Genasense (oblimersen) / Genta - LARVOL DELTA

Harnessing BET-Bromodomain Assisted Nuclear Import for Targeted Subcellular Localization and Enhanced Efficacy of Antisense Oligonucleotides. (PubMed, J Am Chem Soc) - "(+)-JQ1-Oblimersen showed increased effectiveness in an acute myeloid leukemia cell model, showing that this therapeutic may merit re-evaluation. This work demonstrates that the covalent modification of ASOs with a small-molecule nuclear importer can significantly improve target engagement and pave the way for more effective therapeutics."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

Light-activated multimodal nanoplatform for enhanced synergistic therapy of breast cancer. (PubMed, Sci Rep) - "To overcome the drawback of poor water solubility of PDT, HA/G3139/Ce6@Fe3O4 nanosystem was synthesized, which combines the benefits of G3139 antisense oligonucleotides for gene therapy and hyaluronic acid for encapsulation and targeting CD44 receptor...The novel nanosystem demonstrates synergistic anti-cancer effects by combining PDT, gene therapy, and chemodynamic therapy, leading to enhanced apoptosis in breast cancer cells. In conclusion, this approach offers a promising strategy for more effective and targeted breast cancer treatment."

Journal • Breast Cancer • Gene Therapies • Oncology • Solid Tumor • BCL2

Antisense oligonucleotides-based approaches for the treatment of multiple myeloma. (PubMed, Int J Biol Macromol) - "So far, pre-clinical and clinical studies showed promising results when Bcl-2 (Genasense), Mcl-1 (ISIS2048), STAT3 (ISIS345794) and IRF4 (ION251) were targeted using ASOs-based formulations. The relevant genetic targets in ASOs-based MM therapies were described, and the research results obtained in the studies conducted so far were analyzed, with a focus on the ASOs formulations that were already included in clinical trials. In the end, current challenges, and future perspectives of antisense therapy for MM were also discussed."

Journal • Review • Bone Marrow Transplantation • Gene Therapies • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation • BCL2 • IL6 • IRF4 • MCL1 • MYC • STAT3

Review of BCL2 inhibitors for the treatment of Waldenström's macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma. (PubMed, Front Oncol) - "Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax...The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will..."

Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia

DNA-mediated self-assembly oxidative damage amplifier combined with copper and MTH1 inhibitor for cancer therapy. (PubMed, Bioact Mater) - "Meanwhile, the released functional nucleic acid G3139 downregulated the expression of Bcl-2, and accelerated the apoptosis of tumor cells. In conclusion, the HTCG@TA demonstrated significant effect in oxidative damage amplification and tumor inhibition both in vitro and in vivo, which has provided a new outlook for the clinical application of chemo-dynamic tumor treatment and synergistic gene therapy with self-delivery nanoplatforms."

IO biomarker • Journal • Gene Therapies • Oncology • BCL2

Supramolecular Modulator Assisted Cryo-Engineered Porous Cu-DNA Nano-Vehicles for Versatile Theranostic Agent Delivery. (PubMed, Adv Healthc Mater) - "To this end, Cu2+ and nucleic acid therapeutic G3139 self-assemble into a prefabricated solid nanostructure, which subsequently undergoes ultrafast freezing and sublimation to introduce porosity, forming highly porous Cu-G3139 nanoparticles (CG NPs)...This work represents the first demonstration of sublimation-induced pore formation in metal-DNA hybrid nanoparticles without chemical etching, offering a scalable "plug-and-play" platform for personalized cancer therapy without redesign. This versatile pore-engineering strategy, merging supramolecular chemistry with cryo-engineered porosity, opens up new avenues for efficient, customized multidrug delivery for diverse tumor theranostic applications."

Journal • Oncology

Bcl-2 expression in cell lines breast cancer and death program. (PubMed, Cell Mol Biol (Noisy-le-grand)) - "Our team designed a new Antisense Oligonucleotide (ASO) based on Antisense oligo G3139. It also had a synergistic effect with the Tamoxifen. The cationic nano-complex (Niosome) was more efficient than the liposome in delivering designed oligo antisense Bcl-2 in the cancer cells."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • BCL2

Oblimersen Sodium & Combination Chemotherapy in Treating Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma (clinicaltrials.gov) - P1 | N=37 | Terminated | Sponsor: University of Nebraska | Phase classification: P=N/A ➔ P1

Phase classification • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Metal-Organic Frameworks Facilitate Nucleic Acids for Multimode Synergistic Therapy of Breast Cancer. (PubMed, Langmuir) - "In this study, a chemotherapy drug-free nanotherapeutic system based on ZIF-90 encapsulated with Ce6-G3139 and Ce6-DNAzyme for gene and photodynamic therapies was constructed...In addition, the photosensitizer Ce6 carried by the nucleic acid will produce cytotoxic ROS to kill cancer cells after irradiation. The results of this study demonstrated that the designed nanoplatform, which synergistically combines gene and photodynamic therapies, has shown great potential for cancer treatment."

Journal • Breast Cancer • Gene Therapies • Oncology • Solid Tumor • BCL2

Effect of erastin and G3139 on rat liver mitochondria in chronic alcoholic intoxication (PubMed, Biomed Khim) - "G3139 and erastin were also able to influence the studied mitochondrial parameters, and they increased their effect in the liver mitochondria of rats treated with ethanol, as compared to the mitochondria of control rats. We hypothesize that the results of this study may help to elucidate the mechanisms of chronic action of ethanol on mitochondria and contribute to the development of new therapeutic strategies for treating the consequences of ethanol-related diseases."

Journal • Preclinical • Addiction (Opioid and Alcohol)

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials. (PubMed, Clin Transl Oncol) - "Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies...We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed."

Journal • Review • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Solid Tumor • BCL2

Efficient Delivery of the Bcl-2 Antisense Oligonucleotide G3139 via Nucleus-Targeted aCD33-NKSN Nanoparticles. (PubMed, Int J Pharm) - "The results illustrate that aCD33-NKSN/G3139 nanoparticles could improve the antitumor activity of encapsulated G3139 due to aCD33 targeting and the ability to perform nuclear localization, The results offer a promising clinical application potential for the treatment of acute myeloid leukemia. A R T I C L E I N F O."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD33

Structure and Gating Behavior of the Human Integral Membrane Protein VDAC1 in a Lipid Bilayer. (PubMed, J Am Chem Soc) - "We showed that cholesterol, previously shown to reduce the frequency of channel closure, stabilizes the barrel relative to the N-terminal helix. Furthermore, we observed channel closure through steric blockage by a drug shown to selectively bind to the channel, the Bcl2-antisense oligonucleotide G3139."

IO biomarker • Journal • BCL2

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance). (PubMed, Blood Adv) - P3 | "In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124."

Clinical • IO biomarker • Journal • P3 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2

Bcl-2 Antisense Oligodeoxynucleotide G3139 and Paclitaxel in Treating Patients With Recurrent Small Cell Lung Cancer (clinicaltrials.gov) - P1/2; N=12; Completed; Sponsor: University of Chicago; Active, not recruiting ➔ Completed

Clinical • Trial completion • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • BCL2

Evaluation of Pharmacokinetics and Metabolism of Phosphorothioate Antisense Oligonucleotide G3139 in Rat by Capillary Electrophoresis with Laser-Induced Fluorescence. (PubMed, Nucleic Acid Ther) - "The half-life of G3139 and its metabolites was observed at 31 and 68 h, respectively. This study may provide an effective analytical method for the pharmacokinetic and metabolite evaluation required to develop ASOs to treat a variety of diseases."

Journal • PK/PD data • Preclinical

A Novel Peptide-Equipped Exosomes Platform for Delivery of Antisense Oligonucleotides. (PubMed, ACS Appl Mater Interfaces) - "The resulting nanosystem demonstrated a preferential tropism for cells that are parented to their source tumor cells and could remarkably increase the cellular delivery of G3139 with efficient downregulation of antiapoptotic Bcl-2. This work developed a rapid strategy for intracellular delivery of nucleic acids, thus providing more possibilities toward personalized cancer medicine."

Journal • Oncology • BCL2

Rational Design of DNA Framework-Based Hybrid Nanomaterials for Anticancer Drug Delivery. (PubMed, Small) - "Through molecular docking, it is found that a specific structure of the conjugated polymer at major grooves of DNA gives rise to a unique pocket for small-molecular drug doxorubicin (DOX) yielding lower binding energy than conventional DOX binding sites. As a proof of concept, the hybrid nanomaterials equipped with aptamer are used to carry DOX and antisense oligonucleotide G3139, which effectively inhibits solid tumor growth and shows negligible side effects on mice. It is anticipated that this approach would find broad applications in hybrid materials design and precise medicine."

Journal • Oncology • Solid Tumor

A Biomimetic Coordination Nanoplatform for Controlled Encapsulation and Delivery of Drug-Gene Combinations. (PubMed, Angew Chem Int Ed Engl) - "Inspired by natural biomineralization processes, a simple and universal strategy is introduced to construct a biomimetic nanoplatform for systemic codelivery of a nucleic acid therapeutic (G3139) and a chemotherapeutic drug doxorubicin (DOX). Owing to these properties, the system can efficiently accumulate in the tumor and synergistically inhibit tumor growth without apparent systemic toxicity. This work not only provides a new approach to construct MOF-based biomimetic nanoparticle platform, but also proposes a new strategy for delivery of clinically used drug-gene combinations."

Journal • Oncology

Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review. (PubMed, Biomed Res Int) - "In the past few decades, this protein has been demonstrated to have high efficacy in cancer therapy, and several approaches targeting Bcl-2 have been tested clinically (e.g., oblimersen, ABT-737, ABT-263, obatoclax mesylate, and AT-101). In addition, the function and mechanisms of other potentially valuable Bcl-2 inhibitors that did not show efficacy in clinical studies are also discussed. This summary of the development of Bcl-2 inhibitors provides worthwhile viewpoints on the use of biomedical approaches in future cancer therapy."

Clinical • Journal • Review • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo. (PubMed, Biomaterials) - "More apoptosis-associated targets were identified, and a lower level of non-specific protein binding (HSA) revealed that both antisense and aptamer mechanisms might simultaneously exist. A combination of a new delivery system and chemical modifications, such as in LNA-G3139, may have potential clinical application prospects in the future."

Journal • Preclinical • Oncology

Genasense as a 2-hour intravenous infusion in subjects with solid tumors (clinicaltrials.gov) - P1; N=30 -> 25; Active, not recruiting -> Completed; Completion date: Jun 2009 -> Apr 2012

Enrollment • Trial completion • Trial delayed • Oncology

Carboplatin and etoposide with or without oblimersen sodium in treating patients with extensive stage small cell lung cancer (clinicaltrials.gov) - P2, N=63 -> 55; Completed

Enrollment change • Oncology

Regulation of permeability transition pore opening in mitochondria by external NAD(H). (PubMed, Biochim Biophys Acta Gen Subj) - "The mechanism might contribute to the resistance of differentiated cells under different pathological conditions including ischemia/reperfusion."

Journal

T7 Peptide-conjugated Lipid Nanoparticles for Dual-modulation of Bcl-2 and Akt-1 in Lung and Cervical Carcinomas. (PubMed, Mol Pharm) - "In addition, both T7-conjugated Co-ASO-LNPs and non-T7-conjugated Co-ASO-LNPs at a molar ratio of (G3139-GAP to RX-0201-GAP at 1:2) showed efficient downregulation of both Bcl-2 and Akt-1 in both A549 and KB cells. Furthermore, T7-conjugated co-loaded ASOs-LNPs (Co-ASOs-LNPs) produced superior anti-tumor activity, prolonged the overall survival time, and demonstrated tumor targeting activity in an A549 xenograft model."

IO Biomarker • Journal