voxtalisib (SAR245409) / Sanofi, Exelixis - LARVOL DELTA

Convergent CDK4/6 and PI3K/mTOR pathway hyperactivation defines a targetable axis in osteosarcoma across RB1-proficient and RB1-deficient contexts (AACR 2026) - "We evaluated palbociclib, voxtalisib, and the combination across RB1+ and RB1- OS models, using cell lines, patient derived xenografts (PDXs), and an experimental metastasis model. In vivo validation studies are ongoing. These findings identify convergent CDK4/6–PI3K/mTOR hyperactivation as a targetable axis in OS and support further evaluation of CDK4/6i-based strategies, including in RB1-deficient disease."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CDK4 • CDKN2A • RB1

GARD: Genomic Data-Based Drug Repurposing in Head and Neck Cancer with Large Language Model Validation. (PubMed, Cancers (Basel)) - "Drug-gene mapping revealed candidates spanning those already in clinical trials for HNC (e.g., Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, and Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing...HPV stratification enhances precision, literature-based validation strengthens confidence, and integrated drug mapping enables refinement of existing therapies and discovery of novel candidates for personalized treatment strategies. Code Availability: The full implementation of the GARD pipeline, including preprocessing scripts, statistical analysis modules, and visualization tools, is publicly available on GitHub."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • CLDN1 • EGFR • EIF4G1 • HER-2 • PIK3CA • SOX2 • TLR7 • TP53

GARD: Genomic Data based Drug Repurposing in Head and Neck Cancer with Large Language Model Validation. (PubMed, bioRxiv) - "Drug-gene mapping revealed candidates spanning already in clinical trials for HNC (e.g. Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing...These included targeted therapies such as Fostamatinib, Nintedanib, Brigatinib, Regorafenib, and Lenvatinib, as well as emerging compounds like Artenimol, Quercetin, and Acetylsalicylic Acid (Aspirin). Through a combination of genomic analysis, network expansion, and literature validation, the GARD pipeline offers a powerful way to accelerate personalized cancer treatments while reducing cost and development time."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • CLDN1 • EGFR • EIF4G1 • HER-2 • PIK3CA • SOX2 • TLR7 • TP53

Dual CDK4/6-PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma. (PubMed, Neoplasia) - "In vitro sensitivity analyses using palbociclib and voxtalisib demonstrated additive to synergistic OS growth suppression, with palbociclib inducing G1 arrest and senescence, and the combination enhancing autophagy. In an OS lung-colonization model, CDK4/6 inhibition alone markedly reduced OS lung nodules, with combination therapy providing comparable suppression. Dual CDK4/6-PI3K/mTOR inhibition achieves tumor control across various OS models, supporting the use of genomically guided, pathway-targeted strategies for pediatric and AYA OS."

Journal • Preclinical • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor

Voxtalisib inhibits enterovirus 71 replication by downregulating host RAN and restoring IFN-STAT signaling. (PubMed, J Adv Res) - "RAN is a novel antiviral host target that indirectly mediates EV71 replication by regulating the nuclear-cytoplasmic transport of p-STAT1/2. Voxtalisib effectively restores IFN-STAT signaling by modulating RAN, offering a promising host-directed antiviral strategy against enteroviruses."

Journal • Infectious Disease • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis. (PubMed, J Breast Cancer) - "The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer."

Journal • Machine learning • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD8 • CDKN1A • CDKN1B • CDKN2B • ER • PGR

A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme (AACR 2024) - "The current standard of care, consisting of surgery, radiation, and temozolomide (TMZ), has remained unchanged for over the past 15 years despite its limited efficacy and the serious therapy-related adverse events associated to this regimen...To elucidate mechanisms of resistance to PI3K inhibition in GBM, we used a genome-wide functional CRISPR-Cas9 knockout screen to identify genes that mediate resistance to the dual PI3K/mTOR inhibitor XL765 in PTEN-null SF295 GBM cells...Using orthogonal approaches, we will functionally validate our candidate hits through mechanistic studies, with patient-derived models, and with in vivo orthotopic xenografts. Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PIK3CA • PIK3R1 • PTEN

Cancer associated fibroblast dependency in a model of bladder cancer (AACR 2024) - "These organoids were co-edited for Trp53 and Rb1 KO, and further editing of the Pten gene resulted in a nine-fold increase in sensitivity to the kinase inhibitor ipatasertib...While TSC1/TSC2 KO lines exhibited elevated P-S6K signaling, they displayed resistance to Torin 1, Voxtalisib, and Everolimus—kinase inhibitors targeting mTORC1/2. Our research establishes the crucial role of CAFs in bladder tumor formation. Our now established customizable model of bladder cancer is suitable for direct targeting by kinase inhibitors while providing a platform for understanding the genotype-phenotype relationship in bladder cancer."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • PIK3CA • PTEN • RB1 • TSC1 • TSC2

Inverse Impact of Cancer Drugs on Circular and Linear RNAs in Breast Cancer Cell Lines. (PubMed, Noncoding RNA) - "However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Osteosarcoma patient-derived xenografts derived from naive and pretreated metastatic patients with high-risk CDK4/6 hyperactivation signatures are sensitive to dual inhibition of CDK4/6 and PI3K/mTOR (AACR 2023) - "These data provide evidence that combination palbociclib+voxtalisib therapy is safe, efficacious, and increases CDK4/6i efficiency in both pretreated and naive PDX models of OS. These studies provide rationale for earlier therapeutic intervention in pediatric and AYA OS patients with CDK4/6 hyperactivation signatures."

Clinical • Metastases • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CCND3 • CDK1 • CDK4 • CDKN2A • PIK3CA

Integrative genomic analysis facilitates precision strategies for glioblastoma treatment. (PubMed, iScience) - "NVP-BEZ235, GDC-0980, dasatinib and XL765 were ultimately identified to have subclass-specific efficacy targeting patients with a high risk of poor prognosis. Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Voxtalisib and low intensity pulsed ultrasound combinatorial effect on glioblastoma multiforme cancer stem cells via PI3K/AKT/mTOR. (PubMed, Pathol Res Pract) - "The combination of Vox+LIPUS has increased drug effectiveness in targeted GBM and GBMCSCs. Combinatory treatment with PI3K/AKT/mTOR signaling pathway and LIPUS has been thought to help develop more effective therapeutic approaches for GBM."

Cancer stem cells • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

TARGETING PI3K/MTOR MITIGATES RESISTANCE TO CDK4/6 INHIBITION IN RB-PROFICIENT PEDIATRIC AND AYA OSTEOSARCOMAS (CTOS 2022) - "Once tumor volumes reached ~100mm3, mice were randomized and based on dose-finding studies treated with 5-day cycles of daily treatment with the CDK4/6 inhibitor palbociclib (50 mg/kg) +/- the dual PI3K/mTOR inhibitor voxtalisib (50 mg/kg) for 6-8 weeks. This study is of great significance for it provides strong rationale for earlier therapeutic intervention with a combination therapy targeting CDK4/6 and PI3K/mTOR pathways in a subset of OS patients with CDK4/6 hyperactivation. This therapeutic strategy has the potential to minimize disease burden and enhance quality of life in both the un-pretreated and the pre-treated clinical setting."

Clinical • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • AXL • CCND3 • CDK1 • PIK3C3 • RB1

UPLC-MS/MS Technology for the Quantitative Methodology and Pharmacokinetic Analysis of Voxtalisib in Rat Plasma. (PubMed, Front Pharmacol) - "Voxtalisib, is a specific, effective, and reversible dual inhibitor, which inhibits both pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). Finally, the pharmacokinetic profile of the analyte had been availably studied by the UPLC-MS/MS bio-analytical method after rats were treated by intragastric administration with voxtalisib (5 mg/kg). The results indicated that the UPLC-MS/MS technology can effectively and quickly quantify the analyte, and this method can also be used for the pharmacokinetic study of voxtalisib, which can provide reference for the optimization of clinical drug management in the later period."

Journal • PK/PD data • Preclinical • Brain Cancer • Breast Cancer • Glioblastoma • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor • mTOR

β-Carotene Attenuates Apoptosis and Autophagy via PI3K/AKT/mTOR Signaling Pathway in Necrotizing Enterocolitis Model Cells IEC-6. (PubMed, Evid Based Complement Alternat Med) - "Interestingly, these changes induced by β-carotene were partially reversed by rapamycin and voxtalisib. In conclusion, our findings indicated that β-carotene can attenuate apoptosis and autophagy of IEC-6 cells induced by LPS via activating the PI3K/AKT/mTOR signaling pathway. Therefore, β-carotene may be a promising drug used in the clinical treatment of NEC."

IO biomarker • Journal • Gastrointestinal Disorder • ANXA5 • BCL2 • CASP3

Targeting CDK4/6 inhibitor resistance in relapsed RB-proficient osteosarcoma patient-derived xenografts via PI3 Kinase/mTOR inhibition (AACR 2022) - "Combination index and Bliss independence analyses indicated that inhibition of OS growth by exposure to CDK4/6i (Palbociclib or Abemaciclib) and PI3K/mTOR inhibitor (PI3K/mTORi-Voxtalisib or LY3023414) was additive-to-synergistic and lead to increased apoptosis at clinically relevant concentrations. Notably, Palbociclib + Voxtalisib was more efficacious than single-agent (p<0.05, Two-way ANOVA; Holm-Sidak). These data highlight the need to optimize CDK4/6i+PI3K/mTORi dosing schedules and provide evidence that Palbociclib + Voxtalisib therapy is safe, efficacious, and can decrease CDK4/6i resistance in aggressive PDX models of OS."

Clinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • AXL • CCND3 • CDK1 • PIK3C3 • RB1

SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma (AACR 2022) - "SPR965 was more active at 1uM than PI3K/mTOR inhibitors VS-5584, Bimiralisib, PF-04691502, WYE-687, Dactolisib, and Voxtalisib in the Kinase Chemogenomic Set. In SF8894 PDX model SPR965 was more efficacious as it produced similar tumor growth inhibition at 12- and 17-fold lower dose than Buparlisib (PI3K) and Palbociclib (CDK4/6) respectively, both these compounds are in phase 2 clinical trials. In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity."

Late-breaking abstract • Chordoma • Oncology

UC.183, UC.110, and UC.84 Ultra-Conserved RNAs Are Mutually Exclusive with miR-221 and Are Engaged in the Cell Cycle Circuitry in Breast Cancer Cell Lines. (PubMed, Genes (Basel)) - "Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CDKN1B • MIR221

Is voxtalisib effective in cancers other than follicular lymphoma? (Rare Disease Report) - P2, N=167; NCT01403636; "Among 46 patients with FL, the overall response rate was 41.3%, including 5 (10.9%) complete responses...Efficacy was limited against aggressive malignancies, as the study reported the following ORR rates in MCL, DLBCL, and CLL/SLL: 11.9%, 4.9%, and 11.4%. The most frequently reported adverse events (AEs) were diarrhea in 59 (35% of all 167 patients, fatigue in 53 (32%), nausea in 45 (27%), pyrexia in 44 (26%), cough in 40 (24%), and decreased appetite in 35 (21%)."

P2 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization. (PubMed, Front Immunol) - "Furthermore, a in silico screening of druggable targets and compounds from CTRP and PRISM databases was performed, resulting in the identification of five target genes (HMMR, CCNB1, CDC25C, AURKA, and CENPE) and five agents (oligomycin A, panobinostat, (+)-JQ1, voxtalisib, and arcyriaflavin A), which might have therapeutic potential in treating high-risk breast cancer patients. Further in vitro evaluation confirmed that (+)-JQ1 had the best cancer cell selectivity and exerted its anti-breast cancer activity through CENPE. In conclusion, our study provided new insights into personalized prognostication and may inspire the integration of risk stratification and precision therapy."

Epigenetic controller • Journal • Preclinical • Breast Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • AURKA • CCNB1 • CDC25C • GNRP

[VIRTUAL] Targeting CDK4/6 inhibitor resistance in relapsed osteosarcoma via PI3 Kinase inhibition (AACR 2021) - "Cell growth response to CDK4/6i (Palbociclib or Abemaciclib) and a PI3K/mTOR inhibitor (PI3K/mTORi, Voxtalisib) was evaluated in RB+ OS cell lines and an RB+ patient-derived xenograft (PDX)-derived xenoline (TT2-77). However, tumors progressed over time while still on treatment; evaluation of PI3K pathway activation is in progress. These data provide an opportunity to evaluate efficacy of targeting CDK4/6i-induced compensatory pathways in relapsed pediatric and AYA OS."

Eye Cancer • Oncology • Osteosarcoma • Retinoblastoma • Sarcoma • Solid Tumor • CDK1 • RB1

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1; N=259; Completed; Sponsor: EMD Serono; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRAF • EGFR • GNA11 • GNAQ • HER-2 • KIT • KRAS • NRAS • PTEN

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1; N=146; Completed; Sponsor: EMD Serono; N=259 ➔ 146

Clinical • Combination therapy • Enrollment change • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRAF • EGFR • GNA11 • GNAQ • HER-2 • KIT • KRAS • NRAS • PTEN

Study of XL147 (SAR245408) or XL765 (SAR245409) in Combination With Letrozole in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2; N=72; Completed; Sponsor: Sanofi; N=99 ➔ 72

Clinical • Combination therapy • Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1; N=170; Active, not recruiting; Sponsor: EMD Serono; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRAF • EGFR • GNA11 • GNAQ • HER-2 • KIT • KRAS • NRAS • PTEN