P1/2, N=18, Recruiting, University of Aarhus | Not yet recruiting --> Recruiting

In conclusion, the limited role of ABT737 in PTC cell apoptosis is attributed to its promoting effect on Beclin1-dependent autophagy. Therefore, autophagy inhibition based on Beclin1 downregulation can enhance the sensitivity of PTC cells to ABT737-induced death.

This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

P1, N=5, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jan 2024 --> Jan 2025

In conclusion, dihydroartemisinin demonstrates anti-tumor activities in human ALL cells via inhibition of cell survival and growth. Dihydroartemisinin augments the apoptotic effect of ABT-737 by inhibiting the expression of Mcl-1.

In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

P1/2, N=18, Not yet recruiting, University of Aarhus | Trial completion date: Mar 2025 --> Mar 2026 | Initiation date: Sep 2023 --> Mar 2024 | Trial primary completion date: Nov 2024 --> Mar 2025

Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti-dengue therapeutics.

To circumvent these problems, we loaded the Bcl-2 inhibitor ABT-737 in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that were wrapped with phospholipid membranes derived from 4T1 murine mammary cancer cells, which mimic the growth and metastasis of human TNBC...We posit that increasing the dose of ABT CCNPs, altering the treatment schedule, or encapsulating a more potent Bcl-2 inhibitor may yield more robust effects on tumor growth and metastasis. With further development, drug-loaded biomimetic NPs may safely treat solid tumors such as TNBC that are characterized by Bcl-2 overexpression.

We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.

These results were confirmed with an ex vivo human skin biopsy model. These data suggested that modulation of the senescent cell population with soluble factors improved the healing outcome in our in vitro and ex vivo healing models.

Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.

In conclusion, CRGs may play important roles in TNBC development, and they can impact tumor immune microenvironment and patient survival. The Key-TNBC-CRGs interact mutually and can be influenced by common BC-related mutations. Additionally, we established a 11-gene risk model with a robust performance in prediction of 5-15-year survival. As well, some new drugs are proposed potentially effective in TNBC based on the CRG strategy.

And miR-143-3p inhibition reduced cardiomyocytes apoptosis upon H/R, whereas it was reversed by a specific bcl-2 inhibitor ABT-737...Collectively, inhibition of miR-143-3p might alleviate MI/RI via targeting bcl-2 to limit mitochondria-mediated apoptosis. To our knowledge, this study further clarifies the miR-143-3p's pathological role in the early stages of MI/RI, and inhibiting miR-143-3p could be an effective treatment for ischemic myocardial disease.

Combined treatment with S63845 and ABT-737 or MAPK pathway inhibitor enhanced apoptosis but also induced differentiation of tested cells, as well as altering the expression of the MCL-1 protein. Taken together, our data provide the rationale for further studies regarding the use of MCL-1 inhibitor in combination with other pro-survival protein inhibitors.

We studied the combined effect of MEL and drugs from different pharmacological groups, such as cytarabine (CYT) and navitoclax (ABT-737), on the state of the pool of acute myeloid leukemia (AML) tumor cell using the MV4-11 cell line as model. We have shown that introduction of MEL together with CYT or ABT-737 increases expression of the C/EBP homologous protein (CHOP) and the autophagy marker LC3A/B and decreases expression of the protein disulfide isomerase (PDI) and binding immunoglobulin protein (BIP), and, therefore, could modulate endoplasmic reticulum (ER) stress and initiate autophagy. The findings support an early suggestion that MEL is able to provide benefits for cancer treatment and be considered as an adjunct to the drugs used in cancer therapy.

The venetoclax/INK128 regimen exerts significant anti-leukemic activity in various preclinical models through mechanisms involving MCL-1 down-regulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax resistant AML cells, and in in vivoAML models. Further investigation of this strategy appears warranted.

Our apoptotic drug screening resulted in the identification of one potential "novel" drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines...Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML.

It was indicated that DUSP4 can maintain the survival and function of CRC cells by inhibiting BCL2 phosphorylation-dependent autophagic cell death and apoptosis.

Repeated experiments revealed patterns of increased cell killing is achieved when trametinib, MEK inhibitor, and venetoclax, BCL2 inhibitor, are combined with BMF-219 treatment.Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Additionally, we show benefit of combinatorial approaches of menin and FLT3 covalent inhibitors with MEK and BCL2 blockade. These data provide initial pre-clinical evidence for combining pathway specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia.

We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. On the other hand, we found Alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into tBid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis, and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.

Two studies reported the proportion of patients with hypogammaglobulinemia: 0-15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM). This review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.

These compounds revealed a more binding affinity potential than ABT-737, which is a standard inhibitor of the protein. In addition, these scaffolds not only interact with relevant and hotspot residues for the inhibition of Bcl-xL but also possess good pharmacokinetic and excellent toxicity, an endpoint that should be considered for further testing and drug development.

Moreover, ROS scavengers (e.g., NAC) reduced lethality. Collectively, these data suggest that combining T-dCyd with ABT-199 kills MDS cells through an ROS-dependent mechanism, and we argue that this strategy warrants consideration in MDS therapy.

The Bcl-2 inhibitor ABT-737 was used to rescue DDP-resistance induced by loss of ITIH3 in vitro. Lower protein expression levels of ITIH3 were significantly associated with platinum resistance and poor prognosis in ovarian cancer. ITIH3 may predict cisplatin-resistance in ovarian cancer.

While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.

p53-Bad* can induce apoptosis in a panel of liver cancer cell lines with varying p53 mutation statuses and induce apoptosis/reduce HCC tumor burden in vivo in zebrafish. p53-Bad* warrants further investigation as a potential new HCC therapeutic.

Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

Background Venetoclax (bcl-2 inhibitor) was first approved in 2018 for use in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in older patients, or those who have comorbidities that preclude use of intensive induction chemotherapy...70% received venetoclax with decitabine, 21% received venetoclax with azacitidine, and 2% received venetoclax with LDAC...FLT3-ITD was a commonly acquired mutation at time of relapse, thus patients received salvage with targeted agents. Also, as patients relapse, the chance of attaining CR/CRi with subsequent lines of treatment is less than 30% and risk of invasive fungal infection was approximately 15%.

This work was supported by AbbVie, trough supply of venetoclax and navitoclax provided within the therapeutic nominal program (Italian DM 7/9/2017)...For BCP-ALL pts, 6 (75%) had received both inotuzumab and blinatumomab, and 1 also CAR-T-cells; in the whole cohort, 17 pts (53%) had already undergone an allo-SCT...Ven and Ven-Navi-based regimens appear tolerable and show preliminary efficacy in this heavily pre-treated and difficult-to-treat population of pts with ALL and LL, with 43% of pts in CR achieving a MRD negativity and 33% undergoing a subsequent allo-SCT. Survival sub-analyses are in progress and the study continues to accrue pts.

Kinetic analysis of caspase 3/7 activation following venetoclax treatment further demonstrated decreased sensitivity to Bcl-2 antagonism of RS with respect to CLL...In sum, RS cells evolve multiple mechanisms to lower the apoptotic priming and hijack the anti-apoptotic dependencies away from Bcl-2. Further investigations are underway to uncover how such mechanisms could be dismantled for therapeutic purpose.

Downregulation of pro-apoptotic Bax and possible upregulation of Bim protein indicate that there may be more complex interplay between various proteins resulting in different disease course. These results again emphasize the role of LN microenvironment in pathogenesis of B-CLL and may provide insights for treatment strategies combining targeted agents (Btk inhibitors and Bcl-2 antagonists).

Despite recent advances in chronic lymphocytic leukemia (CLL) therapy, such as the use of targeted agents including, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the potent BCL-2 antagonist venetoclax, this disease remains incurable for most patients, who are refractory or become resistant to the novel agents...Other drugs that demonstrated high priming included navitoclax (BCL-XL/BCL-2), nutlin-3 (MDM2), abexinostat (HDAC), gandotinib (JAK2), duvelisib (PI3K δ/γ), idelalisib (PI3Kδ) and cerdulatinib (SYK/JAK)...First, we found that IGHV-mutated CLLs (M-CLLs) became more primed to apoptosis than IGHV-unmutated CLLs (U-CLLs) across the panel of drugs (p<0.001, paired t-test) and significantly in response to fludarabine and umbralisib (FDR<0.1, t-test)...EC-i, associated with the intermediate methylation subtype of CLL, was the most resistant EC to ibrutinib but was very sensitive to navitoclax, more than to any other drug. Altogether, we present a framework that links ex-vivo drug response with molecular features including expression subtypes to highlight new therapeutic opportunities in CLL.

When stratified by molecular profiling alone (without respect to cytogenetics), treatment of IDH1/2mut disease with HMA/VEN appears to offer a significantly increased survival benefit compared to the remaining molecular cohorts analyzed. Ongoing work will determine the event free survival (EFS) and any contribution of IDH1/2 targeted therapies in subsequent lines that may contribute to this finding. Interestingly, the increased survival achieved with IDH1/2mut disease was also observed in the R/R setting.

Here we show in vitro efficacy of DS-1594b, a selective small molecule menin inhibitor, as single agent or in combination with Venetoclax in MLLr and NPM1 mutated cell lines and primary leukemia samples. Preliminary data demonstrate differentiation effects of DS-1594b as single agent in both cell lines and primary AML leukemia samples. Combination effects show synthetic lethality in almost all cell lines except OCI-AML3.

We incubated peripheral blood mononuclear cells for three days with cBTKi – ibrutinib; glutathione inhibitor (also known as mtTP53 modulator) - APR-246; Bcl-2 antagonist - venetoclax; and Mcl-1 antagonist - AZD5991; as single agent and in double or triple combinations and apoptosis was assessed by flow cytometry. Patients were re-sensitized to ibrutinib after loss of C481S clone. Genomic and genetic profile along with pharmacological landscape provide precision medicine for these heavily pretreated patients whose disease is resistant to BTK inhibitors.

The combination of ibrutinib and venetoclax was associated with a major response rate of 93%, and a VGPR rate of 40% in previously untreated WM. However, there was a higher-than-expected rate of ventricular arrhythmia of 9%, which prompted stopping study therapy.

Here, we investigated the effects of the selective Mcl-1 inhibitor S63845 in a series of four CTCL cell lines, in comparison to ABT-263 and ABT-737 (inhibitors of Bcl-2, Bcl-x and Bcl-w). The most striking difference between S63845-resistant and -sensitive cells was identified for Bcl-w, which was exclusively expressed in S63845-resistant cells. Thus, CTCL may be efficiently targeted by BH3 mimetics, providing the right target is preselected, and Bcl-w expression may serve as a suitable marker.

Additionally, Four agents, including ABT737, WIKI4, afuresertib, and GNE 317, were more sensitive in the high-risk group. The Eight-CTZFLs prognostic signature may be a helpful prognostic indicator and may help with medication selection for clear cell renal cell carcinoma.