Molecular Oncology最新文献

PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking these adverse effects is desirable. Here, we evaluated the in vitro effects of the investigational PI3Ki roginolisib (IOA-244) and the approved PI3Ki idelalisib on immune cells and leukemic cells. Roginolisib inhibited chronic lymphocytic leukemia cell signaling and viability in a manner comparable to idelalisib. Both drugs specifically inhibited PI3K-signaling in T cells, validating their on-target effects. Both idelalisib and roginolisib reduced regulatory T-cell frequency in a concentration-dependent manner, with idelalisib demonstrating greater potency. Both inhibitors also reduced T-cell activation and proliferation, but to differing extents. However, only idelalisib induced a pronounced impairment of CD8⁺ T-cell cytotoxic function. Furthermore, idelalisib treatment promoted differentiation of conventional CD4⁺ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.

Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key immunosuppressive target on tumour-associated macrophages (TAMs), where it coordinates protumorigenic and anti-inflammatory functions within the tumour microenvironment (TME). Unfortunately, recent clinical evidence indicates that therapeutic TREM2 blockade has suboptimal efficacy in cancer patients. Now, Von Locquenghien et al. report that MiTE-144, a TREM2 blocking antibody fused to an IL2 variant with TME-restricted activation, demonstrates superior anticancer efficiency compared to TREM2 blockade alone in the preclinical setting. Importantly, MiTE-144 showed reduced systemic inflammation or hepatotoxicity relative to TREM2 blockade and/or 'generic' IL2 immunocytokine approaches. Detailed TME analysis of MiTE-144-treated tumours showed substantial reprogramming of the myeloid compartments, together with activation of NK/CD8⁺ T cells. While this study tackled several limitations of anti-TREM2 monotherapy, more attention is needed towards clinically relevant immunotherapy barriers in therapy-refractory tumour settings.

PIK3R1, a regulatory subunit of class IA phosphoinositide-3-kinase (PI3K), undergoes alternative splicing to generate multiple isoforms, primarily p85α and p55α. The canonical isoform p85α associates with the catalytic subunit p110α to form the active PI3K complex, which regulates key cellular functions such as growth, proliferation, survival, and metabolism. In this study, we performed a comprehensive pan-cancer analysis integrating transcriptomic, proteomic, and genomic data to investigate the expression patterns of p85α and its splicing variant, p55α, and their associations with clinical outcomes. Our findings reveal that while p85α expression is significantly reduced, p55α is elevated in tumors as compared to normal samples. These alterations are linked to poor prognosis across multiple cancer types. Notably, we observed racial disparities in expression patterns, with African American patients exhibiting more pronounced downregulation of p85α and upregulation of p55α than European Americans, potentially contributing to differential clinical outcomes. This is the first study to systematically evaluate p85α and p55α expression across diverse cancers and populations, highlighting the role of alternative splicing in PI3K pathway dysregulation and its relevance to cancer progression and health disparities.

Traditionally, cancer has been viewed largely as a disease of the cell, with extensive research centred on how mutations in driver genes trigger cellular transformation. Beyond cell-intrinsic changes, cancer unfolds as a systemic disease driven by an intricate dialogue between malignant cells and the host's organs and tissues. Modelling this multilayered phenomenon is challenging, as it requires recapitulating coordinated interactions within and across multiple organs, inside an organism that is contended with maintaining normal physiology. In recent years, Drosophila melanogaster has emerged as a powerful model for revealing fundamental mechanisms by which the tumour and host mutually interact. In this review, we highlight recent findings that unravel the intricacies of tumour-host biology using Drosophila. At the microenvironment level, we synthesise mechanistic findings on how tumour growth is modulated through interactions with neighbouring tumour subclones, nonmutated wild-type cells and the immune system. At the macroenvironment level, work in Drosophila has provided mechanistic insights into how tumourigenesis causes systemic host health degeneration and accelerates death, collectively termed paraneoplastic effects. Tumours can remotely induce systemic metabolic rewiring and cachectic tissue wasting to promote progression, while simultaneously compromising the function of several tissues, such as the renal system, blood-brain barrier, the gut and blood haemostasis. Additionally, we discuss how the microbiota and sexual dimorphism have been shown to affect the tumour-host interplay. With this review, we synthesise recent advances in Drosophila tumour-host biology and illustrate how this model illuminates cancer's systemic nature.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. While organ-confined disease has a reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the entire CRPC population. The use of ascorbate, more commonly known as ascorbic acid or Vitamin C, has demonstrated antitumor activity in a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anticancer effects. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitors, by inhibiting DNA damage repair, would augment the toxicity of ascorbate, leading to improved antitumor effects. Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic effects with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and noncastrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control. These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo. These findings implicate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.

The protein kinase p38α is an important regulator of cell homeostasis that has been implicated in the response to many types of stresses. Given the plethora of functions that can be potentially regulated by p38α, this pathway has been linked to many diseases including cancer, suggesting a potential therapeutic interest in targeting p38α. This Viewpoint focuses on the role of p38α stress signaling in cancer development and therapy, discussing recent reports and reflecting on future challenges.

PD-L1 is a key immune checkpoint ligand that suppresses antitumor immunity by engaging PD-1 on T cells. While therapeutic blockade of PD-L1/PD-1 interactions has shown clinical benefit, many patients fail to respond, indicating modulation by other factors. Here, we identified a novel regulatory axis in which the membrane-organizing protein tetraspanin-4 (TSPAN4) modulates PD-L1 in melanoma cells. Using cell surface proximity biotinylation coupled with mass spectrometry, we discovered that TSPAN4 physically associates with PD-L1, with both proteins colocalizing on migrasomes and retraction fibers. Mechanistically, we show that TSPAN4 negatively regulates PD-L1 protein levels by enhancing its degradation and restricting its lateral mobility at the plasma membrane. Loss of TSPAN4 stabilized PD-L1, promoted its interaction with CMTM6, and increased PD-L1 surface availability for PD-1 binding. Functionally, TSPAN4 knockdown in melanoma cells led to more efficient immune checkpoint blockade through PD-1 on T cells. This study identifies TSPAN4 as a negative regulator of PD-L1 at the cell surface of melanoma cells suggesting that targeting TSPAN4 may offer a new therapeutic strategy to enhance immune checkpoint blockade in melanoma and other cancers.

Antibody-drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efficacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FcγR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~30% of the PBS group at day 14. The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efficacy, including for the treatment of immunologically cold tumors.

Several medical therapies modify the risk of developing certain cancers in an individual. The aim of this paper was to provide the scientific justification for the 5th edition of the European Code Against Cancer (ECAC5) recommendation on the use of hormone replacement therapy (HRT) and other drugs used at population scale, such as hormonal contraceptives and aspirin. HRT modifies the risk of developing certain cancers in an individual. Except for vaginal oestrogens, all forms of HRT are associated with an increased breast cancer risk; the risk of serous ovarian cancer and endometrial cancer may also be increased. Despite such an increase in cancer risk, HRT often remains the only option for the management of certain menopausal symptoms for the restoration of quality of life and mental health. Therefore, the ECAC5 recommends using HRT for bothersome menopausal symptoms only after a thorough discussion with a healthcare professional and limiting its use for as short a duration as possible. On review of up-to-date evidence for hormonal contraceptives and aspirin, the ECAC5 Working Group elected not to make a recommendation for the average-risk general population regarding the use of these therapies.

Most European Union (EU) residents live in areas where outdoor air pollution levels exceed the 2021 World Health Organization (WHO) air quality guidelines for fine particles and nitrogen dioxide. Outdoor air pollution is classified as carcinogenic to humans, and both outdoor and indoor air contain established human carcinogens, including diesel exhaust particulates, benzo(a)pyrene [B(A)P] and benzene. The European Code Against Cancer, 5th edition (ECAC5), incorporates recommendations for individuals and policymakers aimed at reducing the cancer burden from both outdoor and indoor air pollution. A critical step is aligning EU air quality limit values with the more stringent 2021 WHO guidelines. This should be complemented by integrated policy measures, including stricter regulation of combustion emissions, promotion of active and environmentally friendly transportation, incentives for cleaner energy sources for heating and cooking, and harmonization with broader EU climate initiatives. At the individual level, emissions and exposure may be reduced by limiting car use, avoiding second-hand smoke, and refraining from burning wood or coal indoors or outdoors. Further exposure reduction may be achieved by limiting walking or cycling along heavily trafficked routes.