Oncotarget最新文献

The protein homeostasis (proteostasis) network includes quality control systems that coordinate protein synthesis, folding, localization, and degradation, and is deregulated in numerous diseases including cancer. Loss of proteostasis can activate lethal cellular stress responses, potentially opening a therapeutic window. Previous research demonstrated that MAL3-101, an inhibitor of heat shock protein 70-kD (HSP70) chaperones, selectively induces rhabdomyosarcoma (RMS) cell death via unfolded protein response (UPR) activation. RMS is the most common pediatric soft tissue sarcoma, and relapsed patients are rarely cured despite transient responses to DNA-damaging therapy. To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 in vivo. We find that inhibition of VCP, which encodes the p97 ATPase that facilitates proteasome-dependent degradation, similarly activates the UPR and induces RMS apoptosis. In mouse models, a preclinical p97 inhibitor showed superior bioavailability and anti-tumor activity compared to MAL3-101. Patient-derived xenografts exhibited a spectrum of p97 inhibitor sensitivities, and RNA sequencing of resistant tumors revealed elevated autophagy, nominating a biomarker of proteostasis adaptability. Together, these findings confirm that proteostasis inhibition can slow RMS growth and suggest that targeting compensatory network components might yield synergistic outcomes.

The anti-tumor actions of the Stearoyl-CoA desaturase (SCD1) inhibitor aramchol in tumor cells remains poorly understood. Aramchol interacted with the multi-kinase inhibitors sorafenib, regorafenib or lenvatinib, to kill GI tumor cells, with regorafenib exhibiting the greatest effect. In HCT116 cells homozygous for the autophagy-regulatory protein ATG16L1 T300, aramchol and regorafenib interacted to activate ATM and the AMPK and to inactivate mTORC1 and mTORC2. As a single agent, regorafenib inactivated eIF2α and it combined with aramchol to elevate GRP78 expression. In HCT116 cells expressing the ATG16L1 A300 isoform the drug-induced dephosphorylation of mTORC1 S2448 and mTORC2 S2481 and the increased phosphorylation of eIF2α S51 were significantly lower than in T300 cells. In cells expressing ATG16L1 T300, but not A300, regorafenib and/or the drug combination inactivated AKT, ERK1/2 and p70 S6K. Regorafenib and aramchol interacted to cause formation of autophagosomes which was significantly greater in cells expressing ATG16L1 T300. Aramchol as a single agent did not stimulate autophagic flux but further enhanced both flux and autolysosome formation caused by regorafenib. Knock down of Beclin1 reduced the lethality of regorafenib and aramchol as single agents and when combined whereas knock down of LAMP2 or BID did not reduce killing caused by aramchol as a single agent but did reduce the lethality of regorafenib alone and regorafenib plus aramchol. In vivo using the HuH7 adult hepatoma cell line, regorafenib and aramchol interacted to suppress tumor growth without normal tissue toxicities.

The precision oncology industry has evolved rapidly within the past two decades, although treatment selection remains a complex undertaking. Access to timely, accurate, and comprehensive molecular profiling data is imperative to improving patient outcomes within the expanding sphere of Food and Drug Administration (FDA)-approved targeted therapies. Caris Life Sciences has developed MI Cancer Seek^®, an FDA-approved whole exome and whole transcriptome sequencing-based molecular test encompassing adult and pediatric tumor profiling, eight companion diagnostics (CDx), and additional laboratory developed test (LDT) capabilities. Patient tissue is maximized through simultaneous analysis of DNA and RNA with minimum input of 50 ng. The clinical and analytical validation presented herein demonstrates non-inferiority of MI Cancer Seek relative to other FDA-approved CDx tests (>97% negative and positive percent agreement), as well as its precision, sensitivity, and specificity. Accordingly, MI Cancer Seek represents a safe and effective comprehensive molecular test option supporting biomarker-directed care for oncology patients.

The estrogen receptor is overexpressed in and promotes 67-80% and 90% of female and male breast cancer cases, respectively. Hormone independence, enhanced motility, and signaling by growth factors have been attributed to aromatase inhibitor (AI) resistance and MAPK pathway activation. We used long-term letrozole-treated (LTLT-Ca) breast cancer cells to evaluate polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential therapies for AI-resistant breast cancer. PCAIs specifically disrupt G-proteins such as KRAS, an upstream regulator of MAPK and PI3K/AKT pathways. PCAIs were tested against the viability, phosphorylation of MAPK and PI3K/AKT pathways, apoptosis, and migration of LTLT-Ca cells. NSL-YHJ-2-27 was potent against LTLT-Ca viability with an EC50 of 4.8 μM. MEK (p-MEK1/2), ERK (p-ERK1/2), and p90RSK (p-p90RSK) phosphorylation were significantly increased by 2-, 2-, and 6.4-fold, respectively. PCAIs increased AKT phosphorylation 36-fold. NSL-YHJ-2-27 at 2, 3 and 5 μM stimulated ROS generation by 4-, 8- and 10-fold, respectively. PCAIs inhibited cell proliferation and colony formation by 95% and 74%, respectively, increased active caspase 7 and BAX 1.5-fold and 56%, respectively. NSL-YHJ-2-27 (10 μM) induced LTLT-Ca spheroid degeneration by 61%. LTLT-Ca cell migration was inhibited by 31 and 80% following treatment with 2 and 5 μM NSL-YHJ-2-27, respectively. NSL-YHJ-2-27 disrupted F-actin filaments, vinculin punctates and levels by 33%. These results indicate that the PCAIs' activation of the MAPK and PI3K/AKT pathways causes apoptosis, possibly through proapoptotic p-p90RSK isoforms, AKT-induced ROS production or anoikis through disruption of focal adhesion. These effects against LTLT-Ca cells suggest potential PCAIs therapeutic applications against antihormonal-resistant breast cancers.

This study investigates the R-spondin family of genes (RSPO1/2/3/4), a group of secreted proteins that act as Wnt regulators, and their subsequent role in advanced prostate cancer (PC). When evaluating transcriptomic data from primary and metastatic PC patients, we found that alterations in RSPO2 were more prevalent than in other RSPO family members or Wnt-regulating genes APC and CTNNB1. Further, we found that RSPO2 alterations in PCs were significantly associated with worse disease-free survival. Through our in silico modeling, RSPO2 exhibited strong positive associations with genes regulating epithelial-mesenchymal transition (EMT) and double-negative prostate cancer (DNPC), but had negative correlations with androgen receptor (AR) and AR-associated genes. Furthermore, 3D modeling of RSPO2 revealed structural differences between itself and other RSPOs. In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1. Conversely, this was not observed when CTNNB1 was overexpressed in the same models. These findings highlight that, in PC, RSPO2 functions as a unique member of the R-spondin family by promoting genes and signaling pathways associated with aggressive PC, and RSPO2 amplifications are associated with poor outcomes in PC patients.

Purpose: To summarize clinically relevant genomic alterations in solid tumor samples from over 10,000 patients.

Methods: Descriptive statistics were used to summarize findings of retrospectively analyzed OncoExTra assay data from solid tumor samples.

Results: The analysis cohort included 11,091 solid tumor samples from 10,768 patients. Therapeutically actionable alterations were present in 92.0% of patient samples. Biomarkers associated with on- or off-label FDA-approved therapies were detected in 29.2% and 28.0% of samples, respectively. The prevalence of hotspot alterations detected at variant allele frequency (VAF) <5% was analyzed among 7,481 samples (67.5%) harboring ≥1 of these events: 13.7% (1,022 of 7,481) had ≥1 alteration detected at VAF <5%, and 9.8% (558 of 5,690) of hotspot alterations associated with an on- or off-label FDA-approved therapy were detected at VAF <5%. Common and rare mutations in the TERT promoter were found in 8.4% (933) of samples. Whole transcriptome sequencing detected clinically relevant fusions in 7.5% of samples, with highest frequencies in prostate cancer (42.0%). The METe14 transcript was found in 14 NSCLC samples (2.7%).

Conclusions: The broad capabilities of the OncoExTra assay detected therapeutically actionable and other clinically relevant genomic events that can inform clinical decision-making for patients with advanced solid tumors.

Background: Despite significant strides in the management of metastatic solid tumors over the past few decades, metastatic disease remains a major clinical challenge, often leading to unfavorable patient outcomes. Circulating tumor cells (CTCs), which shed from the primary tumor, have the potential to disseminate and establish distant metastases, contributing to disease progression and reduced survival rates. Removal of CTCs via extracorporeal blood filtration could have significant therapeutic implications.

Case: A 51-year-old woman was diagnosed with metastatic poorly differentiated adenocarcinoma after presenting with severe abdominal pain. She deferred conventional chemotherapy options and elected treatment with CTC removal using an extracorporeal blood filter. After 9-12 filtration sessions of treatment over 12 months, she reported significant clinical improvement and staging scans demonstrated stable disease without evidence of new metastases.

Conclusion: Therapeutic modalities that explore CTC removal via blood filtration may potentially have promising clinical benefits. More prospective studies are required to determine the utility of this therapeutic strategy in patients with metastatic solid tumors. Our patient demonstrated significant clinical improvement with scans demonstrating stable disease.