navitoclax (ABT 263) / AbbVie - LARVOL DELTA

An evolving landscape – how changing conditioning regimes can improve myelofibrosis transplant outcomes. (ASH 2025) - "Of the 16 cases, seven received Fludarabine/Busulphan/Antithymocyte globulin (Flu/Bu/ATG) conditioning (Fludarabine 30mg/m 2 day -9 to day -5, Busulphan 3.2mg/kg on day -4 and day -3 and rabbit ATG 2.5mg/kg on day -2 and day -1), seven underwent Fludarabine/Cyclophosphamide (Flu/Cy) conditioning (Fludarabine 25mg/m 2 day -6 to day -2 and Cyclophosphamide 1g/m 2 on day -3 and day -2), and two received Fludarabine/Melphalan (Flu/Mel) (Fludarabine 25mg/m 2 day -6 to day -2 and Melphalan 100mg/m 2 on day -2)...Therapies included Ruxolitnib, Momelotinib, splenic irradiation, Hydroxycarbamide, Danazol, Interferon, Cyclophosphamide, Anagrelide, Thalidomide, Panobinostat and Navitoclax...Although limited by a small sample size, these findings indicate that the Flu/Bu/ATG conditioning regimen may be associated with improved outcomes, thereby supporting its adoption as the preferred approach for patients undergoing allogeneic stem cell transplantation for myelofibrosis as per BSH..."

Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Infectious Disease • Myelofibrosis • Pneumonia • Respiratory Diseases • Transplantation • ASXL1 • CALR • JAK2 • SF3B1 • U2AF1

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

Cladribine-based regimens for Relapsed/Refractory Acute Myeloid Leukemia – a real-world multicenter retrospective study (ASH 2025) - "The majority of patients were priorly exposed to venetoclax and azacitidine (87% and 77%, respectively) and 60% had prior allogeneic hematopoietic stem cell transplantation (AHSCT)...The majority (83%) received Clad-LDAC-Ven triplet, one patient received navitoclax as well, one patient received Clad-Ven with decitabine and three patients received Clad-Ven with intermediate-dose cytarabine... This real-world analysis, conducted in a predominantly elderly with R/R AML, suggests that the Clad-Ven-based regimen may offer transient disease control, primarily in patients who subsequently received either HCT or donor lymphocyte infusions. While the regimen may serve as a potential bridging strategy, its overall efficacy appears limited in the absence of consolidative immunotherapeutic interventions and is associated with significant infectious toxicity."

IO biomarker • Real-world • Real-world evidence • Retrospective data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Neutropenia • Septic Shock • IDH1 • MECOM • NPM1 • TP53

Trial in progress: A Phase I/II study to investigate the combination of LP-118, ponatinib, vincristine and dexamethasone (LPVd regimen) in relapsed/refractory T-ALL/lbl (ASH 2025) - P1/2 | "A previousphase 1b/2 study of venetoclax, navitoclax and chemotherapy in R/R T-ALL showed 50% CR rate.Therefore, we anticipate a CR rate of 30% in our study, which combines LP-118 with similarchemotherapy backbone. We will include 6 patients from phase 1 portion in our efficacy analysis.Several correlative studies are planned to identify biomarkers of response and resistance, including BH3profiling, molecular genetic profiling (DNA- and RNA-seq), and pre-TCR signaling activity in baseline vsrelapse samples. This investigator-initiated trial is funded by the Leukemia Lymphoma Society AcademicClinical Trials grant."

IO biomarker • P1/2 data • Acute Lymphocytic Leukemia • Anorexia • Constipation • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Rare Diseases • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1 • TRB

Relapsed acute lymphoblastic leukemia treated with venetoclax and navitoclax: Results of the raven study in children and young adults with relapsed/ refractory ALL (ASH 2025) - P1 | "Notably, many T-ALL are more sensitive to navitoclax than venetoclax.The recommended phase 2 dose (RP2D) of venetoclax and navitoclax in combination with 3-drugreinduction chemotherapy (vincristine, asparaginase, and dexamethasone) has been established. Thiscombination showed acceptable tolerability and promising activity, with 6 of 12 treated childrenachieving minimal residual disease (MRD)-negative remission in prior studies.To further evaluate this approach, we conducted a multicenter phase I/II trial (NCT03194932) ofvenetoclax (240mg/m2/day, max 400mg) and navitoclax (25mg [20 to <45kg] or 50mg [≥45kg]) incombination with 3-drug reinduction chemotherapy in children and young adults with rALL/LLy (block 1).Patients who tolerated block 1 therapy could receive block 2 therapy, which included 2 discrete rolling-6phase 1 arms: arm A, containing high-dose cytarabine, dexamethasone, asparaginase, venetoclax, andnavitoclax; and arm B, combining blinatumomab and..."

Clinical • Acute Lymphocytic Leukemia • CNS Disorders • Infectious Disease • Lymphoblastic Lymphoma • Lymphoma • Septic Shock • T Acute Lymphoblastic Leukemia • BCL2L1

Regulation of ribosomal RNA synthesis in Acute Myeloid Leukemia (ASH 2025) - "Furthermore, dTAGtreatment synergized with the Bcl-2 inhibitors venetoclax and navitoclax to induce apoptosis in the Pol1-degron cells. This synergy did not extend to standard AML chemotherapy agents (daunorubicin orcytarabine), indicating that there is a unique, synthetically lethal interaction between rRNA synthesis andthe Bcl-2 signaling pathway in AML cells.In summary, we show that rRNA synthesis is progressively downregulated during normal hematopoieticdifferentiation but aberrantly amplified in AML cells to support an oncogenic, stem-like state, allowingthem to resist apoptotic stimuli and proliferate indefinitely. Notably, our findings highlight rRNA synthesisas a targetable vulnerability in AML, especially when combined with Bcl-2 inhibition."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • HOXA9 • KIT

Multiomics-guided ex vivo drug sensitivity testing in Relapsed/Refractory Acute Myeloid Leukemia (ASH 2025) - "DNMT3A mutation suggested response tonavitoclax and KPT-330 (OR 8.4, p=0.18; OR 4.2, p=0.5, respectively). Associations were also foundbetween FLT3 mutation or short relapse latency among navitoclax responders (OR 4.2, p=0.5; eachrespectively).FLT3 mutants were associated with ponatinib sensitivity which was linked to FGFR3/FGFR4 upregulationin responders (OR 4.2, p=0.5). Furthermore, samples of patients who relapsed quickly were sensitive toeprenetapopt, wherein responders had upregulation of target gene MDM2 (OR 2.7, p=0.6). All patientsamples were highly sensitive to Panobinostat...Crucially, this proof-of-concept results supports a precision-medicine framework combininggenomic insights with functional drug screening, might offer actionable options for a patient group that isotherwise limited to supportive care alone. Further validation in larger cohorts of specific targets andtranslating and repurposing drugs post exvivo DS through potential clinical trials are ongoing."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2L1 • DNMT3A • FGFR3 • FGFR4 • FLT3 • IDH2 • MDM2 • MIR15A • MIR182

Apoptotic rewiring via PI3K hyperactivation as a therapeutic strategy in B-cell malignancies (ASH 2025) - "Averaging across all testedcell lines, the highest Zero Interaction Potency (ZIP) synergy scores were 44.43 (MCL; n=5) and 34.66 (B-ALL; n=3) for venetoclax, and 35.51 (MCL; n=3) and 33.92 (B-ALL; n=3) for navitoclax combinations...Notably, in MCL cell lines, the SF1670 and venetoclaxcombination exhibited greater synergy than the established combination of the BTK inhibitor ibrutiniband venetoclax (ZIP score: 30.62; n=4)... PI3K hyperactivation via deletion or pharmacological inhibition of PTEN rewires theapoptotic landscape of B-cell malignancies towards BCL2 dependence. Consistent with this shift,combined PTEN and BCL2 inhibition elicits strong synergy, resensitizes venetoclax-resistant cells, anddefines a mechanistic basis for a highly effective therapeutic strategy."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • BCL2L1 • CASP3 • MCL1

Protein degradation of MYC/GSPT1 is a novel treatment modality for aggressive T-cell acute lymphoblastic leukemias (ASH 2025) - "Indeed, ABT-263, a BCL-2/BCL-XL inhibitor, incombination with GT19715 induced synergistic cell death. MYC/GSPT1 protein degradation is highly active in T-ALL cells in vitro, with substantial reduction of MYCand GSPT1, leading to disruption of nascent protein synthesis. GT19715 profoundly extended survival ofmice carrying PDX T-ALL cells by 680%. Persistent T-ALL cells showed sustained BCL-XL levels andcombinatorial inhibition of BCL-XL with MYC/GSPT1 protein degradation synergistically induced celldeath."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • ANXA5 • BCL2 • BCL2L1 • CD1a • CD2 • CD33 • CD34 • CD5 • CD7 • CD8 • GSPT1 • HOXA9 • NOTCH1 • PTPRC

A combination strategy of inotuzumab ozogamicin (InO) and BCL-2 family inhibitors prevents the emergence of PGP+ ino-resistant MRD in B-cell acute lymphoblastic leukemia (ASH 2025) - "Venetoclax (VEN) and navitoclax, not S63845(Mcl1 inhibitor) synergized with InO to enhance the killing of ALL cells. While InO therapy achieves high remission rates, it may induce the emergence of InO-R/Pgp+ALL cells as residual disease. Combination therapy with InO and Bcl-2 family inhibitors may effectivelysuppress the emergence of these InO-resistant clones, thereby prolonging remission duration."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • ABCB1 • CD22

Proteasome inhibition as a potential therapeutic target in thymic cancer. (PubMed, Cell Death Dis) - "Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics."

IO biomarker • Journal • Oncology • Solid Tumor • Squamous Cell Carcinoma • Thymic Carcinoma • Thymic Epithelial Tumor • Thymoma • Thymus Cancer • BCL2 • PSMB10 • PSMB5 • PSMB8 • PSMB9

Identifying metabolic vulnerabilities of recurrent IDH1-R132H mutant glioma by high throughput screening (SNO 2025) - "Notable target pathways include folate metabolism and de novo thymidylate synthesis (methotrexate, raltitrexed, 5-FU), p97 AAA ATPase/VCP chaperone (CB-5083, ML240, eeyarestatin I), mevalonate pathway (Ro 48-8071 fumarate, atorvastatin calcium), and the BCL-2 family (Navitoclax, ABT-737). We are validating these drugs across a panel of patient-derived IDH-mutant gliomasphere models, and examining the combinatorial effects of these agents with vorasidenib and CDK4/6 inhibitors. Our results provide insight into important metabolic pathway dependencies in recurrent IDH1-R132H mutant gliomas that have targeting potential."

IO biomarker • Brain Cancer • Glioma • Oligodendroglioma • Solid Tumor • BCL2 • IDH1 • NAMPT

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

A Phase I/II Study of Mini-Hyper-CVD, Venetoclax and Navitoclax in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ASH 2024) - "Pts with CD20+ ALL also received up to 8 doses of rituximab...Among the 12 pts with B-cell ALL, all had received prior blinatumomab and 9 (75%) had received prior inotuzumab ozogamicin; among the 10 pts with T-cell ALL/LBL, 5 (50%) had received prior nelarabine...Notably, all 3 pts with R/R ETP ALL achieved CR. While response rate and survival appear better than historical expectations with chemotherapy alone in this population, these outcomes appear similar to those achieved with mini-hyper-CVD + venetoclax in a similar cohort of pts with R/R Ph- ALL (Short NJ et al Blood Adv 2023), questioning the benefit of adding a Bcl-xL inhibitor to this regimen."

Clinical • P1/2 data • Acute Lymphocytic Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Oncology • BCL2 • BCL2L1 • CD20

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Myelofibrosis • Oncology

22P.205: Navitoclax in Relapsed or Refractory High-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Thomas Jefferson University | Phase classification: P1/2 ➔ P1

Phase classification • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • BCL2

A Macrophage-Derived 7-Gene Signature Predicts Prognosis and Therapeutic Response in Hepatocellular Carcinoma. (PubMed, IUBMB Life) - "Conversely, the high-risk group exhibited distinct genomic features and was predicted to be more sensitive to specific targeted agents, including Navitoclax and Sorafenib. We identified and validated a novel 7-gene prognostic signature derived from a subpopulation of EGFR-TKI-resistant macrophages. This signature accurately predicts patient survival, offers insights into the molecular mechanisms of therapy resistance in HCC, and provides a promising tool for improved patient stratification and the development of personalized treatment strategies."

Biomarker • Gene Signature • IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • FAM83D • PPM1G • SLC41A3

Differential Responses to the Senolytic Activities of Navitoclax and Venetoclax in Murine Models of Triple Negative Breast Cancer (SABCS 2025) - "This study compared the senolytic potential of the BH3 mimetics, navitoclax and venetoclax, in targeting doxorubicin-induced senescence in two models of triple negative breast cancer (4T1 and E0771 cells). These findings suggest that administration of venetoclax has the potential to enhance suppression of chemotherapy-induced senescent cancer cells, and that it may not be necessary to use senolytic agents that target Bcl-xL. However, given the variable outcomes in the two triple negative breast tumor cell lines, it becomes incumbent to identify the factors that confer susceptibility to Bcl-2 targeting senolytics in anticipation of their potential utilization in the clinic for combination therapy in solid tumors."

IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • BCL2 • BCL2L1 • CDKN1A • TP53

Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition (ASH 2023) - "Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic syndrome (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations...Using the Bliss independence model to calculate synergy, we identifed two drugs that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and navitoclax (a BCL2/BCL-XL inhibitor)...Our findings may also contribute to the development of potentially synergistic therapeutic combinations. In this regard, recent human data have shown that venetoclax can overcome the poor prognosis of spliceosomal mutant AML patients (Senapati et al, Blood 2023); therefore, combining eltanexor with venetoclax could represent a promising SF3B1-specific therapy."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2L1 • SF3B1 • SIK1 • XPO1

Integrative Analysis of Transcriptomic and Proteomic Data Identifies Patterns of Primary Resistance to Venetoclax-Azacitidine and Reveals Targetable Vulnerabilities in Acute Myeloid Leukemia (AML) (ASH 2024) - "Results : In the BCL2 family inhibitor drug sensitivity assay, navitoclax (BCL2/BCLXLi) was the most effective in killing AML blasts of VEN-AZA refractory patients (mean IC50 70 nM) compared with venetoclax (BCL-2i) (1000 nM), A-1331852 (BCLXLi) (1000 nM) and S-63845 (MCL1i) (> 1000 nM)...Patients with high overall TNF expression (C1) were selectively responsive to the IAP inhibitors birinapant and LCL161 ex vivo, suggesting that inhibition of IAPs could be an effective approach for VEN-AZA resistant AML with increased TNF...Additionally, a MEP-like gene signature, combined with eleveted TNF expression in AML blasts, may contribute to venetoclax resistance while concurrently enhancing sensitivity to SMAC mimetics. These findings suggest potential therapeutic targets and stratification markers, paving the way for novel therapy approaches for VEN-AZA refractory AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD276 • CD34 • KIT • MCL1 • MECOM • PRAME • TP53

Use of Combination Therapies Including the XPO1 Inhibitor Selinexor in Is a Potential Effective Therapeutic Strategy to Treat Myelofibrosis Patients (ASH 2023) - "We also evaluated the ability of SEL alone to eliminate MF CD34+ cells and in combination with other candidate drugs such as HDM201 (HDM2 antagonist), ruxolitinib (RUX), pan-BET inhibitor (JQ1) or a Bcl-2/Bcl-xL inhibitor (navitoclax). The effects of SEL combined with either RUX or an HDM2 antagonist more effectively depleted mutated MF CD34+ cells than either drug alone. The combination of SEL+HDM201 spared the reservoir of WT progenitors, and reduced JAK2 mutated progenitor cells to a great degree suggesting that this combination might be associated with less hematological toxicity and greater efficacy."

Clinical • Combination therapy • IO biomarker • Myelofibrosis • Oncology • BCL2 • BCL2L1 • CCNB1 • CD34 • CDKN1A • MYC • RB1 • TP63 • TP73 • XPO1

Phenotypic Drug Response Profiling Identifies Asparaginase-Based Synergistic Combinations for Very High Risk Acute Lymphoblastic Leukaemia (ASH 2023) - "Eight clinically relevant agents with promising sensitizing activity as identified by decreased area-under-the-curve with addition of ASNase were identified (SEL, selinexor; ELTA, eltanexor; VEN, venetoclax; BZM, bortezomib; navitoclax; carfilzomib; mitoxantrone, birinapant). We validated combinations of ASNase with the 8 selected drugs plus 4 drugs used in induction therapy (prednisolone, dexamethasone, vincristine and daunorubicin) using a 4x4 drug matrix in 15 high-risk ALL PDX samples...Our results identify XPO1 inhibitors as a new class of drugs with promising anti-leukaemic activity in BCP-ALL. Co-culture based DRP shows promise in identifying alternative novel sensitive synergistic combinations ex-vivo with decreased toxicity for patients who have an inadequate response to standard therapy."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • XPO1

Enriched Signalling Pathways in Venetoclax-Relapsed Chronic Lymphocytic Leukemia (CLL) Cells and Targeting Using a Protac-Based Bcl-2/Bcl-Xl Degrader (ASH 2023) - "Venetoclax is a specific inhibitor of Bcl-2, the key protein which protects CLL cells from intrinsic apoptosis, whereas the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib kills CLL cells via blockade of B-cell receptor (BCR) signalling. In conclusion, WH25244 is a PROTAC-based Bcl-2/Bcl-xL degrader with the potential to overcome venetoclax-resistant CLL dependent on Bcl-xL and mutant Bcl-2. Relative to its precursor, navitoclax, it shows increased potency against CLL cells and decreased toxicity against platelets in vitro, due to its VHL-dependent activity and minimal expression of VHL in platelets."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ANXA5 • BCL2 • BCL2L1 • MAP3K8 • MCL1

Radiation-induced senescence as a driver of glioblastoma recurrence (SNO 2025) - "Our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence. Ongoing studies are focused on combinatorial treatment with birinapant (to remove senescent GBM cells) and navitoclax (to remove senescent astrocytes) in order to prevent recurrence."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • BIRC3 • CDKN1A • IL6