Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

P2, N=324, Recruiting, University of California, San Francisco | Active, not recruiting --> Recruiting | N=143 --> 324

Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment. The online version contains supplementary material available at 10.1007/s40203-024-00213-4.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=27, Not yet recruiting, University of Nebraska | Trial completion date: Jan 2027 --> Apr 2027 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2026 --> Apr 2026

P1/2, N=36, Not yet recruiting, M.D. Anderson Cancer Center

RAE1 promotes GC cell migration and invasion through the ERK/MAPK pathway and is a potential therapeutic target for GC therapy.

P2, N=52, Completed, Kimberly Perez, MD | Active, not recruiting --> Completed

H3K27M-mutant diffuse gliomas occasionally occur in nonmidline cerebrum. ONC201 exhibits activity in H3K27M-mutant gliomas irrespective of CNS location.

P2, N=101, Terminated, BioMed Valley Discoveries, Inc | Active, not recruiting --> Terminated; Enrollment challenges

P1, N=60, Recruiting, JS InnoPharm, LLC

Furthermore, PP4R1 enhanced the suppressive effects of the ERK inhibitor SCH772984 on GBC. In conclusion, our data showed that PP4R1 is a promising biomarker associated with GBC and confirmed that PP4R1 regulates PKM2-mediated tumor glycolysis, which provides a metabolic growth advantage to GBC cells, thereby promoting GBC tumor growth and metastasis.

Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2 CRC, which could contribute to further development of targeted CRC treatment.

In this study, for the first time, piezoelectrically catalyzed Mg -doped hydroxyapatite (Mg-HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg-HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered...In summary, a dual-targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.

P2, N=19, Terminated, Fox Chase Cancer Center | N=36 --> 19 | Suspended --> Terminated; Slow accrual

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

P1, N=20, Active, not recruiting, University of Nebraska

Despite limited BBB permeability of LY321, combination LY321 and anti-PD-1 treatment amplifies extracranial immune responses that improve intracranial disease control, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.

We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods.

In NSCLC, DHX38 functions as a tumor promoter. DHX38 modulates G3BP1 expression, leading to the activation of the MAPK signaling pathway, thus promoting tumor cell proliferation, metastasis, and the progression of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer.

In the present study, we first found that PCD-related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five-PCD-associated-gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug-sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

P3, N=450, Recruiting, Chimerix

Simvastatin can selectively and effectively eradicate FLT3/ITD AML cells in vitro and in vivo, and its mechanism may be related to the disruption of the HMG-CoA reductase pathway and the downregulation of the MEK/ERK and p38-MAPK signaling pathways.

P2, N=0, Withdrawn, Masonic Cancer Center, University of Minnesota | N=36 --> 0 | Not yet recruiting --> Withdrawn

P2, N=143, Active, not recruiting, University of California, San Francisco | Recruiting --> Active, not recruiting | N=324 --> 143

Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.

P1, N=80, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Feb 2026 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Jun 2026

Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC.

P1, N=20, Active, not recruiting, University of Nebraska | Recruiting --> Active, not recruiting

In conclusion, our results demonstrated that IL-33 plays a protective role in the progression of atherosclerosis by inhibiting cell adhesion via the ERK1/2-IRF1-VCAM-1 pathway. This study may provide a potential therapeutic way to prevent the development of atherosclerosis.

Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2). The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.

The patient continuing to receive the combination at progression and following reirradiation also experienced a marked decrease in tumor size (MR axial diagnosis scan = 1248 mm2, current tumour area = 315 mm2, ~75% reduction), 10 months following radiological detection of progression. These data inform the phase II clinical trial (NCT05009992).

Overall, our data demonstrates the efficacy of ONC201 in H3K27M-mutant DMG and supports ONC201 as the first monotherapy to improve outcomes in patients with H3K27M-mutant DMG for whom few therapeutic options currently exist. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.

P2, N=52, Active, not recruiting, Kimberly Perez, MD | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2023 --> Aug 2023

Treatment with MEK inhibitor (trametinib) was then assessed in two cutaneous (MEL888, MEL624) and one conjunctival (YUARGE 13-3064) melanoma cell line...In a malignant melanoma cell population, MEK inhibition reduced viability in both cutaneous and conjunctival melanoma with a profound downstream reduction in EGR1 expression. Targeted knockdown of EGR1 reduced both cutaneous and conjunctival melanoma cell viability independent of MEK inhibition, suggesting a key role for EGR1 in melanoma pathobiology.

P1, N=24, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2025 --> Jan 2028 | Initiation date: May 2023 --> Mar 2024 | Trial primary completion date: Feb 2025 --> Jan 2026

P1, N=27, Suspended, University of Nebraska | Not yet recruiting --> Suspended

TIC10 can effectively inhibite the proliferation of leukemia cells and induce apoptosis, and have a certain intervention effect on AML induced by MLL-AF9, indicating that TIC10 as a potential candidate drug for the treatment of leukemia.