CC-115 / BMS - LARVOL DELTA

Pharmacological inhibitors of the nonsense-mediated RNA decay identified by high-throughput screening. (PubMed, RNA) - "CF patients carrying a nonsense mutation in the CFTR gene are insensitive to CFTR modulators and cannot benefit from the pharmacological therapy with Kaftrio®...At the end of the screening, we identified and validated by secondary assays three possible candidates acting as NMD inhibitors/modulators that could increase CFTR rescue in patients with PTCs, namely CC-115, samotolisib and elimusertib. The study also provides new insights into the changes occurring to cells transcriptome after the inhibition of the physiological NMD pathway, improving our knowledge of possible side effects of NMD inhibitors. This could help in the development of new compounds with more efficacy and less toxicity, that could be useful for the treatment of different genetic disorders caused by PTCs."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Integrating Metabolomics and Gut Microbiota to Reveal the Therapeutic Effect of Lonicerae japonicae Flos Against Respiratory Syncytial Virus. (PubMed, Metabolites) - "Moreover, correlation analysis revealed significant associations between key bacterial genera, including Gemella, Sutterella, and CC_115, and differential metabolites such as pyridoxamine, uridine monophosphate (UMP), and argininosuccinic acid. JYH may protect against RSV-induced pneumonia by restoring pulmonary metabolic homeostasis and modulating gut microbiota composition. These findings provide new insights into metabolite-microbiota interactions underlying the anti-RSV activity of JYH."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases • Respiratory Syncytial Virus Infections • IFNG • IL6

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma. (PubMed, Neuro Oncol) - "This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design."

Heterogeneity • IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2

Treatment Effect Reanalysis of the Randomized Individual Screening Trial of Innovative Glioblastoma Therapy in Newly Diagnosed Glioblastoma With External Control Data. (PubMed, J Clin Oncol) - P2 | "The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) (clinicaltrials.gov) - P2 | N=460 | Recruiting | Sponsor: Patrick Wen, MD | Trial completion date: Apr 2027 ➔ Apr 2028 | Trial primary completion date: Feb 2027 ➔ Feb 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IDH1

MET/PI3K/AKT Axis maintains SARS-CoV-2 Main protease stability and promotes viral replication (ERS 2025) - "CC115, an AKT inhibitor, exhibited outstanding anti-viral capacity in VeroE6 cells and K18-hACE2 transgenic mice without observable biological toxicity...Collectively, our findings reveal an endogenous "lactate clock" during SARS-CoV-2 infection regulating gene expression to promote viral propagation. This study also reveals a non- canonical role of AKT in SARS-CoV-2 replication and identifies a potential therapeutic target for SARS-CoV-2."

Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation

Homologous Repair-Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy. (PubMed, United European Gastroenterol J) - "Here, we demonstrate a remarkable potency of the PARPi talazoparib in HRD PDAC. Substituting olaparib, currently the only approved inhibitor in PDAC, with talazoparib in our PAD regimen enhanced its efficacy while maintaining comparable tolerability in vivo. Importantly, we show that PAD is an effective therapeutic regimen that can be extended to the most prevalent HR-defective genotypes in PDAC including ATM, BRCA1, BRCA2 and PALB2 in a preclinical setting. Collectively, these data provide a strong rationale to implement the refined regimen, talazoparib-based PAD, as a therapeutic concept tailored for HRD PDAC patients."

Journal • Breast Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • PALB2

The role of the tumour microenvironment in lung cancer and its therapeutic implications. (PubMed, Med Oncol) - "Promising results have been observed with mTOR inhibitors like CC-115 and Vistusertib, especially when combined with immune checkpoint inhibitors, and with JAK inhibitors such as Ruxolitinib, AZD4205, and Filgotinib. These strategies represent a promising direction for lung cancer therapy. This review explores the intricate relationship between the TME and lung cancer, focussing on novel therapeutic approaches that target immune cells, signalling molecules, and fibroblasts within the TME to improve patient outcomes."

Journal • Review • Lung Cancer • Oncology • Solid Tumor

Integrated Microbiome and Metabolomics Analysis Reveals Altered Aggressive Behaviors in Broiler Chickens Showing Different Tonic Immobility. (PubMed, Animals (Basel)) - "16S rDNA sequencing and Linear discriminant analysis effect size (LefSe) identified differential cecal bacterial abundance, notably in the genus cc115 belonging to Firmicutes...The distinct behavioral and physiological profiles observed in broilers with different TI phenotypes are strongly correlated with their specific gut microbiota and differential plasma metabolite profiles. The identified gut microbial signatures serve as key biomarkers for regulating aggressive behavior in broilers, while the differential plasma metabolites represent potential early indicators for detecting stress and behavioral issues in poultry farming."

Journal

Characterisation of Staphylococcus aureus Strains and Their Prophages That Carry Horse-Specific Leukocidin Genes lukP/Q. (PubMed, Toxins (Basel)) - "We examined the genomes, including the lukP/Q prophages, of S. aureus strains belonging to clonal complexes CC1, CC350, CC816, and CC8115. In addition to sequencing, phages were characterised by mitomycin C induction and transmission electron microscopy (TEM)...However, these prophages were different from the ones that carried lukP/Q, and three different integration sites of kinase-carrying phages were identified. These observations confirmed the presence of prophage-located important virulence-associated genes in equine S. aureus and that certain prophages might determine the host specificity of the staphylococcal strains they reside in."

Journal • Infectious Disease

protein kinase inhibitors as Targeted therapy for glioblastoma: A meta-analysis of randomized controlled clinical trials. (PubMed, Pharmacol Res) - "The standard treatment for newly diagnosed GBM includes surgical resection, when feasible, followed by radiotherapy and temozolomide-based chemotherapy. Upon disease progression, the anti-vascular endothelial growth factor-A (VEGF-A) monoclonal antibody bevacizumab, can be considered...For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95% CI, -2.12-0.55, p=0.25; -0.23 months, 95% CI, -0.79-0.34, p=0.43, respectively), and similar non-significant results were observed in the pooled analyses (OS: HR=0.89, 95% CI, 0.59-1.32, p=0.55; PFS: HR=0.83, 95% CI, 0.63-1.11, p=0.21). Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development."

Clinical • Journal • Retrospective data • Review • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

REFINED TARGETING OF DNA DAMAGE RESPONSE AS AN EFFECTIVE THERAPEUTIC STRATEGY FOR HOMOLOGOUS REPAIR-DEFICIENT PANCREATIC CANCER (UEGW 2024) - "Aims & Our previous preclinical work showed synthetic lethality of a multi-pronged DNA repair inhibition strategy using the PARPi olaparib, ATR inhibitor VE-822, and DNA-PK inhibitor CC-115 (termed PAD) in ATM deficiency1. Collectively, these data provide a strong rationale to implement the optimized regimen, talazoparib-based PAD, as a therapeutic concept tailored for the broad subgroup of HR-deficient PDAC patients."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • PALB2

Treatment of Non-Small Cell Lung Carcinoma (NSCLC) Cells with Tumor Treating Fields (TTFields) And DNA-Dependent Protein Kinase (PK) Inhibitors (IASLC-WCLC 2024) - "Nedisertib and CC-115 are potent inhibitors of DNA-PK, a main protein mediating the repair of DSBs through the NHEJ pathway. In addition, the lower effect of both drugs in H1299 cells compared to A549 cells may be explained, at least in part, by the fact that H1299 cells have an amplification mutation in PRKDC, the catalytic subunit of DNA-PK. Future studies will test whether treatment with TTFields plus DNA-PK inhibitors may sensitize cancer cells to irradiation, a treatment modality that induces DSBs."

Anemia • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRCA • PRKDC

Different Impacts of DNA-PK and mTOR Kinase Inhibitors in Combination with Ionizing Radiation on HNSCC and Normal Tissue Cells. (PubMed, Cells) - "Our study focused on the selective DNA-PK-inhibitor AZD7648; the selective mTOR-inhibitor Sapanisertib; and CC-115, a dual inhibitor targeting both mTOR and DNA-PK. However, the dual mTOR/DNA-PK-I CC-115 did not provide a distinct advantage over the use of selective KIs in our investigations, suggesting limited benefits for its application in KI + IR therapy. Notably, the selective mTOR-inhibitor Sapanisertib was only beneficial in HPV+ HNSCC and should not be applied in HPV- cases."

Combination therapy • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC). (PubMed, Br J Cancer) - P1b | "The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor."

Journal • Metastases • P1 data • Cardiovascular • Genito-urinary Cancer • Hypertension • Oncology • Prostate Cancer • Pruritus • Solid Tumor

Functional genomics identifies therapeutic vulnerabilities of glioma subtypes and YAP/TAZ-enriched tumors (SNO 2023) - "For example, mCancers enriched for the most aggressive mesenchymal (MES) and glycolytic/plurimetabolic (GPM) transcriptional subtypes exhibited stronger response to the BET inhibitor JQ1 (and other clinical BET inhibitors) and the DNA-PKcs/mTOR dual inhibitor CC-115. Overall, this study underscores the value of functional genomics in identifying novel vulnerabilities of HGGs and associated response biomarkers. It also highlights the need for further clinical validation of several novel therapies and especially drug combination strategies with strong efficacy in the ex vivo setting."

Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oligodendroglioma • Oncology • Solid Tumor

Application of the GBM-X Data Platform to estimate treatment effects of the experimental therapies of the randomized phase 2 Individualized Screening Trial of Innovative Glioblastoma Therapies (SNO 2023) - P2 | " INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma."

Clinical • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization. (PubMed, J Clin Oncol) - P2 | "The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial."

Journal • P2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • HER-2

CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway. (PubMed, J Cancer) - "Importantly, CC-115 significantly upregulated the expression of Bax and GSDME-N in a xenograft mouse model, with a reduction in tumor size. Our results revealed that CC-115 suppresses tumor growth by inducing GSDME-mediated pyroptosis through the Akt/Bax-mitochondrial intrinsic pathway, indicating CC-115 as a promising therapeutic agent for LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BAX • GSDME

ALLELE: A CONSORTIUM FOR PROSPECTIVE GENOMICS AND FUNCTIONAL DIAGNOSTICS TO GUIDE PATIENT CARE AND TRIAL ANALYSIS IN NEWLY-DIAGNOSED GLIOBLASTOMA (SNO 2018) - P2; "33 patients were enrolled in INSIGhT, a randomized platform adaptive trial comparing standard of care versus adjuvant CC-115, neratinib or abemaciclib in MGMT unmethylated newly diagnosed GBM (NCT02977780). Real-time WES, copy number arrays and functional diagnostics are feasible in newly diagnosed glioblastoma, and can support a variety of biomarker-driven trials. Genomic analyses conducted in a prospective manner can inform subsequent clinical trial analysis aiming at matching outcome with tumor genotyping."

Clinical • Brain Cancer • Oncology • Solid Tumor

Dietary coated essential oil and organic acid mixture supplementation improves health of broilers infected with avian pathogenic Escherichia coli. (PubMed, Anim Nutr) - "LEfSe analysis showed that Firmicutes, Ruminococcaceae, Clostridiales, Clostridia, Lactobacillus, Lactobacilaceae, and cc-115 were enriched in the non-infected but EOA-treated group (P < 0.05). Collectively, dietary EOA supplementation could mildly alleviate E. coli-induced gut injury and inflammation."

Journal • Immunology • Infectious Disease • Inflammation • IFNG • IL10 • IL12A • MUC2 • TJP1

Use of an Experimental Drug, CC-115, With Enzalutamide in Men With Castration-Resistant Prostate Cancer (clinicaltrials.gov) - P1b | N=40 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Jul 2023 ➔ Jan 2023 | Trial primary completion date: Jul 2023 ➔ Jan 2023

Trial completion • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells (DKK 2022) - " The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. In conclusion, we found that DDRi in combination with IR more effectively inhibits tumor growth of HNSCC compared to the single approaches and, most importantly, has a synergistic effect. The combina- tion seems not to affect normal tissue surrounding the tumor more than IR alone. Taken together, combined treatment has the potential to be a therapeutic option that could improve tumor control without increasing Toxicity."

Combination therapy • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

OncSaliva – a feasibility study with promising epigenetic biomarkers for improved detection of head and neck cancer in non-invasive specimen (DKK 2022) - " The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. In conclusion, we found that DDRi in combination with IR more effectively inhibits tumor growth of HNSCC compared to the single approaches and, most importantly, has a synergistic effect. The combination seems not to affect normal tissue surrounding the tumor more than IR alone. Taken together, combined treatment has the potential to be a therapeutic option that could improve tumor control without increasing toxicity."

Biomarker • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma. (PubMed, Mol Oncol) - "A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. Superior anti-tumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology