The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.

Leishmaniasis, caused by the genus Leishmania remains a significant global health challenge. Current chemotherapeutics have limitations in terms of drug resistance, toxicity, and limited efficacy. As most of the currently used chemotherapeutics are single-target drugs, the chances of drug resistance development are very high. To overcome this challenge, the polypharmacology approach to designing multiple molecular target drugs is becoming a promising approach against leishmaniasis. Parasite Leishmania has a unique redox defense system to maintain cellular oxidative stress that helps it survive inside the host oxidative environment generated by the host immune response. This evolutionary divergence of redox systems of Leishmania from the human host is ideal for therapeutic interventions. This review focuses on the currently used anti-leishmanial therapeutics limitations and considers antioxidant defense system as a potential drug target pathway. By focusing on these phylogenetically distinct and parasite-specific enzymes, polypharmacological drugs can be developed to inhibit multiple molecular targets, simultaneously increasing efficacy and reducing the potential for resistance while minimizing adverse effects on the human host. This paradigm, which moves from single target to multi-target shift, holds promise for more effective treatments.

Tirabrutinib is a potent, irreversible, and highly selective Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated significant therapeutic activity in patients with relapsed or refractory B-cell lymphoma. However, the safety and efficacy of tirabrutinib monotherapy have not been systematically assessed. This meta-analysis aims to assess the safety and efficacy of tirabrutinib monotherapy in patients with B-cell lymphoma.

We conducted a comprehensive literature search in Embase, PubMed, Web of Science, and Cochrane Library databases to identify prospective clinical trials evaluating tirabrutinib monotherapy in B-cell lymphoma. Data on efficacy and safety were extracted and analyzed.

A total of seven studies were included in the meta-analysis. The clinical trials primarily involved patients with chronic lymphocytic leukemia (CLL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM). The pooled overall response rate (ORR) was 72.5%, with complete response (CR) rate of 18.6%, stable disease (SD) rate of 13.8%, and partial response (PR) rate of 41.1%. The highest median progression-free survival (mPFS) was observed in patients with CLL, reaching 38.5 months. Neutropenia was the most common adverse event (AE), both all grades and grade ≥3. Additionally, a high incidence of skin-related AEs was reported.

Tirabrutinib monotherapy demonstrates a manageable safety profile and promising efficacy in patients with B-cell lymphoma. However, these findings need to be confirmed by larger and higher-quality randomized controlled trials in the future. Further research should also explore the long-term effects and potential benefits of combination therapies involving tirabrutinib.

Identifier CRD42024552721.

Angioimmunoblastic T-cell lymphoma (AITL) is a clinically aggressive non-Hodgkin lymphoma associated with many immune disorders. The incidence of AITL has gradually increased in Asia in recent years. Malignant AITL cells originate from T follicular helper cells, which have a unique morphology and complex biological characteristics. High-throughput sequencing studies have identified many gene mutations associated with its pathogenesis, including mutations in tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase (NADP+) 2 (IDH2), DNA methyltransferase 3 alpha (DNMT3A), ras homolog family member A (RHOA), and T cell receptor-related genes. Currently, there is no standardized treatment for AITL, the first-line chemotherapy is ineffective, the recurrence rate is high, the overall prognosis of patients is poor, and the median survival time does not exceed three years. New drugs are urgently needed. However, with continuous in-depth study of the molecular genetic mechanism of AITL, some new drugs and therapies have been tested for patients with relapsed and refractory AITL, achieving some therapeutic effects. Increasing clinical studies are evaluating new potential targets for AITL based on specific molecular markers, gradually improving individualized treatment and ultimately improving the clinical prognosis of patients with AITL. This review first summarizes the progress of research on the etiology, clinical pathological characteristics, and molecular genetic mechanisms of AITL to enhance understanding of the disease. It then summarizes the progress of research on its treatment strategies to provide some references for clinically diagnosing and treating AITL.

Duvelisib (DUV) is effective against numerous hematological malignancies; however, it suffers from numerous setbacks like poor aqueous solubility, low cellular uptake and adverse effects. Hyaluronic acid is an excellent ligand for CD44 receptors that are overexpressed on cancer cell surfaces. Thus, for the targeted delivery of DUV in hematological malignancies, we have fabricated hyaluronic acid-coated polylactide-co-glycolide nanoparticles (DUV-P/CH/HA-NPs) through electrostatic interactions. DUV-P/CH/HA-NPs exhibited optimum characteristics such as mean particle size of 183.63 ± 0.23 nm, polydispersity index of 0.261 ± 0.02 and drug loading capacity of 5.75 ± 0.05 %. An in-vitro release study demonstrated sustained release behavior of DUV-P/CH/HA-NPs (77.65 ± 2.89 % release in 48 h). The flow cytometry experiments revealed 1.62-fold and 1.50-fold enhanced uptake of DUV-P/CH/HA-NPs compared to non-coated nanoparticles in MOLT-4 and HH cells, respectively. The DUV-P/CH/HA-NPs showed higher cytotoxicity, arrested the cell cycle in G0/G1 phase and showed increased apoptosis compared to non-coated nanoparticles and free DUV. An in-vivo pharmacokinetic study revealed 2.9-fold and 3.6-fold enhancement in AUC0-t and MRT with the DUV-P/CH/HA-NPs compared to free DUV. Further, toxicity evaluation and hemolysis assessment of DUV-P/CH/HA-NPs indicated good safety for intravenous administration. Conclusively, DUV-P/CH/HA-NPs are an excellent option for selectively targeting hematological malignant cells.

Lymphoma is the sixth most prevalent cancer globally. Non-Hodgkin's lymphomas are the majority group of lymphomas, with B cells accounting for approximately 95% of these lymphomas. A key feature of B-cell lymphoma is the functional perturbations of essential biological pathways caused by genetic aberrations. These lead to atypical gene expression, providing cells with a selective growth advantage. Molecular analysis reveals that each lymphoma subtype has unique molecular mutations, which pose challenges in disease management and treatment. Substantial efforts over the last decade have led to the integration of this information into clinical applications, resulting in crucial insights into clinical diagnosis and targeted therapies. However, with the growing need for more effective medication development, we anticipate a deeper understanding of signaling pathways and their interactions to emerge. This review aims to demonstrate how the BCR, specific signaling pathways like PI3K/AKT/mTOR, NF-kB, and JAK/STAT are diverse in common types of B-cell lymphoma. Furthermore, it offers a detailed examination of each pathway and a synopsis of the approved or in-development targeted therapies. In conclusion, finding the activated signaling pathways is crucial for developing effective treatment plans to improve the prognosis of patients with relapsed or refractory lymphoma. Trial Registration: ClinicalTrials.gov identifier: NCT02180724, NCT02029443, NCT02477696, NCT03836261, NCT02343120, NCT04440059, NCT01882803, NCT01258998, NCT01742988, NCT02055820, NCT02285062, NCT01855750, NCT03422679, NCT01897571.

Angioimmunoblastic T-cell lymphoma (AITL), the most common form of peripheral T-cell lymphoma, originates from follicular helper T (Tfh) cells and is notably resistant to current treatments. The disease progression and maintenance, at least in early stages, are driven by a complex interplay between neoplastic Tfh and clusters of B-cells within the tumor microenvironment, mirroring the functional crosstalk observed inside germinal centers. This interaction is further complicated by recurrent mutations, such as TET2 and DNMT3A, which are present in both Tfh cells and B-cells. These findings suggest that the symbiotic relationship between these 2 cell types could represent a therapeutic vulnerability. This review examines the key components and signaling mechanisms involved in the synapses between B-cells and Tfh cells, emphasizing their significant role in the pathobiology of AITL and potential as therapeutic targets.

Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders.

Peripheral T-cell lymphoma (PTCL) is a highly aggressive type of non-Hodgkin's lymphoma with a poor prognosis. Pyroptosis is a newly discovered procedural cell death mode, which has been implicated to occur in both tumor cells and immune cells. However, the occurrence and effect of pyroptosis on PTCL remain unclear. Here, we found that pyroptosis occurred in interstitial macrophages of PTCL rather than in tumor cells. In clinical specimens, macrophage pyroptosis was associated with a poor prognosis of PTCL. In vitro experiments and gene sequencing results showed that pyroptotic macrophages could upregulate the expression of TLR4 through secreting inflammatory cytokines IL-18. Upregulated TLR4 activated its downstream NF-κB anti-apoptotic signaling pathway, thus leading to malignant proliferation and chemotherapy resistance of tumor cells. Moreover, the expression of factors such as XIAP in the NF-κB anti-apoptotic pathway was downregulated after the knockdown of TLR4, and the malignant promotion effect of pyroptotic macrophages on PTCL cells was also reversed. Our findings revealed the mechanism of pyroptotic macrophages promoting the malignant biological behavior of PTCL and elucidated the key role of TLR4 in this process. In-depth analysis of this mechanism will contribute to understanding the regulatory effect of PTCL by the tumor microenvironment and providing new ideas for the clinical treatment of PTCL.

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

The PI3K/AKT/mTOR signaling pathway is an important signaling pathway in eukaryotic cells that is activated in a variety of cancers and is also associated with treatment resistance. This signaling pathway is an important target for anticancer therapy and holds great promise for research. At the same time PI3K inhibitors have a general problem that they have unavoidable toxic side effects.

This review provides an explanation of the role of PI3K in the development and progression of cancer, including several important mutations, and a table listing the cancers caused by these mutations. We discuss the current landscape of PI3K inhibitors in preclinical and clinical trials, address the mechanisms of resistance to PI3K inhibition along with their associated toxic effects, and highlight significant advancements in preclinical research of this field. Furthermore, based on our study and comprehension of PI3K, we provide a recapitulation of the key lessons learned from the research process and propose potential measures for improvement that could prove valuable.

The PI3K pathway is a biological pathway of great potential value. However, the reduction of its toxic side effects and combination therapies need to be further investigated.

Malignant ascites occurs as a symptom of the terminal stage of cancer, affecting the quality of life through abdominal distension, pain, nausea, anorexia, dyspnea and other symptoms. We describe the current main drug treatments in addition to surgery according to the traditional and new strategies. Traditional treatments were based on anti-tumor chemotherapy and traditional Chinese medicine treatments, as well as diuretics to relieve the patient's symptoms. New treatments mainly involve photothermal therapy, intestinal therapy and targeted immunity. This study emphasizes that both traditional and new therapies have certain advantages and disadvantages, and medication should be adjusted according to different periods of use and different patients. In conclusion, this article reviews the literature to systematically describe the primary treatment modalities for malignant ascites.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphomas with its cell origin determined to be follicular helper T-cells. AITL is characterized by a prominent tumor microenvironment involving dysregulation of immune cells, signaling pathways, and extracellular matrix. Significant progress has been made in the molecular pathophysiology of AITL, including genetic mutations, immune metabolism, hematopoietic-derived microenvironment, and non-hematopoietic microenvironment cells. Early diagnosis, detection of severe complications, and timely effective treatment are crucial for managing AITL. Treatment typically involves various combination chemotherapies, but the prognosis is often poor, and relapsed and refractory AITL remains challenging, necessitating improved treatment strategies. Therefore, this article provides an overview of the pathogenesis and latest advances in the treatment of AITL, with a focus on potential therapeutic targets, novel treatment strategies, and emerging immunotherapeutic approaches.

Follicular lymphoma (FL) is the most common low-grade lymphoma, and although nodal FL is highly responsive to treatment, the majority of patients relapse repeatedly, and the disease has been incurable with a poor prognosis. However, primary FL of the gastrointestinal tract has been increasingly detected in Japan, especially due to recent advances in small bowel endoscopy and increased opportunities for endoscopic examinations and endoscopic diagnosis. However, many cases are detected at an early stage, and the prognosis is good in many cases. In contrast, in Europe and the United States, gastrointestinal FL has long been considered to be present in 12%-24% of Stage-IV patients, and the number of advanced gastrointestinal cases is expected to increase. This editorial provides an overview of the recent therapeutic advances in nodal FL, including antibody-targeted therapy, bispecific antibody therapy, epigenetic modulation, and chimeric antigen receptor T-cell therapy, and reviews the latest therapeutic manuscripts published in the past year. Based on an understanding of the therapeutic advances in nodal FL, we also discuss future possibilities for gastroenterologists to treat gastrointestinal FL, especially in advanced cases.

Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this 'classic' approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The 'novel' polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease.