Estybon (rigosertib) / Traws Pharma, Knight Therap, Specialised Therap, Pint Pharma - LARVOL DELTA

Rigosertib Plus Pembrolizumab in Treating Patients With Unresectable/Metastatic Melanoma Refractory to PD-1 Inhibitors (clinicaltrials.gov) - P2 | N=7 | Terminated | Sponsor: Vanderbilt-Ingram Cancer Center | Trial completion date: May 2029 ➔ Mar 2026 | Active, not recruiting ➔ Terminated; Drug unavailable

Checkpoint inhibition • Trial completion date • Trial termination • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Rigosertib Reverses Hypertrophic Cardiomyopathy in Noonan Syndrome. (PubMed, Circulation) - "Cardiac-targeted Drosophila models expressing RASopathy-associated transgenes were used to evaluate the effects of rigosertib on cardiac hypertrophy and compare its efficacy with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Together, our findings suggest that rigosertib normalizes and reverses RASopathy-associated HCM and other NS-associated syndromic features, supporting its development as a promising treatment for RAF1-associated HCM and, potentially, other RASopathy-dependent pathologies. This study not only highlights the therapeutic potential of rigosertib but also demonstrates the utility of an integrated approach using Drosophila and mammalian models to elucidate drug effects across complex biological systems."

Journal • Cardiomyopathy • Cardiovascular • Developmental Disorders • Genetic Disorders • Hypertrophic Cardiomyopathy • Melanoma • Oncology • Psychiatry • Solid Tumor

Targeting IGF2BP3 in Cancer: From Molecular Structure and Biology to Early Drug Discovery. (PubMed, Int J Mol Sci) - "We then discuss emerging therapeutic approaches, including direct inhibition of IGF2BP3-RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways. By critically highlighting the opportunities and limitations of these approaches and their impact on cancer progression, we provide an integrated perspective combining structural biology, medicinal chemistry, and cancer biology to support the development of next-generation IGF2BP3-targeted therapies."

Journal • Review • Oncology • IGF2BP3

Polyphenol-Rich Duhuo Jisheng Decoction Enhances Mesenchymal Stem Cell-Derived Exosome-Mediated Chondroprotection via PI3K/AKT Signaling in Osteoarthritis. (PubMed, Food Sci Nutr) - "The therapeutic efficacy was evaluated via inflammatory markers, extracellular matrix (ECM) homeostasis, and apoptosis assays, with the PI3K/AKT inhibitor Rigosertib used for mechanistic validation...This study demonstrates that polyphenol-rich DHJST enhances the therapeutic efficacy of BMSC-derived exosomes against OA by activating the AKT signaling pathway and its key nodes, JUN and KDR. This synergistic strategy, combining dietary bioactives with exosome-mediated delivery, represents a promising adjunctive approach for the management of chronic degenerative joint diseases."

IO biomarker • Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • ACAN • ADAMTS5 • BAX • BCL2 • CASP3 • COL2A1 • IL1B • IL6 • JUN • KDR • MMP13 • TNFA

All Screens Lead to Polo-like kinase 1: A Central Node in Cancer Therapeutics and Resistance. (PubMed, Pharmacol Res) - "Emerging evidence supports synergistic potential of new-generation PLK1 inhibitors, such as Onvansertib, with chemo- and immune-therapies. This mini-review and perspective present current insights on PLK1 overexpression and its mechanistic impact on cancer aggressiveness and therapy resistance. We highlight the need for refined patient stratification and innovative combination regimens to exploit PLK1 inhibition in cancer treatment."

Journal • Review • Oncology • PLK1

Large-scale drug screening identifies clinically actionable combinations to overcome BTK/PI3K inhibitor resistance in marginal zone lymphoma (AACR 2026) - "Here, we present data from a large pharmacological screen involving over 3,500 compounds in 2 MZL models with secondary resistance to BTK/PI3Ki, developed through prolonged exposure to idelalisib (Arribas 2022) or ibrutinib (Arribas 2025).Methods...Adding the alisertib (AURKAi), rigosertib (PLKi), fimepinostat (PI3K/HDACi), lanatoside-C (Na+K+ATPase), astragalin (apoptosis), astragaloside-I (WNT) and oridonin (AKT) was of benefit (additivity or synergism) in both parental and resistant cells.Conclusions...Several clinically advanced agents—particularly PAK4/NAMPT, AURKA, WNT, and Na⁺/K⁺-ATPase inhibitors—enhanced or restored the activity of BTKi/PI3Ki. These findings highlight new therapeutic strategies for relapsed/refractory MZL and support clinical evaluation of targeted combinations to overcome acquired resistance."

Clinical • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • AURKA • NAMPT

Rigosertib Plus Pembrolizumab in Treating Patients With Unresectable/Metastatic Melanoma Refractory to PD-1 Inhibitors (clinicaltrials.gov) - P2 | N=7 | Active, not recruiting | Sponsor: Vanderbilt-Ingram Cancer Center | Suspended ➔ Active, not recruiting | N=29 ➔ 7

Checkpoint inhibition • Enrollment change • Enrollment closed • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Rigosertib promotes anti-tumor activity of cancer cells via CETSA revealed novel targets and activates NLRP3-dependent inflammatory responses (AACR 2024) - P1, P1/2, P2 | "Rigosertib is in a Phase 2 program in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa (RDEB-associated SCC) (NCT03786237, NCT04177498), and a Phase 2 trial in combination with pembrolizumab in patients with metastatic melanoma (NCT05764395). These findings indicate that rigosertib may represent an effective compound for inhibition of RAS-MAPK signaling through ROS-mediated JNK activation. The rigosertib-dependent mechanism for NLRP3 activation suggests a reprogramming of the tumor immune environment which may contribute to the synergistic effect seen with immune checkpoint inhibitors pre-clinically and clinically. Clinical trials in several difficult-to-treat cancers continue."

Hematological Malignancies • Lung Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • ERO1A • GLI2 • IL18 • IL1B • NLRP3

IL-1-driven signaling promotes resistance to PI3K and BCL2 inhibitors in B-cell lymphoma preclinical models (AACR 2026) - "A 1,400-compound FDA-approved library was used in combination with copanlisib/venetoclax. VL51 cells with acquired resistance to PI3K/BCL2 inhibitors were characterized by an upregulation of IL1α and IL1β, elevated ERK and STAT3 phosphorylation, and increased expression of pro-survival and cytokine-responsive proteins. IL-1-driven reprogramming promotes resistance to PI3K and BCL2 inhibition in B-cell lymphoma via activation of NF-κB, STAT3, and metabolic survival pathways. Targeting IL-1 signaling or downstream effectors may overcome resistance and offer a promising therapeutic strategy for relapsed or refractory B-cell lymphomas."

IO biomarker • Preclinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ALDH1A1 • AURKA • IL1A • IL1B

Novel marginal zone lymphoma models of resistance to the dual inhibition of PI3K and BCL2 (AACR 2024) - "Multi-drug resistance phenotype was ruled out by confirming sensitivity to vincristine...The response to MCL1-i, mTOR-i, and epigenetic agents (decitabine, HDAC, BET, and EZH2 inhibitors) was maintained. Triple combinations of copanlisib/venetoclax with the AURKA inhibitor alisertib, PLK inhibitor rigosertib, or the multikinase inhibitor amcasertib were active in both parental and resistant cells... We created four novel MZL-derived models of secondary resistance to PI3K and BCL2 inhibitors, which will help clarify possible modalities to overcome resistance. Novel potential targets were already identified, such as AURKA or PLK, to be further exploited."

IO biomarker • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • BCL2 • CD19 • CXCL13 • MCL1 • PIK3CA • PIK3CD

Unlocking therapeutic potential of rigosertib as a selective therapy for ovarian cancer (AACR 2025) - "Subsequent combination drug screening revealed a cooperative effect between rigosertib and PI3K inhibitor (taselisib), suggesting that combining rigosertib with taselisib which restricts mTOR activation enhances therapeutic efficacy. This combination showed synergy across ovarian cancer cell lines, organoids, and xenograft models, with xenograft studies showing a significant reduction in tumor burden. These findings highlight the potential of rigosertib, especially when paired with PI3K inhibitors, to target the unique mutational landscape of ovarian cancer, offering a promising direction for more effective treatments."

Oncology • Ovarian Cancer • Solid Tumor

Understanding the mechanism of action of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma through single cellanalysis (AACR 2024) - "Of note a transient population of RDEB SCC keratinocytes only present after 1 hour of exposure to rigosertib was characterized by increased expression of the potassium regulator KCNRG which has previously been associated with apoptosis in chronic lymphocytic leukemia. Ongoing work is determining the role this gene may play in the mechanism of apoptosis induction in RDEB SCC keratinocytes after exposure to rigosertib."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Squamous Cell Carcinoma • PLK1

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Not yet recruiting | Sponsor: Prof. Johann Bauer

New P2 trial • Oncology • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer

Trial completion date • Trial primary completion date • Oncology • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer | Phase classification: P2 ➔ P1/2

Phase classification • Oncology • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer | Trial completion date: Jun 2023 ➔ Jun 2026 | Trial primary completion date: Dec 2022 ➔ Dec 2025

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer | Trial completion date: Jun 2022 ➔ Jun 2023 | Trial primary completion date: Dec 2021 ➔ Dec 2022

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer | Trial completion date: Jun 2021 ➔ Jun 2022 | Trial primary completion date: Dec 2020 ➔ Dec 2021

Trial completion date • Trial primary completion date • Oncology • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Prof. Johann Bauer | Not yet recruiting ➔ Recruiting | Initiation date: May 2019 ➔ Sep 2019

Enrollment open • Trial initiation date • Oncology • Squamous Cell Carcinoma

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P2 | N=12 | Not yet recruiting | Sponsor: Prof. Johann Bauer | Initiation date: Jan 2019 ➔ May 2019

Trial initiation date • Oncology • Squamous Cell Carcinoma

GPI inactivation mediates pentose phosphate pathway flux switch-on inducing temozolomide resistance in glioma stem cell. (PubMed, Cancer Lett) - "Targeting the ATM/PLK1/GPI axis through combinational treatment with rigosertib may therefore represent a therapeutic strategy. Moreover, PLK1 expression and GPI pT215 levels may serve as potential candidate markers for GBM. Collectively, activation of the ATM/PLK1/GPI axis plays a critical role in regulating PPP flux and TMZ resistance in GSCs."

Journal • Ataxia • Brain Cancer • Glioblastoma • Glioma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • GPI • PLK1

Rigosertib for RDEB-SCC (clinicaltrials.gov) - P1/2 | N=2 | Completed | Sponsor: Prof. Johann Bauer | Recruiting ➔ Completed | N=12 ➔ 2 | Trial completion date: Jun 2026 ➔ Dec 2025

Enrollment change • Trial completion • Trial completion date • Oncology • Squamous Cell Carcinoma

RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b+ Bregs thereby overcoming melanoma PD1-resistance. (PubMed, Nat Commun) - "Here, we show that combined treatment with a RAS/PI3K/AKT-pathway inhibitor rigosertib (RGS), and/or a MEK1/2 inhibitor trametinib (T), plus aCD40, overcomes the ICB resistance of BRAFwtNRASwt and BRAFwtNRASmut melanoma tumors growing in C57BL/6 mice. scRNA-Seq analyses confirm CD40-associated CD11b+ Bregs across cancer types in patients. Our data demonstrate that addition of RAS/PI3K/AKT and MEK inhibitors to aCD40 resolves the issue of aCD40 induction of CD11b+PD-L1+ Bregs and provides alternative therapeutic options for ICB-resistant BRAFwtNRASwt or BRAFwtNRASmut metastatic melanoma."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CD40 • CD8 • ITGAM • PD-1 • PD-L1

Landscape targeted of therapy in advanced pancreatic adenocarcinoma: a network meta-analysis of randomized controlled trials [2010-2024]. (PubMed, J Gastrointest Oncol) - "The SUCRA rankings identified gemcitabine plus nimotuzumab (Gem-Nimot; 98%) as having the highest probability of ranking first for OS, followed by gemcitabine plus masitinib (Gem-Masit; 80%), gemcitabine plus erlotinib (Gem-Erlot; 70%), and gemcitabine plus sorafenib (Gem-Soraf; 23%). For PFS, Gem-Nimot (98%) ranked highest, followed by Gem-Erlot (73%), gemcitabine plus rigosertib (Gem-Rigos; 57%), and gemcitabine plus sunitinib (Gem-Sunit; 8%). This NMA combining network and forest plot results showed that Gem-Nimot provided significant survival benefits in advanced PA. EGFR-targeted combinations demonstrated a significant advantage in both OS and PFS compared with gemcitabine alone, indicating that EGFR inhibition may provide real clinical benefits."

Journal • Retrospective data • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53