Bcl-2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.

The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16)...Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL. TME-mimicking co-culture provides resistance to BH3-mimetics through BCLXL, which can be overcome by inhibition of non-canonical NF-κB.Multidisciplinary profiling reveals how high NF-κB activity leads to crosstalk, and BH3-mimetic resistance counteracted by BTK inhibition.

These systems have good prospects in improving the bioavailability of PTX, enhancing tumor targeting, reducing toxicity, controlling drug release, and reverse tumor multidrug resistance (MDR). This review provides valuable insights into the clinical development and application of PTX-targeted NDDS in the treatment of TNBC.

CA19-9 response to NAT alone is not enough to identify long-term post-resection PDAC survivors. The co-existence of CA19-9 and major pathologic response was predictive of the most optimal survival outcome.

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Feb 2027 | Trial primary completion date: Jun 2026 --> Feb 2027

In human liver microsomes (n = 20) and primary human hepatocytes (n = 15), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1'-hydroxylation) and CYP3A4 protein expression. Differences between the in vitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4β-HC/cholesterol ratio, and the in vivo findings in patients with CLL could be due to age or other factors regulating plasma 4β-HC/cholesterol and/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age-related changes in venetoclax metabolism and plasma 4β-HC/cholesterol ratio.

The Mayo genetic risk models offer pre-treatment and response-based prognostic tools for ND-AML treated with Ven-HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

P1/2, N=105, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Trial completion date: Sep 2022 --> Dec 2026 | Trial primary completion date: Sep 2022 --> Dec 2025

Knockdown of FUNDC1 using shRNA in HEC-1B and Ishikawa EC cells inhibited proliferation, migration and invasion, accompanied by enhanced chemotherapeutic susceptibility to carboplatin and paclitaxel. Accordingly, FUNDC1 could be a prospective prognostic biomarker and potential therapeutic target for EC.

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

Knockout of the endogenous STT3 isoform in TNBC cells partially reduced the glycosylation status of CD24. Our results demonstrate the critical role of N-glycosylation of CD24 in weakening drug sensitivity by inhibiting ferroptosis, highlighting new insights that targeting N-glycosylation of CD24 has great potential to promote chemotherapy sensitivity and efficacy.

Focusing on anticancer drugs, in the last years several PPI modulators have entered clinical trials and venetoclax, which targets Bcl-2 family proteins, has been approved for treating different types of leukemia. This review discusses the clinical development status of drugs modulating several PPIs, such as MDM2-4/p53, Hsp90/Hsp90, Hsp90/CDC37, c-Myc/Max, KRAS/SOS1, CCR5/CCL5, CCR2/CCL2 or Smac/XIAP, in cancer drug discovery.

We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation + allelic deletion or a single mutation with variant allele frequency (VAF) ≥40%; TP53 low risk (TP53LR) included a single TP53 mutation VAF.

Findings that robust CLL cycling associates with progressively decreasing BCL2 protein that directly correlates with decreasing venetoclax susceptibility, combined with past findings that these cycling cells have the greatest potential for activation-induced cytosine deaminase (AICDA)-driven mutations, suggest that venetoclax treatment should be accompanied by modalities that selectively target the cycling compartment without eliciting further mutations. The employment of survivin inhibitors might be such an approach.

P1/2, N=6, Active, not recruiting, Thomas Jefferson University | Recruiting --> Active, not recruiting | N=37 --> 6

P2, N=45, Recruiting, Sun Yat-sen University

The novelty of the study lies in the development of a precise and targeted therapeutic approach tailored to HER2-positive breast cancer, addressing critical gaps in current treatment modalities. Our findings underscore this innovative formulation's clinical relevance and translational potential, paving the way for personalised and effective therapies in HER2-positive breast cancer management.

Our study presents novel evidence regarding pertinent potential target genes and signaling pathways through which CMSP mediates its anti-GC effects, with a particular emphasis on its role in modulating apoptotic signaling pathways. Collectively, these findings underscore the promising candidacy of CMSP as a therapeutic agent for GC that merits further investigation in clinical contexts.

Importantly, the epithelial phenotype induced by low-dose Vit C rendered CR-CSCs sensitive to conventional treatments, enhancing chemosensitivity to Cisplatin, Paclitaxel, and 5-Fluorouracil by 60%-90%. These findings suggest that low dose Vit C could serve as an adjuvant to conventional therapeutic strategies for targeting advanced colorectal cancer by sensitizing CR-CSCs to chemotherapy and potentially reducing tumor recurrence.

This dynamic treatment not only led to nearly complete remission of high-grade ovarian serous cancer but also triggered regression in grade-2 invasive ductal breast cancer after just a few rounds of chemotherapy. Consequently, what started as palliative care evolved into a curative triumph.

Our findings determined that paclitaxel influences the choroid plexus through both direct and indirect mechanisms, resulting in inflammatory profile alterations. Given the pivotal role of the choroid plexus in brain homeostasis, a compromised choroid plexus following chemotherapy may facilitate the spread of peripheral inflammation into the brain, consequently exacerbating the development of neuropathic pain.

P2, N=12, Completed, Bnai Zion Medical Center | Active, not recruiting --> Completed

Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2-C134W and creates a potentially targetable synergy with glucocorticoid signaling.

Paclitaxel induces cognitive deficits through RIPK1-mediated necroptosis. The inhibition of necroptosis may be a potential therapeutic approach to reduce paclitaxel-induced cognitive deficits.

To target this pathway, we investigated the activity of the potent chloroquine-derived autophagy inhibitor, Lys05, on human AML cells, patient samples, and patient derived xenograft models...Moreover, Lys05 overcame hypoxia-induced chemoresistance and improved the efficacy of cytarabine, venetoclax, and azacytidine in vitro and in vivo in AML models. Our results demonstrate the importance of autophagy, specifically mitophagy, as a critical survival and chemoresistance mechanism of AML cells under hypoxic marrow conditions. Therapeutic targeting of this pathway in future clinical studies for AML is warranted.

P2, N=120, Active, not recruiting, University Hospital Tuebingen | Recruiting --> Active, not recruiting

P2, N=45, Recruiting, University of Leipzig | Trial completion date: Jan 2025 --> Jul 2025 | Trial primary completion date: Jan 2025 --> Apr 2025

P2, N=141, Active, not recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Jul 2025 --> Nov 2025

These findings suggest that a one-two punch strategy of pro-senescence therapy induced by chemotherapy treatment followed by senolytic therapy represents a new paradigm for the pharmacological treatment of VS.

AVO was highly active and well-tolerated in patients with previously untreated CLL with high-risk CLL, supporting its use as a new standard of care treatment option.

Here, we employed drug-sensitivity assays, including IC50 calculations, in vitro and in vivo models with various chemotherapeutics, and paclitaxel (PTX) as a representative agent, combined with transcriptomic/proteomic sequencing and clinical prognostic analysis, to identify MDR-related genes and validate their relevance, with the objective of establishing the correlation between PFOS/6:2 Cl-PFESA exposure and MDR in PC at molecular, cellular, and animal model levels...These data suggest that exposure to PFAS may elevate the risk of MDR and subsequent disease progression. Although marketed as a safer alternative to PFOS, the notable impact of 6:2 Cl-PFESA on MDR highlights the necessity for a comprehensive assessment of its potential carcinogenic risks.

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups...Additional studies defining the prognostic role of measurable residual disease following VEN-based treatment have further advanced prognostication capabilities and increased the ability for close disease monitoring and early targeted intervention prior to morphologic relapse. This review summarizes these recent developments and their impact on the treatment and survival of transplant-ineligible patients living with AML.

Our results verified that XIST played a significant role in developing chemoresistance via mediating autophagy in PTX-resistant breast cancer cells. It may be a potential target for breast cancer treatment strategies.

P4, N=44, Active, not recruiting, AbbVie | Trial completion date: Jul 2024 --> Apr 2025 | Trial primary completion date: Jul 2024 --> Apr 2025

Additionally, patients in the low-risk group exhibited improved response to TACE and sorafenib treatments compared to the high-risk group. In contrast, the high-risk group exhibited reduced sensitivity to immunotherapy and increased sensitivity to paclitaxel. In the in-house cohort, high-risk patients displayed higher rates of early recurrence, along with an increased frequency of elevated alpha-fetoprotein, microvascular invasion, and aggressive MRI features associated with HCC. This study has successfully developed a risk score based on MTM and VETC-related genes, providing a promising tool for prognosis prediction and personalized treatment strategies in HCC patients.

Although molecularly targeted therapies have shown efficacy in other hematologic malignancies, currently venetoclax is the only targeted therapy approved for MM (t(11;14))...It addresses gene therapies, small molecule inhibitors and monoclonal antibodies currently under investigation to antagonize oncogenic drivers including MCL-1, BCL9, F11R, and CKS1B, all of which are implicated in cell survival, proliferation or drug resistance. In conclusion, the link between chromosome 1 abnormalities and high-risk disease in MM patients offers a compelling rationale to identify and explore therapeutic targeting of chromosome 1 gene products as a novel precision medicine approach for a poorly served patient population.

P2, N=46, Recruiting, Wake Forest University Health Sciences | Suspended --> Recruiting

When analyzing potential therapeutic strategies, we observed a stronger senolytic activity in these melanoma cell lines when specifically targeting BCL-xL using A-1331852, navitoclax or the PROTAC BCL-xL degrader DT2216. Furthermore, we identified that the main apoptotic inhibition was shaped by BCL-xL and BAK binding increase that prevented mitochondrial permeabilization and apoptosis. To our knowledge, this is the first time that the molecular basis for BCL-xL anti-apoptotic adaptation in senescence is described, paving the way for the development of new molecules that either prevent HRK downregulation or displace BCL-xL binding to BAK to be used as senolytics.

Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing.

In this phase II randomized trial, oral administration of red ginseng powder at 2.0 g per day did not reduce pancreatic cancer patients' fatigue or malaise induced by GnP combination chemotherapy.

Additionally, this study is the first to demonstrate MKRN1 as a downstream gene of KDM7A, showing significant inhibitory effects in both taxol-resistant and drug-sensitive triple-negative breast cancer (TNBC) cells. This research offers new insights into the anticancer mechanisms of KDM7A inhibitors and underscores KDM7A's potential as a therapeutic target against TNBC.

P=N/A, N=110, Active, not recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Unknown status --> Active, not recruiting | Trial completion date: Oct 2020 --> Jan 2025