PTEN deletion

With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 &PTEN mutated BCs and precursor lesions.

The estimated 5-year OS rates were 93.9%, 100%, 80.0%, and 78.7% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. ERG rearrangements and PTEN deletions detected on biopsy samples are associated with poorer oncologic outcomes in prostate cancer patients treated with SBRT and merit further study in a dedicated prospective trial.

Loss of PTEN was also not linked to shifts in creatine kinase-myocardial band (CK-MB), troponin T (TnT), or any other biomarker, or troponin I (Tn1) at baseline or after 12 months of TRS therapy. These results give us important information about how PTEN deletion mutations might work as a predictor for TRS response in women with Her2+ BC.

Notably, these stretches included α-satellite DNA derived from chromosomes 2, 3, 4, 15, and 20, as well as satellite-III DNAs (D1Z1 and DYZ1). These findings align with recent discoveries indicating that α-satellite DNAs are expressed as long-non-coding RNAs in advanced cancer, particularly in the context of PCa.

This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.

P2, N=22, Recruiting, University of Utah | Not yet recruiting --> Recruiting

We also showed that MYB is a dependency factor in T-ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T-ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T-ALL.

Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum through an Aurka-dependent manner. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA.

About half of the breast SCCs exhibited high sTILs and positive PD-L1 expression, which indicated the potential opportunity for immunotherapy. Genomic profile revealed clinically meaningful alterations that might guide targeted treatment decisions in SCC patients.

This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted.

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2026 --> Aug 2024 | Trial primary completion date: Oct 2026 --> Aug 2024

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=78 --> 7

Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.

We also observed region-specific increases in apoptotic cells in the dentate gyrus hilar region that paralleled the regional increases in Ki67+ cells. Our work is accordant with the literature showing that Pten serves as a negative regulator of dentate gyrus neurogenesis but adds temporal and spatial components to the existing knowledge.

Secondary Objectives: 1) To assess the antitumor activity of bortezomib in pts with mCRPC with PTEN deletion as assessed by PSA 50% response rate, duration of PSA response, PSA progression free survival (PFS), objective response rate, duration of response, radiographic PFS, PFS, and OS 2.) To assess the safety and tolerability of B in pts with mCRPC with PTEN deletion. Exploratory analysis: Concurrent PTEN and ATAD1 loss will be correlated with treatment responses with B. Clinical trial information: NCT06029998.

Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.

In HGG (glioblastoma, n=25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n=24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). No treatment-related deaths occurred.ConclusionsErda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.

Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

PTEN loss identified by immunohistochemistry is an independent adverse prognostic factor for both biochemical and metastasis-free survival in prostate cancer patients treated with SRT. Although clinically validated RNA expression assays also exist which are prognostic for outcomes following SRT, stromal contamination in bulk RNA could mask "loss" signals specific to tumor cells, such as PTEN. Further work is necessary to determine the optimal approach to treating patients with poor molecular prognostic features in a salvage setting.

P2, N=22, Not yet recruiting, University of Utah

Our study shows that negative B2 in men on AS is about 20% and these men have a reduced risk of pathologic progression in grade and tumor volume (>3 positive cores/>50% tumor in a single core), hence the intensity of their follow-up can be reduced. Low-risk PTEN/ERG profile is a reliable predictor of absence of disease progression and an indicator of low-grade disease.

According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

PTEN loss identified by immunohistochemistry is an independent adverse prognostic factor for both biochemical and metastasis-free survival in prostate cancer patients treated with SRT. Although clinically validated RNA expression assays also exist which are prognostic for outcomes following SRT, stromal contamination in bulk RNA could mask “loss” signals specific to tumor cells, such as PTEN. Further work is necessary to determine the optimal approach to treating patients with poor molecular prognostic features in a salvage setting.

Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis...Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

BRB administration resulted in reduced tumor growth, enhanced T-cell infiltration to the tongue tumor microenvironment and robust antitumoral CD8+ cytotoxic T-cell activity characterized by greater granzyme B and perforin expression. Our results demonstrate that intralingual injection of tamoxifen in Tgfβr1/Pten 2cKO mice results in discrete quantifiable tumors suitable for chemoprevention and therapy of experimental HNSCC.

The patient with ETV6-NTRK3 fusion was treated with larotrectinib for 28.7 months prior to progression, likely due to acquired NTRK3 gatekeeper mutation (F617L) rendering resistance to larotrectinib, then was on a second generation NTRK inhibitor, selitrectinib, for 16.5 months prior to progression. Triple negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

The liver uptake of F-TBD at 3 and 4.5 months was higher in the two female PTEN knockout mice that would eventually develop HCC and was the most predictive imaging biomarker for HCC in the female cohort. These studies demonstrate the diagnostic and prognostic role of multi-modal imaging in HCC mouse models and provide compelling evidence that disease progression in the PTEN knockout model is highly dependent on gender.

Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Phenotypic characteristics cannot be used to inform variant location in BMPR1a. However, the phenotypic characteristics of BMPR1a DCV carriers, being almost exclusively related to the colon and rectum, can assist in pathogenicity assessment of BMPR1a variants. Given these findings, we propose that carriers of BMPR1a DCVs should only require surveillance for colorectal polyps and malignancy, and that surveillance for gastric polyps and malignancy may be unnecessary. However variant location within BMPR1a does not support differential surveillance recommendations.

An increased number of lymphocytes was associated with an increased percentage of RB1+ nuclei. The study corroborated clinical and histogenetic data, highlighting the importance of the differential diagnosis of these tumors to improve the management of patients and increase their quality of life.

For explainability, the PTEN algorithm was also applied to 19 WSI with heterogeneous (subclonal) PTEN loss, where the percent tumor area with predicted PTEN loss correlated with that based on immunohistochemistry (r=0.58, p=0.0097). These deep learning algorithms to predict ERG/PTEN status provide proof-of-principle that H&E images can be used to screen for underlying genomic alterations in prostate cancer.

The best model of 7/52 genetic CNAs, which included the SPOP alteration, SPP1 alteration, CCND1 amplification, PTEN deletion, CDKN1B deletion, PARP8 deletion, and NKX3.1 deletion, stratified the PCa cases into a localised and advanced disease with an accuracy of 70.0%, sensitivity of 85.4%, specificity of 44.9%, positive predictive value of 71.67%, and negative predictive value of 65.35%. This study validated prognostic gene level CNAs identified in previous studies, as well as identified new genetic markers with CNAs that could potentially impact risk stratification in PCa.

Material and Methods We analysed preoperative core biopsy samples of 20 patients with MRSTS who received 5×5 Gy radiotherapy combined with three cycles of doxorubicin-ifosfamide chemotherapy in a phase II clinical trial (NCTXXXXXXXX). D Undifferentiated pleomorphic sarcoma CDK4 Amplification - - D Dedifferentiated liposarcoma CDK4 Amplification - - E Undifferentiated pleomorphic sarcoma RB1 Nonsense mutation c.958C>T p.R320* D Myxofibrosarcoma AKT2 Amplification - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - E Pleomorphic liposarcoma PTEN Gene deletion - - D Myxofibrosarcoma NF1 Nonsense mutation c.3520C>T p.Q1174* D Malignant peripheral nerve sheath tumor NF1 Nonsense mutation c.1278G>A p.W426* D Malignant peripheral nerve sheath tumor Conclusion The detection of known mutations in MRSTS suggests poor pathological response to neoadjuvant radiochemotherapy. Identified mutations may indicate new therapeutic targets in the treatment of MRSTS.

This study presents a novel GEMM for the study of FOXA1 function in an immunocompetent setting. Our data supports FOXA1 as a critical tumor intrinsic regulator of the TIME. This will have important implications on the design of immunotherapeutic approaches for late-stage PCa often with FOXA1 loss.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation.

This study presents a novel GEMM for the study of FOXA1 function in an immunocompetent setting. Our data supports FOXA1 as a critical tumor intrinsic regulator of the TIME. This will have important implications on the design of immunotherapeutic approaches for late-stage PCa often with FOXA1 loss.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation.

P=N/A, N=1500, Recruiting, University of Kansas Medical Center | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

Notably, LY6D tumor cells are enriched in high-grade and androgen-resistant prostate cancer, providing clinical evidence for their contribution to advanced disease. Our data indicate that early interference with MAPK inhibitors can prevent progression of castration-resistant prostate cancer.

Moreover, we investigated the activation of the mTOR pathway and cell response to mTOR inhibitors. CH3 cells were sensitive to Rapamycin treatment suggesting that mTOR inhibitors may represent a valuable option for patients suffering from PTEN-deleted chordomas.