Molecular Oncology最新文献

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.

Although cancer is a leading cause of death in the European Union, around 40% of cases are preventable. The European Code Against Cancer (ECAC) was developed to inform citizens about key cancer-risk-reducing actions. This study aimed to identify effective ways to present the 5th edition of the code (ECAC5) to optimise awareness of cancer risks in all socioeconomic groups. Using a 2 × 3 × 2 factorial design, 10 027 participants from eight countries were randomised online to receive 'no message' or one of 10 ECAC5 formats differing in message content (cancer risks: present/absent), length of message on cancer prevention actions (longer/shorter/absent) or format (text-only/text with images). The primary outcome was awareness of 16 avoidable cancer risks. Overall mean number of risks recalled was 2.40 (standard deviation: 1.72; range 0-14). Recall was highest when messages included risk information. Adding prevention messages to risk information did not improve risk factor recall. Message length and images had no significant impact. Effects were similar across levels of education and countries. Combined information about risk factors and preventive actions has the potential to equitably increase citizens' very low cancer prevention awareness. How this awareness might change over time or lead to behaviour change is unknown and should be the focus of future evaluations.

Tobacco use, second-hand tobacco smoke (SHS) exposure and alcohol consumption are well-established carcinogens and major public health concerns. In the European Union (EU), tobacco and alcohol use are the leading preventable causes of cancer and four other major noncommunicable diseases (NCDs), significantly contributing to NCD-related morbidity and mortality. Despite declining prevalence, consumption of these substances is still high in the region, especially among the most deprived. There is strong evidence that quitting smoking, minimising exposure to SHS and eliminating or reducing alcohol intake substantially lowers the risk of cancer. Comprehensive public health strategies at both the individual and population level are crucial to prevent cancer and other NCDs. Scientific evidence leads to two recommendations for individual action on tobacco in the European Code Against Cancer, 5th edition: (1) 'Do not smoke. Do not use any form of tobacco, or vaping products. If you smoke, you should quit'; and (2) 'Keep your home and car free of tobacco smoke'; and one on alcohol: (3) 'Avoid alcoholic drinks'.

The 5th edition of the European Code Against Cancer (ECAC5) recommends sustainable, organised screening programmes for: (a) colorectal cancer using biennial quantitative faecal immunochemical test (FIT) for individuals aged 50-74 years. As an alternative strategy, once-only endoscopy may be considered within the same age range; (b) breast cancer using biennial digital mammography for women aged 50-69 years. Implementing this strategy for women aged 45-49 years and 70-74 years can be considered. Other screening strategies or additional examinations could be considered for women with high mammographic density; (c) cervical cancer using human papillomavirus (HPV) screening at intervals no shorter than 5 years for women aged 30-65 years. It is recommended to adapt policies according to vaccination status and screening history; and (d) lung cancer using annual low-dose computed tomography (LDCT) for individuals considered to be at increased risk of lung cancer based on age, history of smoking or validated risk models, with biennial screening as an alternative. Screening should incorporate smoking cessation interventions.

The European Code Against Cancer (ECAC) provides evidence-based public health recommendations to reduce cancer risk across Europe. First launched in 1987, it is periodically updated mainly to reflect scientific advances. The 5th edition (ECAC5), released for the medical oncology community in 2025 and to be presented to the public in 2026, aims to offer an authoritative and practical tool for cancer prevention for individuals and policymakers. Developed by over 60 experts across five Working Groups, ECAC5 expands the 12 recommendations of the 4th edition to 14, incorporating the latest evidence on modifiable cancer risks and effective medical interventions. Key innovations include new guidance on air pollution, cancer-related infections, lung cancer screening and strengthened recommendations on tobacco, alcohol, diet, body weight, and occupational and radiation exposures. A major advancement is the addition of dedicated policy recommendations, acknowledging that many prevention measures require supportive environments and regulation. By aligning cancer prevention with broader noncommunicable disease strategies, ECAC5 aims to enhance uptake and impact. Its effective implementation could prevent up to 40% of new cancers in the EU.