News - AR mutation - LARVOL VERI

Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader. (PubMed, Commun Chem)

Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention.

9 days ago

Journal

AKR1C3 (Aldo-Keto Reductase Family 1 Member C3) • AKR1C1 (Aldo-Keto Reductase Family 1 Member C1) • AKR1C2 (Aldo-Keto Reductase Family 1 Member C2)

AR mutation • AR splice variant 7 • AKR1C3 expression

15d

Developing a Novel Enzalutamide-Resistant Prostate Cancer Model via AR F877L Mutation in LNCaP Cells. (PubMed, Curr Protoc)

We also assessed the efficacy of target protein degraders (TPDs), such as ARV-110 and ARV-667, in both models, and the corresponding validation data are also included here.

15 days ago

Preclinical • Journal

AR (Androgen receptor)

AR mutation • AR T878A • AR F877L • AR H875Y • AR F877L + AR T878A

Xtandi (enzalutamide capsule) • bavdegalutamide (ARV-110)

24d

Biomarker Analysis of Castration-resistant Prostate Cancer Undergoing Treatment With Docetaxel Followed by Enzalutamide (clinicaltrials.gov)

P2, N=30, Active, not recruiting, Instituto do Cancer do Estado de São Paulo | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

24 days ago

Trial completion date • Trial primary completion date • Metastases

AR (Androgen receptor)

AR mutation • AR splice variant 7

docetaxel • Xtandi (enzalutamide capsule)

2ms

Discovery of Novel Anti-Resistance AR Antagonists Guided by Funnel Metadynamics Simulation. (PubMed, Adv Sci (Weinh))

Here, funnel metadynamics is employed to elucidate the inherent regulation mechanisms of three AR antagonists (hydroxyflutamide, enzalutamide, and darolutamide) on AR. Subsequently, docking-based virtual screening toward the dominant binding conformation of AR for darolutamide is conducted, and three novel AR antagonists with favorable binding affinity and strong capability to combat drug resistance are identified by in vitro bioassays. This work provides a novel rational strategy for the development of anti-resistant AR antagonists.

2 months ago

Journal

AR (Androgen receptor)

AR mutation

Xtandi (enzalutamide capsule) • Nubeqa (darolutamide)

2ms

Loss of AR-regulated AFF3 contributes to prostate cancer progression and reduces ferroptosis sensitivity by downregulating ACSL4 based on single-cell sequencing analysis. (PubMed, Apoptosis)

Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.

2 months ago

Journal

AR (Androgen receptor) • ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) • AFF3 (AF4/FMR2 Family Member 3)

AR mutation • AR expression

Xtandi (enzalutamide capsule) • abiraterone acetate • RSL3

2ms

Differences in genomic, transcriptomic and immune landscape of prostate cancer (PCa) based on site of metastasis (mets) (AUA 2024)

This study highlights distinct molecular profiles in metastatic prostate cancer (PCa) based on metastasis site, underlining the importance of personalized treatment strategies. The findings, particularly the variations in gene mutations and AR signaling, are crucial in tailoring management approaches for advanced PCa.

2 months ago

Tumor mutational burden • PD(L)-1 Biomarker • MSi-H Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • BAP1 (BRCA1 Associated Protein 1) • IFNG (Interferon, gamma) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • KMT2C (Lysine Methyltransferase 2C) • APC (APC Regulator Of WNT Signaling Pathway) • SPOP (Speckle Type BTB/POZ Protein)

TP53 mutation • TMB-H • MSI-H/dMMR • PIK3CA mutation • PTEN mutation • BAP1 mutation • APC mutation • AR mutation • AR splice variant 7

VENTANA PD-L1 (SP142) Assay • MI Tumor Seek™

2ms

Real-World Clinical Outcomes and Genomic Profiles of Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) Harboring Both AR-LBD Missense Mutations and AR Copy Number Amplifications (ISPOR 2024)

In this RW analysis, these double mutant mCRPC patients exhibit worse clinical outcomes and different genomic profile relative to patients without these mutations. Further investigation is needed to elucidate the significance of these AR -aberrations and improve prognosis for these patients.

2 months ago

Real-world evidence • Clinical data • Clinical • Real-world • Metastases

FGFR1 (Fibroblast growth factor receptor 1) • CCNE1 (Cyclin E1) • CDK6 (Cyclin-dependent kinase 6)

AR mutation • AR negative

Guardant360® CDx

2ms

Single cell-transcriptomic analysis informs the lncRNA landscape in metastatic castration resistant prostate cancer. (PubMed, NPJ Genom Med)

Prostate-lncRNAs were correlated with AR mutational status and response to treatment with enzalutamide, while TME-lncRNAs were associated with RB1 deletions and poor prognosis. Finally, lncRNAs identified between prostate adenocarcinomas and neuroendocrine tumors exhibited distinct expression and methylation profiles. Our findings demonstrate the ability of single-cell analysis to refine our understanding of lncRNAs in mCRPC and serve as a resource for future mechanistic studies.

2 months ago

Journal • Metastases

RB1 (RB Transcriptional Corepressor 1)

RB1 deletion • AR mutation • RB deletion

Xtandi (enzalutamide capsule)

3ms

Identifying prognostic biomarkers for palbociclib add-on therapy in fulvestrant-resistant breast cancer using cell-free DNA sequencing. (PubMed, ESMO Open)

Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

3 months ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RUNX1 (RUNX Family Transcription Factor 1) • FOXA1 (Forkhead Box A1) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1)

TP53 mutation • HR positive • HER-2 negative • PIK3CA mutation • ER mutation • AR mutation • ESR1 mutation • MAP3K1 mutation • FOXA1 mutation

Ibrance (palbociclib) • fulvestrant

3ms

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration. (PubMed, Prostate Cancer Prostatic Dis)

In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

3 months ago

Journal • Metastases

AR (Androgen receptor)

AR mutation • AR amplification • AR L702H

4ms

Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma. (PubMed, Commun Biol)

Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.

4 months ago

Journal

AR (Androgen receptor)

AR mutation • AR wild-type

4ms

Study of MK-5684 Versus Alternative NHA in mCRPC (MK-5684-003) (clinicaltrials.gov)

P3, N=1200, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | Trial completion date: Jun 2029 --> Aug 2028

4 months ago

Enrollment open • Trial completion date • Metastases

AR mutation

Xtandi (enzalutamide capsule) • abiraterone acetate • prednisone • dexamethasone • ODM-208 • Yonsa (abiraterone acetate)

5ms

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain. (PubMed, ACS Med Chem Lett)

A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure-activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

5 months ago

Journal

AR (Androgen receptor)

AR mutation

5ms

Androgen receptor interacting proteins in prostate cancer development and therapy resistance. (PubMed, Am J Pathol)

Most studies have determined the expression of coactivators and their effects in the presence of increasing concentrations of androgen or the anti-androgen enzalutamide...The role of glucocorticoid receptor in endocrine therapy-resistant prostate cancer has been previously documented. Specific coactivators may interact with glucocorticoid receptor, thus contributing to therapy failure.

5 months ago

Review • Journal

AR (Androgen receptor) • GATA2 (GATA Binding Protein 2) • NCOA3 (Nuclear Receptor Coactivator 3)

AR mutation

Xtandi (enzalutamide capsule)

5ms

MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results. (ASCO-GU 2024)

53% and 33.8% of patients had previously received both abiraterone and enzalutamide, and 63.6% and 55.9% patients had received cabazitaxel in AR-LBD mutation positive and negative groups respectively. Administration of MK-5684 to heavily pre-treated mCRPC patients showed promising antitumor activity. PSA50 responses were most frequent among patients harboring activating AR-LBD mutations. Clinical trial information: NCT03436485.

5 months ago

P2 data • Clinical • Metastases

AR positive • AR mutation

Guardant360® CDx

Xtandi (enzalutamide capsule) • abiraterone acetate • cabazitaxel • ODM-208

5ms

Somatostatin receptor 1 (SSTR1) expression as a potential predictive biomarker for response to androgen receptor signaling inhibitor (ARSI) therapy in metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2024)

To phenotype ARSI-resistant prostate cancer, we compared the RNA-seq profiles of paired metastatic biopsies from 31 mCRPC patients obtained before the initiation of first-line abiraterone or enzalutamide, and upon radiographic progression. SSTR1 expression is a potential predictive biomarker for response to ARSI in mCRPC, with higher SSTR1 expression predicting better response. This observation could be explained by an anti-tumor effect of SSTR1 signaling. Further work is warranted to prospectively validate these findings and to investigate SSTR1 as an actionable drug target to overcome ARSI resistance.

5 months ago

Metastases

AR (Androgen receptor) • SSTR (Somatostatin Receptor) • ARSI (Arylsulfatase Family Member I)

AR mutation

Xtandi (enzalutamide capsule) • abiraterone acetate

5ms

Real-world outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and tumors harboring androgen receptor (AR) ligand-binding domain (LBD) mutations. (ASCO-GU 2024)

Patients with AR LBDâ€“mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.

5 months ago

Real-world evidence • Clinical • Real-world • Metastases

AR (Androgen receptor)

AR mutation • AR L702H

Guardant360® CDx

5ms

A phase 1/2 study of ONCT-534, a dual-action androgen receptor inhibitor (DAARI), in patients with metastatic castration-resistant prostate cancer. (ASCO-GU 2024)

Background: Current therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) include treatment with next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, darolutamide, and apalutamide, which all target the ligand-binding domain (LBD) of the AR, and abiraterone, an androgen biosynthesis inhibitor. The study was opened for enrollment September 2023. Clinical trial information: NCT05917470.

5 months ago

Clinical • P1/2 data • Metastases

AR mutation

Xtandi (enzalutamide capsule) • abiraterone acetate • Nubeqa (darolutamide) • Erleada (apalutamide) • ONCT-534

5ms

Metastatic castration-resistant prostate cancer-emerging trends in therapy (PubMed, Urologie)

New treatment strategies give hope that we will be able to intervene even more effectively in the course of disease of advanced prostate cancer in the future. However, a major challenge, especially for the implementation of targeted treatment approaches, is likely to be the heterogeneity of tumor progression not only inter- but also intrapersonally.

5 months ago

Review • Journal • IO biomarker • Metastases

CDK4 (Cyclin-dependent kinase 4)

AR mutation

5ms

Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer. (PubMed, Front Oncol)

Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. The integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

5 months ago

Journal

BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • GNAQ (G Protein Subunit Alpha Q) • KMT2C (Lysine Methyltransferase 2C) • NOTCH2 (Notch 2) • CREBBP (CREB binding protein) • FAT1 (FAT atypical cadherin 1) • ARID2 (AT-Rich Interaction Domain 2) • TGFB1 (Transforming Growth Factor Beta 1) • PI3K (Phosphoinositide 3-kinases)

BRAF mutation • GNAQ mutation • AR mutation • KMT2C mutation • MLL3 mutation

6ms

Comparative Analysis of Mutational Patterns in Triple Negative Breast Cancer Before and after Neoadjuvant Chemotherapy in Patients with Residual Disease. (PubMed, Gene)

We employed K-means clustering to categorize the patients based on their variant profiles, aiding in the prediction of possible patterns associated with recurrence. Our study was limited by its small sample size and retrospective design, suggesting the need for further validation in larger prospective cohorts.

6 months ago

Journal • Tumor mutational burden

HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • PMS2 (PMS1 protein homolog 2)

AR mutation • PMS2 mutation

6ms

Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial. (SABCS 2023)

Conclusions The hypothesis that ENZ could induce proliferation arrest in HR+/HER2-, PAM50 HER2-E tumors was not confirmed, and ARIANNA was prematurely closed due to the lack of efficacy. Additional research is needed to explore if ENZ may benefit specific populations of pts with breast cancer (e.g. AR-mut tumors) and whether alternative AR modulators are more effective in blocking AR signaling in HR+/HER2-, PAM50 HER2-E tumors

6 months ago

Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)

HER-2 positive • HR positive • HER-2 negative • AR mutation • HR positive + HER-2 negative • PTEN mutation + HR positive

Prosigna™ Breast Cancer Prognostic Gene Signature Assay

Xtandi (enzalutamide capsule)

6ms

A Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of AJ201 In Patients (clinicaltrials.gov)

P1/2, N=24, Recruiting, AnnJi Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

6 months ago

Trial completion date • Trial primary completion date

AR (Androgen receptor)

AR mutation

7ms

Clinical application and potential impact of liquid biopsy on the management of Chinese patients with metastatic castration-resistant prostate cancer (mCRPC): A territory-wide prospective analysis (ESMO Asia 2023)

BRCA2 mutations were detected in 9 (25.0%) patients, 4 of whom were switched to a PARP inhibitor and benefited clinically. In a real-life situation, liquid biopsy could potentially impact physician practices as well as patient outcomes.

7 months ago

Clinical • Tumor mutational burden • PARP Biomarker • MSi-H Biomarker • BRCA Biomarker • Liquid biopsy • Metastases • Biopsy

TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • HRD (Homologous Recombination Deficiency) • DNMT3A (DNA methyltransferase 1) • CDK12 (Cyclin dependent kinase 12)

BRCA2 mutation • MSI-H/dMMR • CDK12 mutation • AR mutation

FoundationOne® Liquid CDx

8ms

Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer. (PubMed, J Med Chem)

Oral administration of ARD-1676 effectively reduces the level of AR protein in the VCaP tumor tissue in mice and inhibits tumor growth in the VCaP mouse xenograft tumor model without any sign of toxicity. ARD-1676 is a highly promising development candidate for the treatment of AR+ human prostate cancer.

8 months ago

Journal

AR (Androgen receptor) • CRBN (Cereblon)

AR mutation

9ms

Molecular heterogeneity of Primary liver carcinomas: early study (ECP 2023)

HCC CK19+/CK7+ targeted therapy might benefit from a CTNNB1, TP53, ALK, EGFR, MAP2K2, RET, PTEN, and IDH2 panel, standardized for PLC spectrum. This knowledge would allow better understanding the clinical course and PLC heterogeneity, together with improving tumor classification and treatment.

9 months ago

EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • FGFR3 (Fibroblast growth factor receptor 3) • FGFR1 (Fibroblast growth factor receptor 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • FGFR4 (Fibroblast growth factor receptor 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • KRT19 (Keratin 19)

TP53 mutation • EGFR mutation • PIK3CA mutation • KIT mutation • ALK mutation • AR mutation • PDGFRA mutation • ERBB3 mutation • EGFR mutation + PIK3CA mutation • EGFR mutation + ALK mutation

Oncomine Precision Assay

9ms

Prostate cancer genetic alterations in Hispanic men. (PubMed, Prostate)

DNA alteration frequencies in primary and metastatic prostate cancer tumors differ among Hispanic-White and non-Hispanic White men. Notably, we found no significant differences in the prevalence of actionable genetic alterations between the groups, suggesting that a significant number of Hispanic men could benefit from the development of targeted therapies.

9 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • AR (Androgen receptor) • CCNE1 (Cyclin E1) • ERG (ETS Transcription Factor ERG) • TMPRSS2 (Transmembrane serine protease 2)

AR mutation

9ms

Anatomical resection improve relapse-free survival in colorectal liver metastases patients with KRAS/NRAS/BRAF mutation or right-sided colon cancer: a retrospective cohort study. (PubMed, Int J Surg)

CRLM patients with gene mutation or right-sidedness can benefit more from AR rather than from NAR.

9 months ago

Retrospective data • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RAS (Rat Sarcoma Virus)

KRAS mutation • BRAF mutation • NRAS mutation • RAS mutation • AR mutation

9ms

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer. (PubMed, JCO Clin Cancer Inform)

Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

9 months ago

Journal • Machine learning • Metastases

RB1 (RB Transcriptional Corepressor 1) • CHEK2 (Checkpoint kinase 2)

RB1 deletion • CHEK2 mutation • AR mutation • AR amplification • RB deletion

10ms

Phase I/II study of bavdegalutamide, a PROTAC androgen receptor (AR) degrader in metastatic castration-resistant prostate cancer (mCRPC): Radiographic progression-free survival (rPFS) in patients (pts) with AR ligand-binding domain (LBD) mutations (ESMO 2023)

There were no grade ≥4 treatment-related adverse events (TRAEs) with 420 mg bavdeg (n=158 across phase 1/2); any grade TRAEs reported in ≥20% of pts were nausea (54%; 1% grade 3), fatigue (35%; 1% grade 3), vomiting (31%; 1% grade 3), diarrhea (25%; 2% grade 3) and decreased appetite (23%; 0 grade 3). Conclusions Bavdeg had encouraging efficacy in post-NHA pts with mCRPC and AR 878/875 or any AR missense LBD mutation (excluding AR L702H alone) and was tolerable; these pt populations will be analyzed in a phase 3 study of bavdeg.

10 months ago

Clinical • P1/2 data • Metastases

AR (Androgen receptor)

AR mutation • AR L702H

bavdegalutamide (ARV-110)

10ms

Combination therapy of envafolimab, suvemcitug, and FOLFIRI in patients with metastatic microsatellite stable (MSS) or mismatch-repair proficient (pMMR) colorectal cancer: Results from a phase II clinical trial (ESMO 2023)

Eligible pts had received at least one prior line of treatment for MSS/pMMR mCRC and were treated with envafolimab plus suvemcitug and FOLFIRI (Irinotecan, Leucovorin, and 5-Fluorouracil)...Conclusions To the best of our knowledge, this is the first study demonstrated promising antitumor activity and a manageable safety profile of immunotherapy plus anti-angiogenic agent and chemotherapy in pts with MSS/ pMMR mCRC who had failed at least one line of therapy. The results support further evaluation of the therapy in a larger population.

10 months ago

Clinical • P2 data • Combination therapy • Mismatch repair • PD(L)-1 Biomarker • IO biomarker • Metastases

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • SMAD4 (SMAD family member 4)

TP53 mutation • KRAS mutation • AR mutation

5-fluorouracil • irinotecan • leucovorin calcium • Enweida (envafolimab) • suvemcitug (APX003)

10ms

Functional implications and therapeutic targeting of androgen response elements in prostate cancer. (PubMed, Biochimie)

Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

10 months ago

Review • Journal

AR mutation • AR overexpression • AR amplification

10ms

Saracatinib synergizes with enzalutamide to downregulate AR activity in CRPC. (PubMed, Front Oncol)

Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.

10 months ago

Journal

AR (Androgen receptor)

AR mutation • AR amplification • AR expression

docetaxel • Xtandi (enzalutamide capsule) • abiraterone acetate • saracatinib (AZD0530)

10ms

The FLT3-ITD allelic ratio and NPM1 mutation do not impact outcomes in AML patients with FLT3-ITD after allo-HSCT: a retrospective propensity-score matching study. (PubMed, Transplant Cell Ther)

Our results suggested that allo-HSCT, especially haplo-HSCT, may overcome the adverse effect of FLT3-ITD mutation, regardless of the NPM1 status or AR. Allo-HSCT could be an ideal option for AML patients with FLT3-ITD.

10 months ago

Retrospective data • Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)

FLT3-ITD mutation • NPM1 mutation • AR mutation • FLT3 wild-type

11ms

Non-coding RNAs in enzalutamide resistance of castration-resistant prostate cancer. (PubMed, Cancer Lett)

Also, the contributions of epithelial-mesenchymal transition and glucose metabolism to Enz resistance are discussed. We summarize the different mechanisms of miRNAs, lncRNAs, and circRNAs in the progression of CRPC and Enz resistance, and highlight the prospect of future therapeutic strategies against Enz resistance.

11 months ago

Review • Journal

AR (Androgen receptor)

AR mutation • AR splice variant 7 • AR-V7 mutation

Xtandi (enzalutamide capsule)

11ms

ARDENT: Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov)

P1/2, N=250, Recruiting, Arvinas Androgen Receptor, Inc. | Trial completion date: Oct 2023 --> Nov 2024 | Trial primary completion date: Feb 2023 --> Mar 2024

11 months ago

Trial completion date • Trial primary completion date • Metastases

AR mutation

abiraterone acetate • bavdegalutamide (ARV-110)

12ms

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer. (PubMed, Front Mol Biosci)

The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for both Snail+ and enzalutamide-resistant prostate cancer.

12 months ago

Journal • IO biomarker • Synthetic lethality

MET (MET proto-oncogene, receptor tyrosine kinase)

AR mutation

Xtandi (enzalutamide capsule) • abiraterone acetate • Nubeqa (darolutamide) • Erleada (apalutamide)

12ms

Adapting to hormone-therapy resistance for adopting the right therapeutic strategy in advanced prostate cancer. (PubMed, Expert Rev Anticancer Ther)

First- and second-generation HT resistance has been associated with several AR-dependent and AR-independent mechanisms, ranging from the amplification of the AR gene locus to somatic AR mutations and the intratumoral synthesis of androgens from adrenal steroids and cholesterol. As reported in the current review, the development of novel and effective treatments is needed to personalize anticancer therapies in this setting and to finally improve clinical outcomes in patients with HT resistant disease.

12 months ago

Journal • Metastases

AR (Androgen receptor)

AR mutation

Xtandi (enzalutamide capsule) • abiraterone acetate