buparlisib (AN2025) / Novartis, Adlai Nortye, Nippon Kayaku - LARVOL DELTA

High event-free (EFS) and overall survival (OS) after non-total body irradiation (TBI) conditioning and allogeneic hematopoietic cell transplantation (HCT) in next-generation-sequencing minimal residual disease (NGS-MRD) negative B-acute lymphoblastic leukemia (B-ALL): Results from the EndRAD trial (PTCTC ONC1701) (ASH 2025) - P2 | "Based upon retrospectivedata showing low rates of relapse, we hypothesized that patients with negative pre-HCT MRD by next-generation-sequencing of IgH B-cell receptor rearrangements (NGS-MRD) could achieve 2-year EFSexceeding 75% with a non-TBI regimen, an outcome comparable to those receiving TBI-based regimens. The Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) conducted a phase IIprospective trial at 45 Centers in North America (ONC1701 EndRAD: NCT03509961) between 2018 and2025 to evaluate outcomes of myeloablative non-TBI conditioning regimens for allogeneic HCT in B-ALLpatients at lower risk for relapse defined by absence of NGS-MRD (Clonoseq) of B-cell receptorrearrangements (BCR) just prior to HCT...Mismatched related/haploidentical grafts received post-transplant cyclophosphamide orTCRαβ/CD19 depletion according to institutional preference...Of patientsenrolled, 33% were White/Non-Hispanic, 37% Hispanic, 12% Black or African American, and..."

Biomarker • Clinical • IO biomarker • Minimal residual disease • Next-generation sequencing • Residual disease • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • CNS Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Transplantation

Retraction Note: Buparlisib induces eukaryotic elongation factor-2 expression to cause treatment failure for lung cancer cells. (PubMed, Mol Genet Genomics) - No abstract available

Journal • Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor

Targeting MCL-1 Overcomes Adaptive Resistance to PI3K Inhibition in Thymic Carcinoma (IASLC-WCLC 2026) - "Pharmacologic MCL-1 inhibition with S63845 further enhanced the antitumor effect of buparlisib, resulting in greater growth suppression and increased apoptosis compared with either monotherapy alone. Dual targeting of PI3K and MCL-1 restored apoptotic sensitivity and produced synergistic antitumor effects in human TC models. These findings support combined PI3K and MCL-1 inhibition as a promising therapeutic strategy for overcoming treatment resistance in a subset of patients with TC."

Mantle Cell Lymphoma • Oncology • Solid Tumor • Thymic Carcinoma • Thymus Cancer

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck. (PubMed, Clin Cancer Res) - "Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset."

Biomarker • Journal • P1 data • Head and Neck Cancer • Oncology • Otorhinolaryngology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TNFA

BURAN: A phase III study of buparlisib (BUP) plus paclitaxel (PAC) in patients with PD-1(PD-L1)-pretreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) (ESMO 2025) - P3 | "Notably, the control arm (PAC alone) demonstrated a longer OS than historically observed in the phase II BERIL-1 trial (median 6.5 mos), potentially contributing to the outcome. Subgroup analyses will be presented at the meeting."

Clinical • Late-breaking abstract • Metastases • P3 data • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Pathway to Chordoma Treatment: A Review on CDKN2A and Therapeutic Targeting. (PubMed, Cancers (Basel)) - "Preclinical studies in CDKN2A-deficient chordoma cell lines and patient-derived xenografts demonstrated sensitivity to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including palbociclib, flavopiridol, and abemaciclib. Combination strategies pairing palbociclib with buparlisib or rapamycin produced greater antitumor effects, particularly in p16^INK4A- and PTEN-deficient models...Preclinical data support CDK4/6 inhibition, particularly in biomarker-selected CDKN2A-deficient tumors, and suggest that combination approaches targeting complementary pathways such as PI3K/mTOR may further enhance therapeutic efficacy. Together, these findings support the clinical relevance of CDKN2A as both a prognostic biomarker and a promising therapeutic target in chordoma."

Journal • Review • Chordoma • Eye Cancer • Oncology • Osteosarcoma • Retinal Disorders • Solid Tumor • CDKN2A • PTEN

Perioperative safety and long-term outcomes of mesh repair in nonagenarians undergoing elective inguinal hernia repair: a single-center retrospective study. (PubMed, Hernia) - "In clinically selected nonagenarians undergoing elective inguinal hernia repair, mesh repair showed acceptable perioperative safety and favorable long-term local outcomes. Preoperative functional status, rather than chronological age alone, should be emphasized in surgical decision-making."

Journal • Retrospective data • Gastroenterology • Pain

Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer. (PubMed, Drugs) - "Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population...Future directions include rational combination strategies, improved biomarker-driven selection, and novel..."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • AKT1 • HER-2 • PIK3CA • PTEN

Modular in vitro evaluation of buparlisib-polymeric nanomedicines in 2D and 3D models of glioblastoma. (PubMed, Front Toxicol) - "Overall, linker chemistry, cell-line-specific behaviour, and model dimensionality strongly influenced the biological performance of the polymeric buparlisib formulations. The redox-sensitive polymer conjugate therefore represents the more promising strategy for further development."

Journal • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Benefits and challenges of adding BKM120 to a BI-3406 plus trametinib combination therapy. (PubMed, BMC Cancer) - "The addition of BKM120 to the combination of BI-3406 and trametinib provides minimal therapeutic benefit while introducing significant adverse effects, underscoring the need for caution when considering clinical applications."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • CDKN2A • KRAS • PD-L1

Spatial Biomarker Deep Learning Model Predicts Response to PI3K Inhibition in Head and Neck Cancer. (PubMed, Cancers (Basel)) - "Background: Buparlisib, combined with paclitaxel, improved survival in BERIL-1 trial patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). AI-extracted spatial features from H&E slides were associated with overall survival benefit from buparlisib in R/M HNSCC. These scalable biomarkers support image-based patient selection strategies and are being prospectively evaluated in the BURAN phase 3 trial."

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

Reconstructive Surgery for Ureteral Strictures in Renal Transplant Patients: A Comparative Analysis Between Robotic and Open Surgery (ATC 2026) - "This study aims tocompare the efficacy and safety of robotic surgery versus conventional open surgery in the management of post-transplant ureteralstrictures.* This was a single-center retrospective study of patients who underwent surgery for post-KT ureteral stricture between 2000 and2025, either by open or robotic approach... Robotic surgery appears to be a safe and effective option for the treatment of post-KT ureteral strictures. Compared with opensurgery, it is associated with a lower rate of major complications while achieving equivalent functional and recurrence outcomes.These results support the progressive integration of this technique as a first-line approach in experienced centers.Comparative outcomes between open and robotic surgeryOutcomeOpen (95% CI)Robotic (95% CI)p-valueClavien ≥ III (%)30.7% (18.2–47.0)9.8% (3.5–24.5)0.03Recurrence (%)12.1% (5.2–25.5)7.6% (2.4–21.8)0.41Postoperative eGFR (ml/min)46.6 (41.3–52.0)41.6 (35.2–48.1)0.20Postoperative..."

Clinical • Surgery • Transplantation

SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy. (PubMed, J Med Chem) - "Combining SDUY104 with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Efficacy of buparlisib according to PIK3CA mutation status in recurrent or metastatic head and neck squamous cell carcinoma: A multicenter phase II trial. (PubMed, Oral Oncol) - "Although the trial met the primary endpoint, buparlisib monotherapy was associated with unacceptable toxicity and showed limited efficacy in heavily pretreated HNSCC patients."

Journal • P2 data • CNS Disorders • Depression • Dermatitis • Dermatology • Diabetes • Head and Neck Cancer • Immunology • Oncology • Psychiatry • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Discovery and development of a novel PI3K-CDK4/6 dual inhibitor PC-13 for the treatment of breast cancer (AACR 2026) - "Breast cancer continues to be a major cause of cancer-associated mortality globally, underscoring the urgent need for innovative therapeutic strategies. Furthermore, PC-13 exhibits reasonable pharmacokinetic properties and achieves significant tumor growth suppression in a T47D xenograft model, with efficacy comparable to the Palbociclib-Buparlisib combination regimen, while maintaining a promising safety profile. Our findings highlight the potential of concurrent PI3K and CDK4/6 inhibition as a novel and effective therapeutic approach for breast cancer, supporting further development of PC-13 as a clinical candidate."

Breast Cancer • Oncology • Solid Tumor

Multitargeted kinase inhibitor LCI139 overcomes chemotherapy resistance in patient-derived non small cell lung cancer organoids by harnessing intrinsic and extrinsic apoptosis (AACR 2026) - "Treatments included LCI139 (0.25-1μM), chemotherapeutics (carboplatin, gemcitabine, pemetrexed, cisplatin), and single-agent inhibitors: PI3K (Buparlisib), CDK4/6 (Ribociclib), CDK9 (AZD4573), AURKA (Barasertib), AURKB (Alisertib). LCI139 demonstrates superior anti-tumor activity versus standard chemotherapeutics in resistant NSCLC through dual activation of intrinsic (cell cycle arrest-induced) and extrinsic (metabolic stress-induced) apoptotic pathways. Efficacy in both cell lines and PTOs validates this micro-physiological platform for drug development, supporting translational potential of multitargeted kinase inhibition for overcoming therapeutic resistance, as aligned with FDA guidance."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • AURKA • AURKB • CASP3 • CASP8 • CASP9 • CDK4 • CDK9

Prognostic Stratification and Subtyping of Glioblastoma Using Transient Receptor Potential Channels. (PubMed, Hum Mutat) - "High TRPRS was associated with diminished cytotoxic T-cell infiltration and predicted resistance to multiple therapeutics-including cisplatin, carmustine, gefitinib, buparlisib, and afatinib. Functional assays demonstrated that IFNGR2 knockdown suppressed glioma cell proliferation and attenuated NF-κB signaling, underscoring its role as a key driver within the TRP network. TRPRS provides a robust, biologically grounded tool for simultaneous prognostication and therapy guidance in GBM, highlighting TRP signaling as a therapeutic vulnerability."

Biomarker • IO biomarker • Journal • Bladder Cancer • Brain Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • IFNAR2 • PTEN • TP53

Targeting the CCL5/CCR5-PI3K-AKT axis suppresses hepatic stellate cell-induced breast cancer metastasis. (PubMed, Cancer Cell Int) - No abstract available

Journal • Breast Cancer • Oncology • Solid Tumor

PIKHER2: Safety and Efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=24 | Terminated | Sponsor: Institut Paoli-Calmettes | N=106 ➔ 24 | Suspended ➔ Terminated; Drug development withdrawn

Enrollment change • Trial termination • Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Copy number variation in Sonic hedgehog-medulloblastoma with unique p53 mutations: Inhibition of PI3K/AKT/mTOR pathways with HDAC inhibitors can serve as therapeutic options (AACR 2026) - "Effects of small molecule inhibitors targeting PI3K (Buparlisib; BKM-120) and HDAC (LBH-589) in SHH-MB cells (Daoy), were assessed via functional assays, such as cell proliferation, migration, cell cycle, and drug resistance. Furthermore, small molecule PI3K and HDAC inhibitors suppressed PI3K/AKT/mTOR pathways inhibiting cell proliferation, migration, and tumor formation. These studies provide evidence of genomic anomalies as well as treatment options for SHH-MB."

P53mut • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • IDH2 • KRAS • PTEN • TP53

A novel class of multitarget small molecule PI3K-CDK4/6-CDK9-AURAKA/B inhibitor harnesses Warburg effect against non-small cell lung cancer (AACR 2025) - "Here, we describe how LCI139 harnesses the Warburg effect to induce synthetic lethality in NSCLC. LCI139-sensitive (NCI-H1703) and resistant (NCI-H1781) human NSCLC cells, identified from prior IC50 experiments, were treated with LCI139 (0.25 and 0.5μM) or single agent inhibitors PI3Ki (BKM120), CDK4/6i (Ribociclib), CDK9i (AZD4573), and AURKAi (Alisertib). Multitarget inhibitor, LCI139 is uniquely designed to harness the Warburg effect to induce synthetic lethality in glycolysis-reliant NSCLC by 1) inducing metabolic stress (pAMPK), 2) lowering the threshold to metabolic stress response (FoxO3 stabilization), and 3) enhancing caspase-dependent cell death non-canonical Cas8 activation."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • BCL2L11 • CDK9 • SLC2A1

SF2523, a dual PI3K-BRD4 inhibitor, enhances KRAS (G12C) or EGFR (exon 19/21) mutant targeted inhibitors in non-small-cell lung cancer (NSCLC) (AACR 2025) - "Sotorasib and Adagrasib are a second line therapy for KRAS G12C mutant NSCLC...SF2523 IC50 in EGFR mutated NSCLC cells ranged from 90-230nM, while in KRAS mutated NSCLC cells ranged from 144-217nM versus Buparlisib plus JQ1 in the μM range...In contrast, combinations of SF2523 plus Nindetinib (VEGFR inhibitor) or Rapamycin (mTOR inhibitor) were additive in potency with EGFR and KRAS mutant NSCLC cell lines...In a SCID H2030 KRAS G12C mouse xenograft model, SF2523 at a dose of 150 mg/kg was well tolerated without weight loss with tumor growth inhibition of >60% at 6 weeks. In conclusion, our results demonstrate SF2523 is active alone and is synergistic with Osimertinib or Sotorasib in inhibiting EGFR or KRAS mutant NSCLC cell lines and is active as a single agent in a KRAS G12C mutated H2030 CDX NSCLC mouse model."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKT1 • BRD4 • EGFR • KRAS • MYC • PIK3CA • PTEN

Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for in vitro evaluation of targeted therapeutic efficacy (AACR 2025) - "Therapeutic susceptibility of the established Oncopig WT, PTENKO, AXIN1KO, and ARID1KO HCC cell lines was assessed for PI3K inhibitors (GSK2636771, BAY 80-6946, and BKM120). These results validate the utility of the Oncopig HCC model for preclinical evaluation of novel targeted therapeutics in vitro. Future work demonstrating consistent results in vivo will enable the genetically defined Oncopig HCC model to be an ideal animal system to test precision medicine therapeutics prior to entry into the clinic.Therapeutic Susceptibility (Log IC50 (µM))PI3K InhibitorOncopig WT HCCOncopig AXIN1KO HCCOncopig ARID1KO HCCOncopig PTENKO HCCHuman PTEN Null CellsGSK26367711.461.170.660.07ResponsiveBAY80-694611.55.64.52.38ResponsiveBKM1202.050.95NA2.3Non-Responsive"

Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • ARID1A • KRAS • PTEN

OKI-219 is an inhibitor of PI3Kα H1047R that has brain penetrance and anti-tumor activity in a preclinical intracranial model of metastatic breast cancer (AACR 2024) - "The FDA-approved PI3K inhibitor alpelisib lacks CNS activity, and brain-penetrant alternatives such as buparlisib and paxalasib were not approved due to toxicity associated with a lack of mutant selectivity. Here we show that OKI-219 had consistently good brain penetrance across multiple species by multiple methods of measuring free drug levels in the brain. We further demonstrated that OKI-219 had anti-tumor activity against xxT47D-luc tumors in an intracranial mouse model that is similar to activity in the same tumor when implanted subcutaneously, demonstrating that the brain levels achieved were pharmacologically active. These data indicate the potential for activity of OKI-219 in CNS disease settings, including metastatic brain cancer, which are not currently addressed with existing PI3K pathway inhibitors."

Late-breaking abstract • Metastases • Preclinical • Brain Cancer • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

NF1 mutations in lung adenocarcinoma preclinical models and potential targeted therapies: The crucial role of the RAS-MAPK pathway (AACR 2025) - "No sensitivity was observed in these models when treated with the mTOR inhibitor AZD8055 or the PI3K inhibitor Buparlisib alone. We then performed in vivo pharmacological tests on the LUAD PDX: Trametinib alone and in combination with Buparlisib resulted in significant tumor volume reductions of 72% and 84%, respectively. Collectively, these findings establish a promising possible efficacy of MEK inhibitors for LUAD patients with NF1 homozygous mutation."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • NF1