malignancies.

ONCOLOGY LETTERS (2021)

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Article Oncology

Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment

Marc Wiesehofer et al.

Summary: Metastatic castration-resistant prostate cancer is difficult to treat with a short life expectancy. Neuroendocrine differentiation of prostate carcinoma cells is related to increased AKT3 expression, potentially impacting the aggressiveness of the cancer. The study aims to demonstrate the role of AKT3 in neuroendocrine differentiation, showing its presence in neuroendocrine cells and its potential oncogenic consequences. The findings suggest AKT3 as a potential therapeutic target and diagnostic tool in neuroendocrine prostate cancer.

CANCERS (2021)

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Article Oncology

SWATH-MS Based Proteomic Profiling of Prostate Cancer Cells Reveals Adaptive Molecular Mechanisms in Response to Anti-Androgen Therapy

Chamikara Liyanage et al.

Summary: Androgen targeted therapy is crucial in managing advanced prostate cancer, but resistance often develops. This study identified key molecular signatures induced by anti-androgen therapy, including activation of oncogenic regulators like MYC and PSF/SFPQ, which promote tumor growth and proliferation. Targeting these molecules could improve treatment efficacy in castration-resistant prostate cancer.

CANCERS (2021)

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Review Biochemistry & Molecular Biology

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

Rosalin Mishra et al.

Summary: The PI3K pathway is crucial in cancer development and is a promising therapeutic target. Clinical trials are ongoing to evaluate the efficacy and potential risks associated with PI3K inhibitors in overcoming resistance to current therapies.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Oncology

Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations

Jii Bum Lee et al.

Summary: TAS-117, a potent and selective allosteric pan-v-akt inhibitor, showed limited antitumor activity and manageable toxicity in heavily treated cancer patients. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1(E17K) mutations.

INVESTIGATIONAL NEW DRUGS (2021)

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Review Oncology

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

Nithin Sadeesh et al.

Summary: Recent methodological developments in proteomics have allowed for comprehensive studies of cancer, aiding in understanding cancer development and treatment evasion. While genetic and transcriptomic aspects of prostate cancer are relatively well-known, proteomics reveals changes in cancer metabolism, post-transcriptional RNA regulation, and post-translational protein regulatory pathways.

CANCERS (2021)

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Article Oncology

Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer

Santosh Gupta et al.

Summary: This study identified common genomic alterations in CTCs from AR-V7-negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment. The alterations were linked to lineage plasticity, epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.

MOLECULAR CANCER RESEARCH (2021)

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Review Oncology

Emerging Roles for AKT Isoform Preference in Cancer Progression Pathways

Seamus E. Degan et al.

Summary: The PI3K-AKT pathway is frequently mutated in human cancers, with PTEN loss and gain-of-function mutations in PIK3CA and AKT1 being common factors. Drug targeting PI3K or AKT as monotherapies have shown limited efficacy against solid tumors in clinical trials, but may be more effective when combined with inhibitors of other oncogenic drivers. Different AKT isoforms have distinct roles in oncogenic progression, and the success of PI3K/AKT inhibitors may depend on targeting specific AKT isoforms and their preferred pathways.

MOLECULAR CANCER RESEARCH (2021)

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Review Urology & Nephrology

Resistance to second-generation androgen receptor antagonists in prostate cancer

Keith T. Schmidt et al.

Summary: The introduction of second-generation androgen receptor antagonists has revolutionized the treatment of metastatic prostate cancer, offering tolerable and effective alternatives to chemotherapy. However, the issue of treatment resistance remains a significant challenge, and researchers are exploring various approaches to address this issue.

NATURE REVIEWS UROLOGY (2021)

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Article Multidisciplinary Sciences

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Sylvan C. Baca et al.

Summary: The study reveals that the transcription factor FOXA1 plays a crucial role in the development of neuroendocrine prostate cancer (NEPC) by regulating specific regulatory elements. Additionally, the expression of NE lineage TFs ASCL1 and NKX2-1 in PRAD cells can reprogram FOXA1 to bind to NE regulatory elements and induce enhancer activity.

NATURE COMMUNICATIONS (2021)

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Review Biochemistry & Molecular Biology

The Role of PI3K Inhibition in the Treatment of Breast Cancer, Alone or Combined With Immune Checkpoint Inhibitors

Zhizhu Zhang et al.

Summary: This review discusses the role of PI3K pathway in breast cancer, evaluates the clinical development of PI3K inhibitors in early and metastatic breast cancer settings, and examines the evidence for the potential synergistic benefit of combination treatment with PI3K inhibition and immunotherapy in breast cancer treatment.

FRONTIERS IN MOLECULAR BIOSCIENCES (2021)

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Article Oncology

Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer

Rebecca Dent et al.

Summary: In a study on triple-negative breast cancer patients, adding the oral AKT inhibitor ipatasertib to paclitaxel treatment prolonged overall survival, especially in patients with specific gene alterations. The final overall survival results showed a numerical trend favoring the ipatasertib-paclitaxel group, with a median survival exceeding 2 years.

BREAST CANCER RESEARCH AND TREATMENT (2021)

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Review Oncology

Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

Laura A. Sena et al.

Summary: The review summarizes the evidence that fatty acid synthesis drives progression of prostate cancer, although the mechanisms behind this beneficial effect still remain unclear. It emphasizes the functional importance of activating the fatty acid synthesis pathway in promoting prostate cancer aggressiveness.

CANCER RESEARCH (2021)

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Article Oncology

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition

Lisa M. Butler et al.

Summary: The study identified distinct lipid features in prostate cancer tissues, including enhanced fatty acid synthesis and elongation. Targeting the regulation of lipid composition may be a crucial therapeutic approach for prostate cancer.

CANCER RESEARCH (2021)

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Article Oncology

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer

Shannon N. Westin et al.

Summary: This study aimed to confirm the recommended phase II dose for the combination of olaparib and capivasertib in multiple cancers, and evaluate molecular markers of response and resistance. Promising responses, especially in endometrial cancer, were observed among the 38 enrolled patients. Therapy resistance was associated with specific signaling pathways and metabolic factors.

CLINICAL CANCER RESEARCH (2021)

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Article Oncology

A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3K beta Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Debashis Sarker et al.

Summary: The study investigated the combination of enzalutamide and the PI3K beta inhibitor GSK2636771 in patients with PTEN-deficient mCRPC. Results demonstrated acceptable safety and tolerability of the drug combination, but limited antitumor activity was observed.

CLINICAL CANCER RESEARCH (2021)

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Review Oncology

Targeting the PI3K-AKT-mTOR Pathway in Castration Resistant Prostate Cancer: A Review Article

Jason Cham et al.

Summary: This review of recent clinical trials on targeted therapies against the PI3K-AKT-mTOR pathway found that pan-PI3K inhibitors and selective PI3K inhibitors have not shown significant clinical efficacy. AKT inhibitors may have significant adverse effects, but showed some evidence of improved survival.

CLINICAL GENITOURINARY CANCER (2021)

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Review Medicine, General & Internal

Prostate cancer

Shahneen Sandhu et al.

Summary: Management of prostate cancer is rapidly evolving with advances in understanding the genomic landscape, improved imaging methods, and personalised therapeutics targeting DNA repair pathways. The therapeutic framework for metastatic disease has shifted, with oligometastatic disease being evaluated for metastatic-directed therapies, and novel androgen pathway inhibitors showing significant survival benefits as first-line therapy for metastatic disease. Emerging research into molecular characterisation and novel therapeutics, such as targeted radioisotopes and immunotherapy, hold promise for improving patient outcomes.

LANCET (2021)

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Article Biochemistry & Molecular Biology

SPOP-mediated ubiquitination and degradation of PDK1 suppresses AKT kinase activity and oncogenic functions

Qiwei Jiang et al.

Summary: The study reveals that E3 ligase SPOP mediates the ubiquitination and degradation of PDK1, and mutations in SPOP impair this process, leading to activation of the AKT kinase in prostate cancer. This highlights the oncogenic roles of SPOP loss-of-function mutations and PDK1 gain-of-function mutations in tumorigenesis through AKT activation.

MOLECULAR CANCER (2021)

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Article Cell Biology

An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Alastair Davies et al.

Summary: The study demonstrates that prostate cancer can transition to a high-plasticity state in response to potent androgen receptor antagonism, maintaining AR activity and rerouting transcriptional activity through changes in chromatin architecture. This reprogramming is mediated by EZH2 and favors stem cell and neuronal gene networks, highlighting the potential for reversing treatment resistance in prostate cancer.

NATURE CELL BIOLOGY (2021)

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Review Biotechnology & Applied Microbiology

PI3K inhibitors are finally coming of age

Bart Vanhaesebroeck et al.

Summary: Overactive PI3K is a frequently activated pathway in cancer, but therapeutic PI3K pathway inhibitors face challenges such as poor drug tolerance and resistance. Several targeted PI3K inhibitors have received regulatory approval, and their potential in cancer immunotherapy has been highlighted.

NATURE REVIEWS DRUG DISCOVERY (2021)

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Article Biochemistry & Molecular Biology

Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Kaisa-Mari Launonen et al.

Summary: The study used ChIP-SICAP to uncover the chromatome composition around endogenous AR in CRPC cells, revealing the roles of SMARCA4 and SIM2 in chromatin accessibility and AR target gene expression. Depletion of SMARCA4 impacted a restricted set of AR target genes involved in cell morphogenetic changes, while silencing of SIM2 affected a larger group of androgen-regulated genes related to cellular responses and proliferation in CRPC cells.

ONCOGENE (2021)

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Article Oncology

miR-148a, miR-152 and miR-200b promote prostate cancer metastasis by targeting DNMT1 and PTEN expression

Venhar Gurbuz et al.

Summary: The study explored the regulatory network of 'epi-miRNA-mRNA' in prostate cancer, revealing a potential negative association between overexpression of DNMT1 and decreased expression of PTEN. High levels of DNMT1 were found to be positively correlated with the aggressiveness of cancer and PSA, GS, and TNM staging.

ONCOLOGY LETTERS (2021)

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Article Multidisciplinary Sciences

Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers

Ninghui Mao et al.

Summary: Understanding the mechanisms driving PI3K isoform dependency in prostate cancer can help in designing effective clinical trials. Mutations in PIK3CA or PIK3CB can result in PI3K p110 isoform dependency, with direct inhibition of AKT potentially being more effective than PI3K inhibition in PTEN-deficient prostate cancers. Selective targeting of specific PI3K isoforms based on contextual factors like PTEN status and PIK3CA/PIK3CB alterations may offer novel therapeutic strategies.

NATURE COMMUNICATIONS (2021)

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Review Oncology

Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

Gaurav Chauhan et al.

Summary: Treatment options are expanding for prostate cancer patients with metastasis, but the lack of personalized treatment information and the variability of androgen receptor activity in prostate cancer tissues can impact treatment effectiveness. Understanding the molecular basis of androgen receptor regulation may help improve treatment plans and patient survival.

CANCERS (2021)

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Review Pharmacology & Pharmacy

Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention

Nazanin Momeni Roudsari et al.

Summary: The importance of the PI3K/Akt/mTOR pathway in prostate cancer treatment and the clinical applications of natural agents and small molecule inhibitors targeting this pathway are discussed in the study. Research suggests that natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms, with inhibition of Akt and suppression of mTOR 1 activity being the main therapeutic approaches. Combination therapy has been shown to improve the efficacy of these inhibitors in suppressing prostate cancer progression or overcoming resistance by cancer cells.

PHARMACEUTICS (2021)

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Article Biochemistry & Molecular Biology

A Novel Controlled PTEN-Knockout Mouse Model for Prostate Cancer Study

Sen Liu et al.

Summary: The study investigated the impact of age on prostate cancer using an experimental model with Pten conditional knockout mice at different ages. Results showed that aged mice exhibited accelerated PI3K/AKT/mTOR signaling and increased prostate cancer onset and progression compared to young mice. This model could be useful for further research on cancer related to aging.

FRONTIERS IN MOLECULAR BIOSCIENCES (2021)

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Meeting Abstract Oncology

Preclinical characterization of LOX-22783, a highly potent, mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor

Anke Klippel et al.

MOLECULAR CANCER THERAPEUTICS (2021)

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Meeting Abstract Oncology

Androgen Receptor (AR) N-Terminus-Domain-Binding Small Molecule Degraders for the Treatment of AR Splice Variant-Positive Castration-Resistant Prostate Cancer

Ramesh Narayanan

MOLECULAR CANCER THERAPEUTICS (2021)

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Review Andrology

Genomic Profiling of Prostate Cancer: An Updated Review

Koji Hatano et al.

Summary: Understanding the genomic profiling of prostate cancer is crucial for guiding treatment, with a focus on liquid biopsy and actionable molecular alterations presenting as emerging areas of interest.

WORLD JOURNAL OF MENS HEALTH (2021)

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Article Genetics & Heredity

Updates in Prostate Cancer Research and Screening in Men at Genetically Higher Risk

Elizabeth K. Bancroft et al.

Summary: Prostate cancer is a common and deadly disease, with current research focusing on personalized risk assessment through genetic variants and targeted screening for high-risk populations, as well as the importance of germline genetics in selecting treatments for advanced disease.

CURRENT GENETIC MEDICINE REPORTS (2021)

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Article Oncology

Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

Yuanyuan Qiao et al.

Summary: ESK981 is an effective MTKI that enhances therapeutic response in prostate cancer by inhibiting autophagy. It upregulates CXCL10 expression to promote T cell infiltration, enhancing the efficacy of immune checkpoint blockade therapy.

NATURE CANCER (2021)

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Article Oncology

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer

Preeti Narayan et al.

Summary: The FDA granted regular approval to alpelisib in combination with fulvestrant for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer patients. Results from the SOLAR-1 study showed a significant improvement in PFS with the combination therapy compared to the control group.

CLINICAL CANCER RESEARCH (2021)

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Article Biochemistry & Molecular Biology

DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals

Xiaoyu Chen et al.

ONCOGENE (2020)

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Article Oncology

A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer

M. P. Kolinsky et al.

ANNALS OF ONCOLOGY (2020)

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Article Oncology

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Patrick Y. Wen et al.

CLINICAL CANCER RESEARCH (2020)

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Review Pharmacology & Pharmacy

Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor

Marianne D. Sadar

EXPERT OPINION ON DRUG DISCOVERY (2020)

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Article Oncology

Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer

Andrea P. Myers et al.

INTERNATIONAL JOURNAL OF CANCER (2020)

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Article Multidisciplinary Sciences

Androgen receptor-binding sites are highly mutated in prostate cancer

Tunc Morova et al.

NATURE COMMUNICATIONS (2020)

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Article Oncology

Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia A Comparison of Treatment Outcomes in Clinical Trial Participants vs Medicare Beneficiaries

Steven T. Bird et al.

JAMA ONCOLOGY (2020)

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Review Oncology

An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer

Michael Brave et al.

CLINICAL CANCER RESEARCH (2020)

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Article Urology & Nephrology

Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer

Cameron Herberts et al.

EUROPEAN UROLOGY (2020)

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Article Oncology

Androgen receptor degraders over come common resistance mechanisms developed during prostate cancer treatment

Steven Kregel et al.

NEOPLASIA (2020)

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Article Oncology

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial

A. Jo Chien et al.

JOURNAL OF CLINICAL ONCOLOGY (2020)

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Article Multidisciplinary Sciences

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance

Joshi J. Alumkal et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

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Article Endocrinology & Metabolism

Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer

Jinhui Zhang et al.

PROSTATE (2020)

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Article Oncology

Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor

Remi Adelaiye-Ogala et al.

MOLECULAR CANCER THERAPEUTICS (2020)

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Article Oncology

Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer

Tie Zhou et al.

EUROPEAN JOURNAL OF CANCER (2020)

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Review Biochemistry & Molecular Biology

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Boris Y. Shorning et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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Article Genetics & Heredity

Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Mark M. Pomerantz et al.

NATURE GENETICS (2020)

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Article Multidisciplinary Sciences

Targeting the PLK1-FOXO1 pathway as a novel therapeutic approach for treating advanced prostate cancer

Lilia Gheghiani et al.

SCIENTIFIC REPORTS (2020)

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Article Medicine, General & Internal

Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide

Karim Fizazi et al.

NEW ENGLAND JOURNAL OF MEDICINE (2020)

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Article Biochemistry & Molecular Biology

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc

Oh-Joon Kwon et al.

ONCOGENE (2020)

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Article Oncology

Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase

Richard Karlsson et al.

CANCERS (2020)

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Review Cell Biology

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Daniel J. Turnham et al.

CELLS (2020)

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Review Biochemistry & Molecular Biology

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

Elisabeth A. Messner et al.

BIOMEDICINES (2020)

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Review Biochemistry & Molecular Biology

Targeting DNA Damage Response in Prostate and Breast Cancer

Antje M. Wengner et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)

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Article Biochemistry & Molecular Biology

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

Inchul You et al.

CELL CHEMICAL BIOLOGY (2020)

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Review Urology & Nephrology

Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer

Simeng Wen et al.

ASIAN JOURNAL OF UROLOGY (2020)

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Review Oncology

DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer

Vincent Giguere

TRENDS IN CANCER (2020)

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Article Oncology

A phase 2 study of ofatumumab (Arzerra®) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL)*

Christine I. Chen et al.

LEUKEMIA & LYMPHOMA (2019)

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Article Biochemistry & Molecular Biology

Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity

Manqi Zhang et al.

ONCOGENE (2019)

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Article Oncology

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer

Laura Cato et al.

CANCER CELL (2019)

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Article Oncology

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Tatsuo Sugawara et al.

INTERNATIONAL JOURNAL OF CANCER (2019)

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Article Medicine, Research & Experimental

MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling

Wei Wang et al.

JOURNAL OF CLINICAL INVESTIGATION (2019)

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Article Medicine, General & Internal

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer

Karim Fizazi et al.

NEW ENGLAND JOURNAL OF MEDICINE (2019)

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Article Biochemistry & Molecular Biology

LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex

Zhiqun Shang et al.

NUCLEIC ACIDS RESEARCH (2019)

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Review Oncology

PIK3CA in cancer: The past 30 years

Rand Arafeh et al.

SEMINARS IN CANCER BIOLOGY (2019)

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Review Biochemistry & Molecular Biology

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Gergana E. Stoykova et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2019)

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Review Biochemistry & Molecular Biology

Dysregulated Transcriptional Control in Prostate Cancer

Simon J. Baumgart et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2019)

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Article Oncology

Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naive Primary Prostate Cancer

Daniel E. Spratt et al.

CLINICAL CANCER RESEARCH (2019)

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Review Medicine, General & Internal

The efficacy and safety of neoadjuvant buparlisib for breast cancer A meta-analysis of randomized controlled studies

Qian Luo et al.

MEDICINE (2019)

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Article Oncology

Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer

Sarah P. Blagden et al.

CLINICAL CANCER RESEARCH (2019)

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Article Urology & Nephrology

Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer

Anis A. Humid et al.

EUROPEAN UROLOGY (2019)

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Article Medicine, Research & Experimental

Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Adam Sharp et al.

JOURNAL OF CLINICAL INVESTIGATION (2019)

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Article Oncology

Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

Johanna C. Bendell et al.

ONCOLOGIST (2019)

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Article Oncology

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Yan Xing et al.

BREAST CANCER RESEARCH (2019)

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Article Chemistry, Multidisciplinary

The mechanism of PI3K activation at the atomic level

Mingzhen Zhang et al.

CHEMICAL SCIENCE (2019)

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Article Oncology

The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo

Fei Shi et al.

ONCOTARGET (2018)

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Article Medicine, Research & Experimental

Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer

Yuqian Yan et al.

EMBO MOLECULAR MEDICINE (2018)

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Article Chemistry, Medicinal

Phthalimide conjugations for the degradation of oncogenic PI3K

Wenlu Li et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Review Biochemistry & Molecular Biology

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Ekaterina Nevedomskaya et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2018)

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Meeting Abstract Oncology

An open-label phase 1/2a study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer (mCRPC).

Dana E. Rathkopf et al.

JOURNAL OF CLINICAL ONCOLOGY (2018)

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Article Oncology

SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer

Etienne Audet-Walsh et al.

MOLECULAR CANCER RESEARCH (2018)

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Review Urology & Nephrology

Clinical implications of PTEN loss in prostate cancer

Tamara Jamaspishvili et al.

NATURE REVIEWS UROLOGY (2018)

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Article Biochemistry & Molecular Biology

Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer

Yundong He et al.

NUCLEIC ACIDS RESEARCH (2018)

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Article Multidisciplinary Sciences

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

Zhong Chen et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2018)

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Article Endocrinology & Metabolism

Tumor heterogeneity, aggressiveness, and immune cell composition in a novel syngeneic PSA-targeted Pten knockout mouse prostate cancer (MuCaP) model

Petra W. van Duijn et al.

PROSTATE (2018)

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Article Multidisciplinary Sciences

Coactivator condensation at super-enhancers links phase separation and gene control

Benjamin R. Sabari et al.

SCIENCE (2018)

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Article Oncology

Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth

Helen B. Pearson et al.

CANCER DISCOVERY (2018)

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Review Oncology

mTOR signalling and cellular metabolism are mutual determinants in cancer

Dirk Mossmann et al.

NATURE REVIEWS CANCER (2018)

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Article Hematology

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

Changchun Deng et al.

BLOOD (2017)

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Article Oncology

BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models

Oliver Politz et al.

INTERNATIONAL JOURNAL OF CANCER (2017)

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Article Biochemistry & Molecular Biology

Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer

P. L. Martin et al.

ONCOGENE (2017)

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Article Oncology

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

Andrew J. Armstrong et al.

EUROPEAN JOURNAL OF CANCER (2017)

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Article Cell Biology

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Etienne Audet-Walsh et al.

GENES & DEVELOPMENT (2017)

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Article Oncology

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

Trisha M. Wise-Draper et al.

TARGETED ONCOLOGY (2017)

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Article Chemistry, Medicinal

Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors

Klemens Hoegenauer et al.

ACS MEDICINAL CHEMISTRY LETTERS (2017)

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Article Oncology

Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Masayuki Yamaji et al.

CANCER MEDICINE (2017)

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Review Oncology

AR Signaling and the PI3K Pathway in Prostate Cancer

Megan Crumbaker et al.

CANCERS (2017)

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Article Oncology

Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion

Yinhui Yang et al.

CANCER RESEARCH (2017)

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Article Public, Environmental & Occupational Health

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences

Cindy Ke Zhou et al.

AMERICAN JOURNAL OF EPIDEMIOLOGY (2017)

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Article Pharmacology & Pharmacy

Copanlisib: First Global Approval

Anthony Markham

DRUGS (2017)

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Article Oncology

A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer

Cynthia X. Ma et al.

CLINICAL CANCER RESEARCH (2017)

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Article Oncology

A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors

Joaquin Mateo et al.

CLINICAL CANCER RESEARCH (2017)

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Article Pharmacology & Pharmacy

INPP4B overexpression suppresses migration, invasion and angiogenesis of human prostate cancer cells

Haiwen Chen et al.

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY (2017)

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Article Oncology

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Mirjam Blattner et al.

CANCER CELL (2017)

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Article Oncology

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

Maria I. Carlo et al.

ONCOLOGIST (2016)

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Article Oncology

Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer

Emmanuel S. Antonarakis et al.

ONCOLOGIST (2016)

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Article Chemistry, Medicinal

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

Timothy P. Heffron et al.

ACS MEDICINAL CHEMISTRY LETTERS (2016)

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Article Multidisciplinary Sciences

Combined AKT and MEK Pathway Blockade in Pre-Clinical Models of Enzalutamide-Resistant Prostate Cancer

Paul Toren et al.

PLOS ONE (2016)

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Review Biochemistry & Molecular Biology

Role of mTOR Inhibitors in Kidney Disease

Moto Kajiwara et al.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2016)

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Article Biochemistry & Molecular Biology

Integrative Clinical Genomics of Advanced Prostate Cancer

Dan Robinson et al.

CELL (2015)

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Article Oncology

FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma

Barry W. Miller et al.

CLINICAL CANCER RESEARCH (2015)

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Article Medicine, Research & Experimental

Androgen receptor profiling predicts prostate cancer outcome

Suzan Stelloo et al.

EMBO MOLECULAR MEDICINE (2015)

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Article Urology & Nephrology

High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models

Rute B. Marques et al.

EUROPEAN UROLOGY (2015)

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Review Oncology

Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review

Zebo Huang et al.

FUTURE ONCOLOGY (2015)

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Article Biochemistry & Molecular Biology

Additive Effect of Zfhx3/Atbf1 and Pten Deletion on Mouse Prostatic Tumorigenesis

Xiaodong Sun et al.

JOURNAL OF GENETICS AND GENOMICS (2015)

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Article Genetics & Heredity

The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis

Mark M. Pomerantz et al.

NATURE GENETICS (2015)

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Article Oncology

US Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

Yang-Min Ning et al.

ONCOLOGIST (2015)

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Article Endocrinology & Metabolism

Synergistic Anticancer Efficacy of MEK Inhibition and Dual PI3K/mTOR Inhibition in Castration-Resistant Prostate Cancer

Hongzoo Park et al.

PROSTATE (2015)

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Article Oncology

Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and-resistant prostate cancer

Wenqing Qi et al.

ONCOTARGET (2015)

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Article Biochemistry & Molecular Biology

Crosstalking between Androgen and PI3K/AKT Signaling Pathways in Prostate Cancer Cells

Suk Hyung Lee et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2015)

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Review Oncology

Androgen receptor phosphorylation: biological context and functional consequences

Yulia Koryakina et al.

ENDOCRINE-RELATED CANCER (2014)

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Review Genetics & Heredity

Molecular regulation of hypothalamus-pituitary-gonads axis in males

Jia-Min Jin et al.

GENE (2014)

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Article Oncology

The Androgen Receptor Induces a Distinct Transcriptional Program in Castration-Resistant Prostate Cancer in Man

Naomi L. Sharma et al.

CANCER CELL (2013)

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Review Cell Biology

Mini-review: Foldosome regulation of androgen receptor action in prostate cancer

Laia Querol Cano et al.

MOLECULAR AND CELLULAR ENDOCRINOLOGY (2013)

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Article Oncology

Synergistic Targeting of PI3K/AKT Pathway and Androgen Receptor Axis Significantly Delays Castration-Resistant Prostate Cancer Progression In Vivo

Christian Thomas et al.

MOLECULAR CANCER THERAPEUTICS (2013)

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Article Multidisciplinary Sciences

被撤回的出版物: Functional Role of mTORC2 versus Integrin-Linked Kinase in Mediating Ser473-Akt Phosphorylation in PTEN-Negative Prostate and Breast Cancer Cell Lines (Retracted article. See vol. 13, art. e0202299, 2018)

Su-Lin Lee et al.

PLOS ONE (2013)

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Article Multidisciplinary Sciences

MiR-424/503-Mediated Rictor Upregulation Promotes Tumor Progression

Chitose Oneyama et al.

PLOS ONE (2013)

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Article Endocrinology & Metabolism

FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants

Laura R. Bohrer et al.

PROSTATE (2013)

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Article Endocrinology & Metabolism

Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice

Sanjeev Shukla et al.

PROSTATE (2013)

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Article Oncology

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β-catenin signaling in prostate cancer cells

Monica Ciarlo et al.

INTERNATIONAL JOURNAL OF CANCER (2012)

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Article Chemistry, Medicinal

Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

James F. Blake et al.

JOURNAL OF MEDICINAL CHEMISTRY (2012)

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Review Biochemistry & Molecular Biology

Intrinsic disorder in the androgen receptor: identification, characterisation and drugability

Iain J. McEwan

MOLECULAR BIOSYSTEMS (2012)

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Article Oncology

Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent

Jing Ni et al.

CANCER DISCOVERY (2012)

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Article Oncology

Cell Autonomous Role of PTEN in Regulating Castration-Resistant Prostate Cancer Growth

David J. Mulholland et al.

CANCER CELL (2011)

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Article Oncology

Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer

Brett S. Carver et al.

CANCER CELL (2011)

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Article Oncology

Decreased Expression and Androgen Regulation of the Tumor Suppressor Gene INPP4B in Prostate Cancer

Myles C. Hodgson et al.

CANCER RESEARCH (2011)

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Article Oncology

mTOR Complex 2 Is Required for the Development of Prostate Cancer Induced by Pten Loss in Mice

David A. Guertin et al.

CANCER CELL (2009)

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Article Biochemistry & Molecular Biology

DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival

Timothy R. Peterson et al.

CELL (2009)

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Article Biochemistry & Molecular Biology

Androgen receptor acetylation sites differentially regulate gene control

Hortensia Faus et al.

JOURNAL OF CELLULAR BIOCHEMISTRY (2008)

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Review Endocrinology & Metabolism

The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling

Margaret M. Centenera et al.

MOLECULAR ENDOCRINOLOGY (2008)

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Article Multidisciplinary Sciences

Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis

Shidong Jia et al.

NATURE (2008)

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Review Oncology

PTEN, more than the AKT pathway

Carmen Blanco-Aparicio et al.

CARCINOGENESIS (2007)

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Article Biochemistry & Molecular Biology

Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo

Veronique Calleja et al.

PLOS BIOLOGY (2007)

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Article Biochemistry & Molecular Biology

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