P1/2, N=25, Completed, Icahn School of Medicine at Mount Sinai | Recruiting --> Completed

Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.

P1, N=6, Recruiting, Thomas Jefferson University | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

The efficacy of Rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and Poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53-wild-type CU-ACC1...TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.

Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.

Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.

P1/2, N=20, Recruiting, Icahn School of Medicine at Mount Sinai | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras-Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes.

P2, N=29, Recruiting, Vanderbilt-Ingram Cancer Center | Not yet recruiting --> Recruiting

P2, N=29, Not yet recruiting, Vanderbilt-Ingram Cancer Center

Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration...This study elucidates the role of KLHL17 in the development and progression of NSCLC using clinical samples and NSCLC cell lines. The results show that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway, and suggest that KLHL17 may be a novel therapeutic target for the treatment of NSCLC.

Objective: To investigate the effect of rigosertib (RGS) combined with classic chemotherapy drugs including 5-fluorouracil, oxaliplatin, and irinotecan in colorectal cancer. The combination of RGS and oxaliplatin has a stronger anti-tumor effect on KRAS mutant colorectal cancer. RGS single agent will not cause significant bone marrow suppression and hepatorenal injury in mice, but its side effects may increase correspondingly after combined with chemotherapy.

The alterations in the cell cycle and in cell-cycle-related proteins were observed in A549 at lower concentrations than U87-MG. In conclusion, with this article we have demonstrated that Rigosertib has different efficacy depending on the cell line considered and that it could be a potential antineoplastic agent against lung cancer in humans.

Two drugs, namely Rigosertib and Proscillaridin A, were first identified as potential stemness inhibitors for melanoma and colon cancer, respectively. Overall, mining embryonic stem cell data provides a valuable way to identify cancer stemness regulators.

Therefore, we took a systematic approach to test how AQP1, AQP3 and AQP5, which are often over-/ectopically expressed in breast cancer, affect total viability of 3-dimensional (3D) breast cancer cell spheroids when treated with the conventional anticancer chemotherapies Cisplatin, 5-Fluorouracil (5-FU) and Doxorubicin, a Combination of the three drugs as well as the Combination plus the Ras inhibitor Salirasib. Thus, this study supports a significant role of AQPs in the response to conventional chemotherapies. Evaluating the role of individual proteins that contribute to resistance to chemotherapies is essential in advancing personalized medicine in breast carcinomas.

Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration. These results suggest that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway. Therefore, KLHL17 may be a novel therapeutic target for the treatment of NSCLC.

Two of the responders had STK11 co-mutations and low PD-L1 expression at diagnosis. Conclusions Combination of Rigosertib and Nivolumab is safe, well tolerated and has shown early efficacy for the treatment of KRAS mutated NSCLC patients with prior progression on ICI.

Aza combined with a multi-kinase inhibitor of RAS and MAPK pathways, rigosertib (RAS/MAPK), reverses the bone marrow failure state and demonstrates an ORR of 54% in patients who failed a prior HMA based therapy. In the clinic RAS/MAPK modulation combined with Aza reverses bone marrow failure in MDS. Further studies are underway to determine the correlation of the histone modification and innate immune signaling changes, as well as the role of RAS/MAPK modulation, to determine how these mechanisms contribute to the improvement in hematopoiesis in MDS patients.

Computer-aided molecular modeling studies compared anticancer agents, salirasib and γ-tocotrienol, with the active site of galectin-3 and β-lactose (a known ligand)...In TS/A cells, 6-15 μM tocotrienol induced a dose-responsive increase in doxorubicin staining inside the nucleus...These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer. This study was supported in part by funding from the Louisiana Cancer Foundation.

OncoTreat analysis predicted sensitivity to camptothecin, seliciclib, galunisertib, and rigosertib in both fibroblast- and chondroblast-like subpopulations. In conclusion, using network-based systems biology approaches in OS, we identified pharmacologically accessible MR subtypes differentiating survival at the bulk tissue level, and defining three distinct tumor subpopulations at the single-cell level with unique predicted drug sensitivities.

The ERK signaling cascade and downstream molecules are potential targets of action of AL in CCA.

P1/2, N=20, Recruiting, Icahn School of Medicine at Mount Sinai | N=30 --> 20 | Trial completion date: Jan 2022 --> Dec 2022 | Trial primary completion date: Jan 2022 --> Dec 2022

In conclusion, we hypothesized the mechanism of the action of Rigosertib against cholangiocarcinoma EGI-1 cells, highlighting the importance of proteins involved in the regulation of cell cycles. The CDK1-Cyclin B complex and p53 play an important role, explaining the Block in the G2/M phase of the cell cycle and the effect on cell viability.

Notably, the biosimulation predicted lenalidomide to be beneficial for these patients...Of note, these genomic markers suggested a likelihood of benefit from other therapies, including vincristine, JQ1 and rigosertib... The Cellworks Biosimulation Platform identified novel polygenic biomarkers of response that can be employed to determine the optimal therapy for relapsed AML patients. Biosimulation permits avoidance of cytotoxic drugs with little chance of efficacy and reveals vulnerabilities in each patient's cancer that can be exploited to improve disease control. In AML, biosimulation promises to improve intensive therapy regimens by tailoring chemotherapy to optimize disease control and minimize toxicity.

Rigosertib (RIGO), a Ras mimetic which had been shown to interfere with the Ras-Raf binding domain, has limited single-agent activity (ORR 15%) and failed to provide a survival benefit compared to standard of care in MDS patients failing an HMA. RIGO has effects on innate immune signaling and histone modification of both activator and repressor marks. Further studies are underway to determine the correlation of the histone modification and innate immune signaling changes, and if these mechanisms contribute to the improvement in hematopoiesis in MDS patients.

Here, using samples collected from a global Phase 3 trial randomizing HR-MDS pts post HMA failure to I.V. rigosertib (RGS) or physician’s choice (PC) (INSPIRE: NCT02562443), we analyzed the landscape of driver mutations in HR-MDS after HMA failure and investigated the association with the clinical outcomes... High-risk gene mutations, such as TP53 , ASXL1 , RUNX1 , and STAG2 (Ogawa. Blood 2019). were significantly enriched in MDS pts with HMA failure, suggesting their role in HMA resistance and disease progression.

The addition of a novel Ras mimetic that inhibits Ras/Raf signaling, Rigosertib (RIGO), yields a response rate of 54% of HMA failures and results in significant improvement in hematopoiesis overcoming the epigenetic clinical resistance phenotype but the mechanism is still elusive. Altogether results indicate RIGO appears to promote maintenance of a PSCP, while the RIGO/AZA SC appears to push the cells toward a cycling stage with increased expression of genes associated with OXPHOS. In comparison, when treated with RIGO, cells remain in a less differentiated stage. Studies are underway to determine the linkage of these pathways with hematopoiesis and the immune landscape.

This led to the development of sotorasib as a second-line treatment of KRAS mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.

Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.

We further identified vincristine and rigosertib as a potential promising drug combination treatment. Our results show that rigosertib might be a useful therapeutic agent for MYCN-amplified neuroblastomas, especially in combination with existing agents.

Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.

In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CXR motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

RIGO alone appears to promote maintenance of a primitive stem cell population in a less differentiated state, while the RIGO/AZA sequenced combination appears to encourage cells to enter a cycling stage. Further studies are underway to determine the effect of metabolic changes on differentiation and maintenance of hematopoietic stem cells.

Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.

Computer-aided molecular modeling studies were carried out within the active site of galectin-3 based on the crystal structure (5EXO) obtained from the protein data bank with a known ligand, and anticancer agents (salirasib, γ-tocotrienol, and β-lactose) galectin-3 docking scores and amino acid interactions were determine...In summary, these results demonstrate for the first time that γ-tocotrienol treatment inhibits extracellular galectin-3 expression and disrupts galectin-3 carbohydrate binding and activation of +SA and TS/A mammary tumor cells. These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer.

Notably, multiplex IHC analysis showed that BRAF inhibitor treatment significantly induces CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. Our preclinical data support the therapeutic use of RGS plus αPD1+αCTLA4 in RAS/RAF/MEK and/or PI3K pathway-activated melanoma tumors and point to the need for clinical trials to determine the clinical benefit of RGS plus ICB for metastatic melanoma patients who do not respond to ICB alone.The authors sincerely thank Onconova Therapeutics, Newtown, PA 18940 for kindly supplying Rigosertib for this work.

For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Ourstudy is supportive that local treatment of ON-01910.Na may be a novel, effectivemodality benefiting patients with PLK1-aberrant tumors.