navitoclax (ABT 263) / AbbVie - LARVOL DELTA

Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis. (PubMed, Cell Death Dis) - "This study explores the potential of BCL2 inhibitors, specifically Navitoclax and Venetoclax, to shift cell death pathways from necrosis to apoptosis and thereby mitigate disease severity. Together, these findings demonstrate that selective BCL2 inhibition with Venetoclax promotes apoptosis, reduces necrosis, and improves outcomes in AP, supporting its repurposing as a therapeutic strategy. However, BCL2 inhibition does not benefit CP and may aggravate fibrosis, underscoring the need for context-specific approaches."

IO biomarker • Journal • Fibrosis • Hematological Disorders • Immunology • Inflammation • Pancreatitis • Thrombocytopenia • CCL8 • S100A8

Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress. (PubMed, Hypertension) - "Young (4-6 months) mice were injected with doxorubicin and subsequently treated with ganciclovir or the senolytic ABT263. Cellular senescence and the circulating SASP milieu contribute to doxorubicin-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following doxorubicin exposure."

Journal

CTSS in the tumor microenvironment links immune escape and immunotherapy sensitivity in kidney renal clear cell carcinoma. (PubMed, Discov Oncol) - "Mutation profiling uncovered distinct genomic alterations in 5q35.3 among CTSS-high tumors, while drug response prediction identified eight potential therapeutic agents (e.g., Navitoclax, Ibrutinib) exhibiting enhanced efficacy in these patients. Notably, CTSS expression strongly correlated with immune cell infiltration and established immunotherapy biomarkers, supporting its dual role as both a prognostic indicator and predictor of immune response. This study provides mechanistic insights into IE in KIRC and positions CTSS as a promising biomarker and therapeutic target for precision immunotherapy."

Biomarker • IO biomarker • Journal • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • CTSS

Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells. (PubMed, Int J Mol Sci) - "The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment."

IO biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • BCL2 • BCL2L1

S913 phosphorylation of Ulk1 protects the heart from aging through inhibition of cardiac senescence. (PubMed, Cardiovasc Res) - "The chS913A mice exhibit premature cardiac aging, which is mediated through stimulation of cardiomyocyte senescence. The results support the role of the GSK-3β-Ulk1-autophagy pathway in the heart during aging. Thus, these mice could be useful in studying cardiac aging and senescence."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Immunology • CDKN1A • IL6

A human neuron alzheimer's disease model reveals barriers to senolytic translatability. (PubMed, Alzheimers Res Ther) - No abstract available

Journal • Alzheimer's Disease • CNS Disorders

Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Nov 2024 ➔ Jan 2027 | Trial primary completion date: Nov 2024 ➔ Jan 2027

Trial completion date • Trial primary completion date • Myelofibrosis • Neutropenia

Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic effects in AR-V7-expressing CRPC models. (PubMed, Cancer Res Commun) - "Patients often develop resistance to next-generation hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide)...Combinations targeting Bcl-xL (A-1331852 and navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) and a patient-derived organoid model (LuCaP 167 CR)...We showed similar synergistic efficacy with the Bcl-xL targeting PROTAC in combination with S63845 in the 3D spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • BCL2L1 • CASP3 • CASP7

NK-Cell-Derived Extracellular Vesicles Engineered to Carry Senolytics Eliminate Chemotherapy-Induced Senescent Osteosarcoma Cells. (PubMed, J Extracell Vesicles) - "EVs were engineered to contain doxorubicin (Dox), termed iRGD-EVs-Dox, and used to induce cellular senescence in OS cells, followed by delivery of the Bcl-2 family inhibitor ABT-263 in similar engineered EVs (iRGD-EVs-ABT-263), to specifically eliminate the senescent OS cells induced by Dox. Our results demonstrate that iRGD-EVs have efficient targeting ability to OS cells and iRGD-EVs-ABT-263 effectively induced senolysis of Dox-induced senescent OS cells in vitro and repressed tumour growth in OS cell xenograft mouse models. Taken together, our results demonstrate the therapeutic efficiency of using engineered EVs from NK cells to deliver first a chemotherapeutic agent to induce senescent OS cells followed by a senolytic drug to eliminate chemotherapy-induced senescent OS cells, providing a novel strategy for more effective cancer treatment."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Exploring molecular and modular insights into space ionizing radiation effects through heterogeneous gene regulatory networks. (PubMed, NPJ Microgravity) - "Furthermore, we predicted 20 potential therapeutic compounds, including small molecules (e.g., Navitoclax) and Traditional Chinese Medicine ingredients (e.g., Genistin, Saikosaponin D), which may alleviate radiation-induced damage such as pulmonary fibrosis and oxidative stress. These findings provide novel insights into the molecular mechanisms of space ionizing radiation and may contribute to developing effective strategies to protect astronaut health during space missions."

Heterogeneity • Journal • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases

BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer. (PubMed, Mol Cancer Ther) - "Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • KRAS • PIK3CA

Paclitaxel-induced mitotic arrest results in a convergence of apoptotic dependencies that can be safely exploited by BCL-X L degradation to overcome cancer chemoresistance. (PubMed, bioRxiv) - "In HGSOC xenografts, targeted degradation of BCL-XL using the platelet-sparing proteolysis-targeting chimera (PROTAC) DT2216 matches the efficacy of paclitaxel monotherapy while avoiding the chronic thrombocytopenia induced by BCL-XL inhibitors such as navitoclax (ABT-263). Moreover, DT2216 treatment blunts the rapid apoptotic adaptation caused by other BCL-X L inhibitors, indicating that targeted degradation of pro-survival proteins may yield more durable responses than inhibition alone. These findings uncover a mechanistic framework for safely exploiting the apoptotic dependency convergence caused by mitotic arrest and substrate detachment and support the clinical development of BCL-XL-targeting PROTACs to overcome chemoresistance in ovarian cancer and other solid tumors."

Journal • Hematological Disorders • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • BCL2L1 • MCL1

PCNA in Pan-Cancer: A Prognostic Biomarker Unveiled Through a Data-Driven, Multidimensional Analysis of Transcriptomics, Immunity, and Functional Profiling. (PubMed, ACS Omega) - "Unlike previous studies, tumor-specific genetic alterations, such as amplification and hypomethylation, and the paradoxical immune microenvironment linked to PCNA were explored, suggesting potential immune evasion mechanisms. Additionally, new therapeutic avenues reveal PCNA's relationship with drug sensitivity to agents like Navitoclax and Ciclopirox, providing invaluable insights for pharmacological interventions."

Biomarker • Journal • Pan tumor • Oncology • PCNA

Effectiveness of PROTAC BET Degraders in Combating Cisplatin Resistance in Head and Neck Cancer Cells. (PubMed, Int J Mol Sci) - "We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor that has senolytic properties. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation • BCL2 • BCL2L1 • BIRC5 • BRD4 • MYC • RAD51

Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice. (PubMed, Res Sq) - "Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ). A comparison with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc. This study reinforces the efficacy of senolytic treatments in ameliorating local senescence and intervertebral disc fibrosis."

Journal • Preclinical • Back Pain • Fibrosis • Immunology • Musculoskeletal Pain • Pain • CDKN1A • JUNB • ZFP36 • ZFP36L1

Proffered Paper: Heterogeneous oncogene dosage driven by extrachromosomal DNA determines neuroblastoma response to therapy (EACR 2025) - "Consequently, a senolytic "one-two punch" using doxorubicin and navitoclax achieved significant tumor growth control in neuroblastoma PDX models. This study establishes how ecDNA-driven MYCN variability underpins tumor heterogeneity and therapy resistance. This study establishes how ecDNA-driven MYCN variability underpins tumor heterogeneity and therapy resistance. Conventional treatments eliminate high-MYCN cells, but low-MYCN cells survive, persist in senescence, and regain proliferative capacity. Refining therapeutic strategies to target low-MYCN cells may improve outcomes for high-risk MYCN-amplified neuroblastomas."

Heterogeneity • Neuroblastoma • Oncology • Solid Tumor • MYCN

Sequential Targeting of IAP and BCL-2 Family Proteins May Enhance Apoptotic Sensitivity in Non-Small Cell Lung Cancer (EACR 2025) - "Targeting survival pathways with Smac mimetics (e.g., Birinapant, Compound A) and BH3 mimetics (e.g., S63845, ABT-263) offers a promising approach...Necroptosis was assessed using RIPK1 and RIPK3 inhibitors (Necrostatin-1, GSK872) but did not significantly contribute to cell death.Group 2 cells underwent additional treatment with BH3 mimetics (S63845, ABT-199, WEHI-539, ABT-263)... Our findings highlight the importance of sequential drug administration in apoptosis induction. Smac mimetics effectively induced apoptosis in sensitive NSCLC cells, while resistant cells may require BH3 mimetics. The lack of necroptotic response confirms apoptosis as the primary mechanism."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • BCL2 • FHIT • KRAS • MCL1 • RIPK1 • TNFA • TP53

Novel applications of senolytics to prevent treatment resistance in cervical cancer (EACR 2025) - "These findings demonstrate a clear link between chemotherapy-induced senescence and treatment resistance, supporting the therapeutic potential of senolytics in overcoming drug resistance. This study underscores the importance of integrating senolytics into conventional treatment regimens, advancing personalized therapeutic strategies to improve outcomes for cervical cancer patients."

Cervical Cancer • Oncology • Solid Tumor • ABCB1 • ANXA5 • CDKN1A

SEQUENTIAL ALLOGENEIC STEM CELL TRANSPLANTATION FOR VENETOCLAX-EXPOSED RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME WITH INCREASED BLASTS-2 (EHA 2025) - "Three different 10-day preconditioning backbone regimens were used: ACTIVE (actinomycin D 12.5 mcg/kg (days 1-3), cytarabine 20 mg/m2 (days 1-10), venetoclax 600 mg (days 1-10), De-ACTIVE (decitabine 20 mg/m2 (days 1-10) added to ACTIVE) or De-CAVE (decitabine 20 mg/m2 (days 1-10), cytarabine 20 mg/m2 (days 1-10), venetoclax 600 mg (days 1-10)...Gilteritinib, revumenib, and BCR-ABL1 inhibitor exposure was reported in 16 % (4/25), 12 % (3/25), and 8 % (2/25), respectively...Cladribine (40 %, 10/25), gilteritinib (12 %, 3/25), trametinib (16 %, 4/25), navitoclax (28 %, 7/25), and ponatinib (8 %, 2/25) were added to the preconditioning... Upfront sequential alloSCT demonstrates high antileukemic efficacy in poor-risk, R/R AML, or MDS-IB2 patients with previous venetoclax exposure."

Acute Myelogenous Leukemia • Infectious Disease • Mucositis • Myelodysplastic Syndrome • Septic Shock • Transplantation • BCR • TP53

A new beta-gal targeting PET imaging for precise dynamic monitoring of premature aging and senolytic treatment response (SNMMI 2025) - "A stable PET probe, 68Ga-MGal, was obtained with >95% labeling and putative purity. The probe was specifically recognized by β-Gal both in vitro and in vivo and showed an obvious dependence property on the concentration and reaction time of β-Gal. In vivo studies showed a significantly higher uptake of CT26.CL25 tumors with high expression of β-Gal after injection of 68Ga-MGal and lower uptake of CT26.WT tumors in the control group."

Fibrosis • Immunology • Oncology

Beyond BCL2 (B cell lymphoma) and BTK (Bruton tyrosine kinase) inhibitors: novel agents and resistance mechanisms for chronic lymphocytic leukemia. (PubMed, Discov Oncol) - "CLL has demonstrated acquired resistance to BTK inhibitors and BCL2 inhibitors, necessitating the development and evaluating of treatment options beyond their use. Cancer immunotherapies such as bispecific antibodies and chimeric T cell therapies present with viable therapies for CLL. Novel agents have also been developed that enhance the cytotoxic effect of T cells. Future studies may focus on the developing treatments that overcome the acquired resistance that results when treatment with standard of care targeted therapies ibrutinib and venetoclax."

IO biomarker • Journal • Review • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Targeting Cellular Senescence to Enhance Human Endometrial Stromal Cell Decidualization and Inhibit Their Migration. (PubMed, Biomolecules) - "Although non-flavonoids exhibited notable cytotoxicity, dasatinib, but neither ABT-737 nor navitoclax, enhanced decidualization. Furthermore, flavonoid-senolytics and dasatinib consistently eliminated senescent eSCs. These findings support future studies to assess the therapeutic potential of in vivo supplementation with flavonoid senolytics on eSC function using menstrual effluent."

Journal • Endometriosis • Gynecology • Infertility • Sexual Disorders • Women's Health • TP53

SNAI2 cooperates with MEK1/2 and HDACs to suppress BIM- and BMF-dependent apoptosis in TERT promoter mutant cancers. (PubMed, PLoS One) - "Treatment with the pan-BCL2 inhibitor, navitoclax (NX), in combination with MEK inhibition, significantly increased apoptosis, indicating that these cells are capable of undergoing intrinsic apoptosis, with BIM likely playing a critical role...Our findings show that TPM cancers exhibit specific small molecule vulnerabilities, driven by the convergence of RAS-MEK signaling and impaired HDAC regulation dependent on pro-apoptotic BH3-only proteins. Based on our findings, we propose that stratifying cancers based on TPM may identify a subset of tumors that are responsive to innovative combinations of inhibitors targeting these axes."

IO biomarker • Journal • Oncology • BCL2L11 • MAP2K1 • SNAI2 • TERT

Virus-Induced Cellular Senescence Causes Pulmonary Sequelae Post-Influenza Infection. (PubMed, Aging Cell) - "Treatment with the senolytic drug ABT-263 also accelerated epithelial repair without affecting pulmonary fibrosis or emphysema...Finally, AP20187 treatment of p16-ATTAC mice at 15 dpi led to complete recovery of the airway epithelium at 28 dpi. Thus, virus-induced senescent cells contribute to the pulmonary sequelae of influenza; targeting senescent cells may represent a new preventive therapeutic option."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Infectious Disease • Inflammation • Influenza • Pneumonia • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • CDKN1A

B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA CAUSES PARACRINE SENESCENCE IN MESENCHYMAL STROMAL CELLS TO SUBVERT THE TREATMENT RESPONSE IN ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA (EHA 2025) - "Given the prominence of senescence in SD1-exposed HS27a cells, we tested the effects of two different senolytic drugs venetoclax (BCL2i) and navitoclax (BCL2i/BCLXLi) in vitro. We show that BCR::ABL1 but not ETV6::RUNX1 or KMT2A::AFF1-expressing ALL cells, can induce paracrine senescence in HS27a MSC cells. Paracrine senescence in the stromal microenvironment may be a component of treatment response in B-ALL. Senolytic drugs screens are warranted.*First two and last two authors contributed equally"

Clinical • Stroma • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ABL1 • AFF1 • CAFs • CXCL10 • CXCL8 • ETV6 • HMGB2 • IL10 • IL6 • KMT2A • LMNB1 • NFKB1 • RUNX1 • SERPINE1 • SOD2