The necessity of dose adjustments based on these two covariates remains to be validated in a larger population. The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research.

P1/2, N=150, Active, not recruiting, Orinove, Inc. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Jan 2023 --> Jan 2024

P1/2, N=350, Active, not recruiting, Orinove, Inc. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=24, Active, not recruiting, Orinove, Inc. | Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

To test this hypothesis, a novel IRE1α inhibitor, STF-083010, was used...Furthermore, the apoptosis rate was increased in a dose-dependent manner with emodin treatment. Thus, emodin induced ER stress in HepG2 cells by activating the IRE1α-XBP1 axis and induced apoptosis, indicating that emodin can cause hepatotoxicity.

P1/2, N=150, Active, not recruiting, Orinove, Inc. | Trial completion date: Mar 2023 --> Dec 2023

P1/2, N=350, Active, not recruiting, Orinove, Inc. | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients.

Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1α RNase inhibitor STF083010...The results suggest that XBP1s functions to induce IRE1α expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1α expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1α-targeting is a potential therapeutic strategy for colon cancer.

P1/2, N=350, Active, not recruiting, Orinove, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2023 --> Jun 2023

P1/2, N=150, Active, not recruiting, Orinove, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2022 --> Mar 2023 | Trial primary completion date: Oct 2022 --> Feb 2023

P1/2, N=150, Recruiting, Orinove, Inc. | Trial completion date: Jun 2022 --> Dec 2022 | Trial primary completion date: Jun 2022 --> Oct 2022

In this study we showed that combined inhibition of autophagy and the proteasome synergistically induces cell death in multiple myeloma. Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and UPR-directed therapy as promising novel in vitro treatment strategy against multiple myeloma.

P1/2, N=350, Recruiting, Orinove, Inc. | Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Mar 2022 --> Jan 2023

SS (1 μM) was assumed to trigger apoptosis in MCF7 cells. The results indicate that both adaptive and proapoptic UPR signaling pathways are activated in cells, depending on the nature and concentration of the ER stress inducer.

This study indicated that POU4F3 may work as a tumor suppressor in LUAD via regulating the PERK/eIF2α/ATF4/CHOP pathway. We made it possible to develop POU4F3 as a diagnostic, therapeutic, and prognostic target of LUAD.

Trichomonas vaginalis induces apoptosis through mitochondrial ROS and ER stress responses, and also promotes ER stress-mediated mitochondrial apoptosis via the IRE1/ASK1/JNK/Bcl-2 family protein pathways in SiHa cells. These data suggest that T. vaginalis-induced apoptosis is affected by ROS and ER stress response via ER-mitochondria crosstalk.

P1/2, N=150, Recruiting, Orinove, Inc. | Trial completion date: Mar 2022 --> Jun 2022 | Trial primary completion date: Dec 2021 --> Jun 2022

Anti-apoptotic BCL-2 expression significantly increased, and Caspase 3/7 activity and cell death also decreased. 5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress and lipoapoptosis by attenuating GRP78 via HO-1 induction.

No abstract available

Agomelatine improved neurodegeneration in a rat model of hippocampal aging by attenuating ROS production, ER stress, mitochondrial dysfunction, excitotoxicity, and apoptosis.

We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

The results indicate that neuropathic pain associated with PTX-induced peripheral neuropathy can be alleviated by HES administration and that it is a promising compound for cancer patients. In addition, it is thought that the results of the present study contain information that will shed light for researchers regarding further studies to be conducted with HES.

P1/2, N=350, Recruiting, Orinove, Inc.

Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti-lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer.

Moreover, melanoma had also been inhibited effectively in vivo. As a result, the endoplasmic reticulum stress is a promising target with clinical potential in nanomedicine and cancer therapy.

In summary, activating these lipids or the associated downstream machinery in acidosis-related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical 'sense-respond' axis should effectively target astrocytic tumour growth.

Patients received sorafenib/sintilimab or lenvatinib/sintilimab combined first-line therapy and the response was assessed at 3-6 cycles of therapy. MDM4 was capable of predicting disease progression, and a panel mRNA and lncRNA of eight genes may also predict the response. Further validation is needed to verify these biomarkers.

BH3 mimetic drugs, like the BCL2-specific inhibitor Venetoclax, have been successfully used in the clinic to treat certain cancers, and MCL1-selective inhibitors are currently in clinical development...We observed that ELP4-KO results in increased resistance to proteasome inhibitor Bortezomib and other ER stress inducers like Tunicamycin, Thapsigargin, and BrefeldinA as a monotherapy or in combination with AZD5991...Moreover, ER stress response gene signature has been shown to be repressed in drug-resistant MM. Taken together, an integrated elongator and IRE-XBP1 gene signature could be a strong predictor of therapy response in MM .

Targeted therapies such as ibrutinib (IBR; BTK inhibitor) and venetoclax (VEN; BCL2 antagonist) have revolutionized the management of CLL, however ~20% of patients relapse, signifying the urgent need for novel therapeutics for CLL patients especially those with refractory/relapse (ref/rel) disease. N3 is a novel pre-therapeutic lead that targets multiple survival and proliferation pathways through the inhibition of NF-κB activity and upregulation of UPR. We show that its highly cytotoxic in tumor B cells while sparing normal B cells. Moreover, N3 sustained its anti-tumor properties under different TME stimuli and in IBR resistant cells, indicating the potential use of this compound in rel/ref patients following evaluation in murine CLL models.

NCP26, a novel ATP-competitive and Pro non-competitive EPRS inhibitor, induces MM cytotoxicity both in vitro and in vivo by triggering AAR and EPRS-Pro-rich proteins pathways. Our data provide the preclinical rationale for development of NCP26-based clinical candidates to improve patient outcomes in MM.

Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.

In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.

Hepatic IRE1α/XBP1 and other constituents of the UPR signaling were activated in older FXR-/- mice indicating increased ER stress . DKO mice have increased expression of inflammation, apoptosis and proliferation pathways, indicating that the activation of XBP1s observed in older FXR-/- mice is protective . The interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses .

In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.