Estybon (rigosertib)

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.

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

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.

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.

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.

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.

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.

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.

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.

Several promising drugs are in the horizon, including the hypoxia-inducible factor stabilizer roxadustat, telomerase inhibitor imetelstat, oral hypomethylating agents (CC-486), TP53 modulators (APR-246 and ALRN-6924), and the anti-CD47 antibody magrolimab. Targeted therapies approved for acute myeloid leukemia treatment, such as isocitrate dehdyrogenase inhibitors and venetoclax, are also being studied for use in MDS. In this review, we provide a brief overview of pathogenesis and current treatment strategies in MDS followed by a discussion of newer agents that are under clinical investigation.

PubMed and abstracts from annual meetings were searched in May 2020 to review recent studies on novel HMAs (e.g. ASTX727, CC-486, guadecitabine), molecularly targeted agents (e.g. mutant IDH1/2 inhibitors, BCL-2 inhibitors, APR246), and immune therapies (e.g. MBG453, anti-CD47) for the treatment of HR-MDS patients with HMA failure. Several molecules targeting cell signaling (e.g. rigosertib) are also in development...The improved understanding of molecular mechanisms of pathogenesis and immune evasion are offering further opportunities for the rational design of novel agents. Efforts to optimize frontline HMA-based treatment are of paramount importance.

P2, N=3, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Terminated Per PIs request due to low accrual

For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a phase III stage, i.e., the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.

P1/2, N=30, Recruiting, Icahn School of Medicine at Mount Sinai | Not yet recruiting --> Recruiting | Initiation date: Feb 2020 --> Jun 2020

Preliminary analysis of this study showed that RGS has a definite inhibitory effect on RAS mutant colorectal cancer via inhibiting cell proliferation & inducing endogenous apoptosis. The RAS downstream BRAF-MEK-ERK & PI3K-AKT signaling pathway maybe the main target of RGS.

P1/2, N=30, Not yet recruiting, Icahn School of Medicine at Mount Sinai