Targeting CD39 as a Therapeutic for Cancer Immunotherapy.

Background/Objectives: Diabetic macular edema (DME) are major causes of visual impairment worldwide, with vascular endothelial growth factor (VEGF) playing a central role in disease pathogenesis. Intravitreal anti-VEGF therapy is the current standard of care for center-involving DME. Methods: This narrative review summarizes and compares the pharmacological properties, clinical efficacy, safety, and real-world performance of aflibercept and brolucizumab in the treatment of DME, based on randomized controlled trials and observational studies published between 2014 and 2025. Results: Both agents demonstrate significant improvements in visual acuity and retinal anatomy. Brolucizumab has shown non-inferior visual outcomes and, in several studies, greater reductions in central retinal thickness with the potential for extended dosing intervals, suggesting reduced treatment burden. However, post-marketing data have identified an increased risk of intraocular inflammation, including retinal vasculitis and retinal vascular occlusion, associated with brolucizumab, which has influenced its clinical use. Conclusions: Both aflibercept and brolucizumab are effective anti-VEGF therapies for diabetic macular edema, but they differ in durability and safety considerations. Aflibercept remains a reliable first-line option for many patients, while brolucizumab may be considered in carefully selected cases where treatment burden is a priority. Individualized treatment selection based on clinical characteristics, patient preferences, and safety considerations is essential for optimizing long-term outcomes.

<h3>Background</h3> Somatic isocitrate dehydrogenase 1 mutations (<i>IDH1</i>m) convert α-ketoglutarate to the oncogenic metabolite R-2-hydroxyglutarate (2-HG). <i>IDH1</i>m are detected in approximately 13% of intrahepatic cholangiocarcinomas (CCAs).¹ Ivosidenib, an oral inhibitor of...

Colorectal Cancer (CRC) accounts for nearly 10% of all cancer cases and is the second-leading cause of cancer-related deaths worldwide. The increased incidence of CRC in younger demographics underscores the need for improved screening and prognostication. These enhancements are crucial to augment staging practices which focus on accurate evaluation of local lymph node involvement and distant metastasis. Essential trace elements such as copper and iron within the tumor microenvironment (TME) present novel therapeutic strategies- e.g., copper in cell proliferation/signaling and iron in pro-tumorigenic pathways, amongst other multifaceted roles. Despite advancements in spatial imaging/sequencing for detailed mapping of elemental abundance and gene expression profiles at near-subcellular resolution, the understanding of metal signaling and transport pathways in tumors is limited. This gap highlights the need for sophisticated informatics software for data integration and analysis. We developed a computational workflow for spatial multimodal analysis of elements, genes, cell-types, and histological features, applied to a unique CRC case (pT3) as proof-of-concept. Elemental imaging at 5-micron resolution was performed using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICPTOF-MS). The 10x Genomics Visium spatial transcriptomic (ST) CytAssist assay captured spatial variation in gene expression within 55-micron spots, with 40X H&amp;E-stained whole slide imaging (Leica Aperio GT450). Cell type proportions within spots were determined through integration of single cell RNASeq. Regions within, around and away from tumor were annotated by a pathologist. ST and LA-ICPTOF-MS were integrated through co-registration software developed at Biomedical National Elemental Imaging Resource. Local Getis-Ord spatial statistics defined hotspots with high elemental concentration. Wilcoxon tests were used to perform differential expression analysis based on metal hotspots, followed by identification of associated biological pathways through Enrichr with Bonferroni adjustment. Preliminary findings revealed distinct trace element distributions in the TME. For instance, Copper was localized within tumor, correlating with pathways related to immune response and activation (overlap=10/89, p&amp;lt;0.0001). Iron was found concentrated at the proliferative front of the tumor, associated with the epithelial to mesenchymal transition pathway and extracellular matrix remodeling (overlap=25/291, p&amp;lt;0.0001), as well as with a mesenchymal phenotype (W=11.7, p&amp;lt;0.0001), identified through cell type deconvolution. Future work will expand on these findings across multiple tissue contexts as means to capture biological processes governing tumor metastasis, recurrence and survival for biomarker discovery and therapeutics development. Citation Format: Aruesha Srivastava, Neha Shaik, Yunrui Lu, Matthew Chan, Alos Diallo, Serin Han, Ramsey Steiner, Tracy Punshon, Brian Jackson, Linda Vahdat, Louis Vaickus, Jack Hoopes, Fred Kolling, Jonathan Marotti, Joshua Levy. Multimodal analysis of metals, spatial transcriptomics, and histological structures in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4949.

Cancer immunotherapy has been revolutionized through the implementation of the state-of-the-art "chimeric antigen receptor" (CAR)-mediated therapies. CAR-based technologies, which encompass CAR T cells, CAR macrophages, and CAR-NK cells, show great promise in the treatment of various cancers. Despite the success of CAR-based therapies in treating malignancies, they face numerous challenges, including dysfunction of effector innate and adaptive immune cells, immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and on-target/off-tumor bio-toxicity. The CD47/SIRPα axis is recognized as a critical innate immune checkpoint and is important in regulating myeloid-derived clearance of tumor cells and the innate-adaptive cells' cross-talk in cancer immunity. This signaling axis has risen as a promising target to boost the CAR-based immunotherapies by overcoming phagocytic inhibition and modulating immune evasion. This narrative review explores the integration of CD47/SIRPα modulation as an adjunct to CAR therapies. CD47/SIRPα immune-modulation revealed its potential to boost infiltration, persistence, and phagocytic activity of the immune cells. However, its blockade also poses challenges, including hematologic toxicities, CAR T cell clearance, and compensatory escape pathways. Future work will depend on selective targeting, combinatorial checkpoint modulation, and engineered CAR designs that preserve safety while unlocking durable responses. Herein, we discuss pre-clinical and clinical advancements, safety considerations, and cutting-edge advancements.

The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.

Introduction Female Sexual Dysfunction (FSD) encompasses conditions affecting desire, arousal, orgasm, or causing sexual pain, impacting a large proportion of women across age groups. Hypoactive Sexual Desire Disorder (HSDD) is the most prevalent subtype, affecting up to 28% of premenopausal women. FSD negatively influences quality of life and relationships, yet remains underdiagnosed due to stigma, limited provider training, and underutilization of effective therapies. Flibanserin and bremelanotide are FDA-approved for HSDD, though their mechanisms and comparative efficacy are not fully defined. Testosterone therapy, while not FDA-approved in the U.S., is frequently prescribed off-label and has shown benefit in improving libido, adding complexity to treatment decisions. Objective To compare the mechanisms of action, efficacy, safety, and clinical considerations of FDA-approved treatments for FSD, flibanserin and bremelanotide, in addition to off-label testosterone therapy. Methods This narrative review draws from randomized controlled trials, meta-analyses, and clinical guidelines focused on pre- and postmenopausal women with HSDD. Primary outcomes included changes in sexual desire, satisfying sexual events (SSEs), FSFI scores, and adverse effects. Secondary outcomes included patient distress, adherence, and tolerability. Results Flibanserin, typically administered as a daily oral tablet, has demonstrated statistically significant improvements across all domains of the Female Sexual Function Index (FSFI), including desire, arousal, lubrication, orgasm, satisfaction, and pain (p &amp;lt; 0.05). Trials report an increase of 0.5 to 1 SSE/month and a mean FSFI total score improvement of 2.5 points in premenopausal women vs. placebo. Bremelanotide, an on-demand melanocortin receptor agonist, increases desire and reduces distress, with ~0.7 additional SSEs/month. Bremelanotide has shown statistically significant improvements across all FSFI domains, including desire, arousal, lubrication, orgasm, satisfaction, and pain. On average, premenopausal women taking bremelanotide experienced a 1.7-point improvement in FSFI total score compared to placebo (p &amp;lt; 0.05). Testosterone therapy has been shown in clinical trials to significantly improve sexual desire, arousal, orgasm, and the frequency of sexually satisfying events in both naturally and surgically menopausal women. On average, it is associated with 1 to 2 additional sexually satisfying events per month compared to placebo. FSFI total scores significantly improved in the testosterone group (7.2 vs 4.6 in control), with meaningful improvements also observed across individual FSFI domains (p &amp;lt; 0.05). Although not FDA-approved, the Global Consensus Position Statement supports its use in postmenopausal women with HSDD, provided a thorough risk-benefit discussion is conducted and modifiable contributing factors are addressed. Testosterone is contraindicated in women with androgen-sensitive conditions, and regular monitoring of serum testosterone levels is recommended to ensure safet Conclusions HSDD remains underrecognized, yet growing pharmacologic options offer meaningful benefits. Flibanserin, bremelanotide, and testosterone each present unique mechanisms and efficacy profiles. Personalizing treatment based on patient goals, safety considerations, and lifestyle factors is key. Ongoing research is needed to guide long-term use, improve clinician confidence, and expand access to care. Disclosure No

Mechanism of Traditional Chinese Medicine extract in the treatment of diabetic erectile dysfunction.

Medulloblastoma targeted therapy: From signaling pathways heterogeneity and current treatment dilemma to the recent advances in development of therapeutic strategies

Chinese‐German Cooperation Group Tumor Immunology: Another inspiring Meeting in Deidesheim

Tumor immunosuppression is commonly braided with chronic inflammation during tumor development. However, the relationship between immunosuppression and inflammation in tumor microenvironment is still unclear. We have demonstrated that mast cells are accumulated and exacerbate the inflammation and immunosuppression in tumor microenvironment via SCF/c-kit signaling pathway. Here, we further elucidate the underlying mechanism, which involves both myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. Our data showed that mast cells mobilized the infiltration of MDSCs to tumor and induced the production of IL-17 by MDSCs; MDSCs-derived IL-17 indirectly attracted Treg cells, enhanced their suppressor function, and induced the IL-9 production by Treg cells; in turn, IL-9 strengthened the survival and protumor effect of mast cells in tumor microenvironment. Our findings disclose a closed loop among mast cells, MDSCs and Treg cells in tumor microenvironment, which provides a new insight into the paralleled developments of inflammation and immunosuppression in tumor microenvironment. Based on these findings, we propose that targeting tumor inflammation might be a potential strategy to reverse the immunosuppression of tumor microenvironment, thus facilitating cancer immunotherapy.

Background: Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer, yet no targeted therapy has been approved specifically for this disease. There is a critical need for innovative treatment approaches for patients with IBC. There is a paucity of data on immune checkpoint inhibitors (ICIs) in IBC, yet a strong biological rationale exists to lay the groundwork for testing the efficacy of ICIs in IBC. We have previously shown that an anti–epidermal growth factor receptor (EGFR) antibody, panitumumab (sponsored by Amgen), combined with Abraxane (sponsored by Bristol Myers Squibb), and carboplatin followed by 5-fluorouracil, epirubicin, and cyclophosphamide achieves a very high pathologic complete response (42%) in patients with triple-negative receptor status (TN-IBC) (NCT01036087). We hypothesize that inducing a broad shift in the IBC tumor microenvironment (TME), a critical driver of the IBC clinical phenotype and metastasis, from an immunosuppressive to an immunoreactive phenotype can enhance the efficacy of ICIs. Here we report the impact of targeting EGFR on ICI effectiveness by modulating the immunosuppressive TME in TN-IBC. Methods: We examined the effects of panitumumab on components of the immune TME in IBC patient tissues collected before and after panitumumab treatment. Furthermore, we analyzed panitumumab effects in an IBC SUM149 humanized mouse model (SUM149-hu-NSG-SGM3) by using multiplex immunofluorescence staining (mIF) of single-cell RNA-sequencing (scRNA-seq) and multicolor flow cytometry. We examined the changes in chemokines in humanized mouse tissue after panitumumab treatment using a cytokine antibody array and enzyme-linked immunosorbent assay (ELISA). We also studied the mechanism of EGFR regulation of immunosuppressive chemokine expression via transcription factor EGR1 by using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and chromatin immunoprecipitation (ChIP) assays. In addition, we tested the efficacy of panitumumab combined with anti-PD-L1 antibody (Bio X Cell, clone 29E.2A3) in reducing IBC tumor growth in a humanized IBC SUM149 mouse model. Results: IBC patients who achieved pathologic complete response after receiving panitumumab/neoadjuvant chemotherapy had increased levels of CD8+ T-cells and decreased levels of M2 macrophages and T-reg cells. In the humanized mouse model, panitumumab treatment reduced IBC tumor growth and increased immune response that favors an antitumor effect, as shown by scRNA-seq, flow cytometry, and mIF analyses. In addition, we observed that panitumumab treatment increased the expression of chemokines that function as a chemoattractant for CD8+ T-cells, including CXCL10, CCL4, and CXCL9. We also observed that panitumumab treatment reduced EGR1 expression, leading to the downregulation of chemokines involved in the recruitment of immunosuppressive M2 macrophages and T-reg cells, including CCL2, CCL20 CXCL5, and IL-8. Finally, panitumumab enhanced the reduction in tumor growth by anti-PD-L1 antibody treatment; furthermore, the combination of panitumumab and anti-PD-L1 antibody increased the presence of CD8+ T-cells and reduced the presence of T-reg cells and M2 macrophages more effectively than either treatment alone. Conclusion: Panitumumab treatment converts the immunosuppressive IBC TME to an immunoreactive status by modulating the global expression of chemokines by downregulating the EGR1 transcription factor. This modulation of the TME by panitumumab improves the inhibition of IBC tumor growth by an ICI. Our study is the first to demonstrate that targeting the EGFR/EGR1 axis remodels the IBC TME by regulating chemokine expression, thus boosting the antitumor immune response in IBC and response to ICI. Citation Format: Xiaoping Wang, Takashi Semba, Ganiraju C. Manyam, Jing Wang, Shan Shao, Francois Bertucci, Pascal Finetti, Savitri Krishnamurthy, Lan ThiHanh Phi, Troy Pearson, Jared K. Burks, Evan N. Cohen, James M. Reuben, Fei Yang, Hu Min, Nicholas Navin, Toshiaki Iwase, Yichao Shen, Xiang Zhang, Debu Tripathy, Naoto T. Ueno. Remodeling the inflammatory breast cancer tumor microenvironment to enhance immunotherapy: Novel therapeutic development [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-08.

In drug development, about 1 in 1000 interesting compounds reaches the market. Drug safety is only relative and needs to be considered in the context of efficacy. Ultimately, the standards of safety and efficacy are determined by society. Drug safety can be enhanced by adequate patient education, i.e. patients should understand their disease as well as the risks and benefits of their medication. There is often considerable public pressure on the Government and regulatory authorities to alter some aspects of the drug development process. While we should not engage in poor science or alter regulations unthinkingly, the process should be re-examined and re-evaluated as the usual methods of evaluating risk/benefit may not be suitable for a particular disease or patient population. Public pressure has influenced changes in the USA, such as the parallel track testing, early release of drugs etc. It is important to realise that absolute toxicity is rare. Relative toxicity is more usual but may be influenced by many factors such as disease processes, drug dose, duration of administration, kinetic parameters or immunological factors. Clinical considerations in the drug development process include the predictability of adverse reactions in some patient populations, problems of over-dosage, unexpected drug-drug interactions and availability of patient monitoring. Economic factors such as total cost of the drug regimen, availability of alternative therapies, expense of sponsor-initiated special studies and surveillance, liability risk and the potential cost of altered labelling, warning notices and even market withdrawal are also considered. Thus, there are general guidelines, but the clinical, safety and toxicity considerations involved in the development of each drug may be special or unique.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Metabolic diseases, including type 2 diabetes mellitus (T2DM) and obesity, represent interconnected chronic conditions driven by complex neuroendocrine and metabolic dysregulation. Recent pharmacological advances have introduced dual incretin receptor agonists that simultaneously target glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) pathways, offering enhanced therapeutic potential beyond conventional mono-agonist therapies. This review synthesises qualitative thematic evidence from major clinical trials, mechanistic studies, and real-world observational research to evaluate the clinical effectiveness and safety considerations of dual agonists in metabolic disease management. Guided by neuroendocrine integration theory, metabolic flexibility frameworks, and chronic disease systems models, the review explores how dual agonists improve glycemic control, promote substantial weight loss, and modify cardiometabolic risk factors. Thematic synthesis indicates that synergistic hormonal modulation enhances appetite regulation, insulin sensitivity, and adipose tissue remodelling, while adverse effects remain largely gastrointestinal and manageable through dose-escalation strategies. Policy implications regarding cost, access, and preventive pharmacotherapy are discussed alongside biotechnology innovations such as multi-agonist drug design and personalised metabolic medicine. Overall, dual agonists represent a transformative therapeutic class with significant implications for integrated metabolic disease management. Keywords: Dual agonists; GLP-1; GIP; metabolic disease; obesity; type 2 diabetes; incretin therapy

The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy–lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a “double-edged sword” for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that “conventional” agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.