Cancer Therapy Research Articles

The m6A methyltransferase METTL3 modifies Kcnk6 promoting on inflammation associated carcinogenesis is essential for colon homeostasis and defense system through histone lactylation dependent YTHDF2 binding

Inflammation induces tumor formation and plays a crucial role in tumor progression and prognosis. KCNK6, by regulating K(+) efflux to reduce NLRP3 Inflammasome-induced lung injury, relaxes the aorta. This study aims to elucidate the effects and biological mechanism of KCNK6 in inflammation-associated carcinogenesis, which may be essential for colon homeostasis and the defense system. To induce colitis, mice were given 3.0% Dextran Sodium Sulfate (DSS) in their drinking water for 7 days. The Azoxymethane (AOM) +DSS method was used to induce colon cancer in the mice model. Bone marrow-derived macrophages (BMDM) from Kcnk6-/- mice, AW264.7 cells, and human colon cancer HCT116 and Caco2 cells were used as in vitro models. The loss of Kcnk6 prevented spontaneous colitis and restored mucosal integrity and homeostatic molecules. Additionally, the loss of Kcnk6 reduced the severity of AOM/DSS-induced carcinogenesis. Kcnk6 promoted cell viability and proliferation in HCT-116 or Caco-2 cells. The loss of Kcnk6 inhibited the levels of inflammatory factors in BMDM cells. Kcnk6 accelerated potassium channel activity, inducing NLRP3 inflammasome activation. METTL3-mediated m6A modification increased Kcnk6 stability in a YTHDF2-dependent manner. Histone lactylation activated the transcription of YTHDF2/Kcnk6. Our study revealed the important role of Kcnk6 in inflammation-associated carcinogenesis progression. The m6A methyltransferase METTL3 and histone lactylation increased Kcnk6 stability in a YTHDF2-dependent manner, providing a potential strategy for inflammation-associated carcinogenesis or colorectal cancer therapy.

Future AI Will Most Likely Predict Antibody-Drug Conjugate Response in Oncology: A Review and Expert Opinion.

The medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize the findings of recent late-phase clinical trials using these conjugates for cancer therapy.

Advances in immunotoxin engineering: precision therapeutic strategies in modern oncology.

Immunotoxins (ITs) are specialized therapeutic agents designed for targeted treatment, particularly in cancer therapy. They consist of a monoclonal antibody or antibody fragment linked to a potent cytotoxic agent, such as bacterial- or plant-derived toxins like diphtheria toxin, ricin, or pseudomonas exotoxin. The monoclonal antibody component specifically binds to antigens expressed on the surface of target cells, facilitating the internalization of the IT. Once inside the cell, the cytotoxic agent is released, disrupting essential cellular processes and leading to cell death. This targeted approach minimizes damage to healthy tissues while effectively eliminating diseased cells. The production of ITs involves two primary methods: recombinant fusion and chemical conjugation. In recombinant fusion, genetic engineering is used to create a fusion protein that combines the antibody and toxin, ensuring precise control over their ratio and functionality. In chemical conjugation, pre-existing antibodies are chemically linked to toxins, allowing for greater flexibility in combining different antibodies and cytotoxic agents. Each method has its advantages and challenges, influencing the specificity, production complexity, and therapeutic potential of the resulting ITs. As research advances, ITs continue to show promise not only in oncology but also in treating other diseases, including inflammatory conditions and atherosclerosis. The precise targeting and potent effects of ITs make them a valuable tool in the development of new therapeutic strategies.

Synthesis, cytotoxicity and 99mTc-MIBI tumor cell uptake evaluation of 2-phenylbenzothiazole tagged triazole derivatives.

Aim: The extensive utilization of 2-phenylbenzothiazole due to their wide array of biological activities, particularly in cancer therapy, has caused great attention to explore more potent derivatives.Materials & methods: We report the synthesis of 2-phenylbenzothiazole tagged 1,2,3-triaozle (8) through Cu(I)-catalyzed cycloaddition of alkyne side chain with aryl-substituted azides.Results: The in vitro experiments, using MTT and 99mTc-MIBI cell uptake methods, demonstrated the remarkable anticancer activity of these compounds against A549, SKOV3 and MCF7 cell lines.Conclusion: Compounds 8b, 8f and 8i possessed high cytotoxic activity as compared with doxorubicin. Compound 8g has a similar inhibitory effect on the proliferation of breast cancer cells as doxorubicin. In silico study indicated that compound 8 would be a good lead for the development of new potent anticancer agents.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers

BackgroundCardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction).MethodsAnalysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG).ResultsGDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort.ConclusionGDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Complete response and long-term survival to endocrine monotherapy in a patient with metastatic breast cancer in a low-income country: a case report

BackgroundBreast cancer is the most common cancer in women. Progression-free survival for hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer treated with endocrine therapy in combination with cyclin4/6-dependent kinase is approximately 25 months. This case represents metastatic breast cancer treated with endocrine therapy, leading to long-term survival.Case presentationA 40-year-old Syrian woman diagnosed with hormone receptor-negative breast cancer was treated surgically with adjuvant chemotherapy and radiotherapy. She developed local and nodal recurrences that were hormone receptor-positive, followed by a recurrence of malignant pleural effusion. She was initially treated with chemotherapy and then placed on endocrine therapy with a complete response from 2014 until now. The patient also suffered from adverse events of medications, such as heart failure and osteoporosis, which were treated appropriately.ConclusionThis case demonstrates a long-lasting complete response to metastatic breast cancer with malignant pleural effusion. This shows the validity of endocrine therapy in recurrent hormone receptor-positive breast cancer, especially in countries that cannot afford targeted therapies or genetic tests. It also highlights the necessity for a better understanding of the prognostic and predictive factors.

New multifunctional hybrids as modulators of apoptosis markers and topoisomerase II in breast cancer therapy: synthesis, characterization, and in vitro and in silico studies.

Recently, molecular hybrids of two or more active pharmacophores have shown promise for designing and synthesizing anticancer drugs. Herein, a new multifunctional hybrid (PAHMQ), combining azobenzene and quinoline pharmacophores, and its M(ii) complexes (MPAHMQ) have been successfully developed and structurally characterized. The MTT assay revealed CuBHTP as the most efficient and safe breast cancer treatment, with an IC50 of 11.18 ± 0.39 μg mL-1 and a high selectivity index (SI) of 5.63 for cancer MCF-7 cells over healthy MCF10A cells. Moreover, the CuPAHMQ-treated MCF-7 cells experience a dramatic impact with regard to key apoptotic markers, including an increase in P53 and Bax expression, with a decrease in Bcl-2 expression levels compared to the untreated MCF-7 cells. Additionally, CuPAHMQ effectively halted the growth and division of MCF-7 cells by inducing cell cycle arrest in the crucial G1 and S phases, ultimately inhibiting both Topo II activity and cell proliferation. Molecular docking investigations validated the CuPAHMQ complex's groove binding and topoisomerase II binding, establishing it as a potent anticancer drug.

Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.

Exploring Radioiodinated Anastrozole and Epirubicin as AKT1-Targeted Radiopharmaceuticals in Breast Cancer: In Silico Analysis and Potential Therapeutic Effect with Functional Nuclear Imagining Implications.

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

Development and Assessment of a Predictive Model for Ki-67 Expression Using Ultrasound Indicators and Non-Morphological Magnetic Resonance Imaging Parameters Before Breast Cancer Therapy.

To formulate a predictive model for assessing Ki-67 expression in breast cancer by integrating pre-treatment ultrasound features with non-morphological magnetic resonance imaging (MRI) parameters, encompassing functional and hemodynamic indicators. A retrospective study was conducted on 167 patients. All patients underwent a breast mass biopsy for histopathological and Ki-67 analysis prior to neoadjuvant chemotherapy (NAC) treatment. Additionally, all patients underwent ultrasonography and MRI examinations prior to the biopsy. The recorded variables were Ki-67, apparent diffusion coefficient (ADC) values, Max Slope, time to peak (TTP), signal enhancement ratio (SER), early enhancement rate (EER), time-signal intensity curve (TIC), tumor maximum diameter, tumor margins and boundaries, aspect ratio, microcalcification, color Doppler flow imaging grading, resistance index (RI), and axillary lymph node metastasis. Statistical analysis was performed using the R software package. Normally distributed continuous data are presented as mean ± standard deviation (SD), skewed continuous data as median, and categorical variables as frequency or percentage. The dataset was randomly divided into a modeling group and a validation group following a 7:3 ratio, employing a predetermined random seed. The selection of variables was conducted using the random forest algorithm. Specifically, in the initial analysis, we trained a random forest model using all available variables. By evaluating the Gini importance scores of each variable, we identified those that contributed the most to predicting Ki-67 expression. The predictive model for Ki-67 expression was constructed using selected variables: Maximum Diameter, ADC value, SER value, Max Slope value, TTP value, and EER value. Within the validation group, the evaluation metrics demonstrated an Area under the curve of 0.961 with a 95% confidence interval ranging from 0.865 to 0.995. The model achieved a kappa score of 1.00, precision of 0.949, recall of 1, an F1 score of 0.974, sensitivity of 100%, specificity of 85.71%, a positive predictive value of 94.87%, and a negative predictive value of 100%. The combination of non-morphological MRI parameters and pre-treatment ultrasound features in a breast cancer prediction model powered by RF machine learning demonstrated favorable clinical outcomes and improved diagnostic performance.

MLLT6/ATF2 Axis Restrains Breast Cancer Progression by Driving DDIT3/4 Expression.

Epigenetic deregulation is strongly associated with tumor progression. The identification of natural tumor suppressors to overcome cancer metastasis is urgent for cancer therapy. We investigate whether myeloid/lymphoid or mixed-lineage leukemia translocated (MLLT) family members contribute to breast cancer progression and found that high MLLT6 expression predicted a better prognosis and that gradually decreased MLLT6 expression was accompanied by breast cancer malignancy. MLLT6 was downregulated by hypoxia-induced enrichment of DNMT1 at the MLLT6 promoter. The results of in vitro functional experiments indicated that MLLT6 depletion promoted colony formation and cell migration, probably by hampering apoptosis. RNA profiling revealed that the apoptotic pathway was downregulated following stable knockdown of MLLT6. DNA damage-inducible transcript 3/4 (DDIT3/4) were among the top 10 downregulated genes and may have expression patterns similar to that of MLLT6. Restoring DDIT3/4 expression in cells with MLLT6 depletion blocked colony formation and cell migration and attenuated the successful colonization of breast cancer cells in vivo. We also determined that the transcription factor activating transcription factor 2 is a binding partner of MLLT6 and participates in the MLLT6/ATF2 axis, which was reinforced by inhibition of AKT signaling, in turn inducing DDIT3/4 expression by establishing an active chromatin structure at the DDIT3/4 gene promoters. As MLLT6 promotes breast cancer cell apoptosis by inducing DDIT3/4 expression during metastasis, it could be a novel tumor suppressor. Implications: Control of MLLT6 expression via inhibition of PI3K/AKT kinase activity is a potential therapeutic approach for the management of metastatic breast cancer.

Platinum Group Metals Nanoparticles in Breast Cancer Therapy

Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has emerged as a promising approach to cancer diagnosis, imaging, and therapy. Several preclinical studies have demonstrated that compounds and nanoparticles formulated from platinum group metals (PGMs) effectively treat breast cancer. PGMs are chemically stable, easy to functionalise, versatile, and tunable. They can target hypoxic microenvironments, catalyse the production of reactive oxygen species, and offer the potential for combination therapy. PGM nanoparticles can be incorporated with anticancer drugs to improve efficacy and can be attached to targeting moieties to enhance tumour-targeting efficiency. This review focuses on the therapeutic outcomes of platinum group metal nanoparticles (PGMNs) against various breast cancer cells and briefly discusses clinical trials of these nanoparticles in breast cancer treatment. It further illustrates the potential applications of PGMNs in breast cancer and presents opportunities for future PGM-based nanomaterial applications in combatting breast cancer.

Citrus aurantifolia-derived carbon quantum dots with red fluorescence emission for codelivery with curcumin as theranostic liposomes for lung cancer

BackgroundCarbon dots (CDs) derived from Citrus aurantifolia represent a promising platform for advanced cancer therapy and diagnostics (theranostics). These CDs are synthesized through a sustainable and cost-effective hydrothermal method, utilizing fruit juice as a green carbon source. Despite the potential, research on the synthesis of citrus-based CDs, especially regarding their red fluorescence emission, which is crucial for enhanced tissue penetration and biomedical efficacy, remains limited.ResultsIn this study, CDs were successfully synthesized from C. aurantifolia fruit, yielding nanoparticles below 5 nm in size (PDI 0.231 ± 0.04). Characterization revealed favorable optical properties, including excitation-dependent fluorescent behavior with prominent red emission under higher excitation wavelengths, a quantum yield of 8.17%, and stable photoluminescence. Chemical composition analysis using XPS, FTIR, and XRD confirmed the purity and structure of the CDs.To explore their biomedical application, CDs were co-loaded with curcumin into liposomes. The formulations had a mean size of 177.2 ± 3.6 nm (PDI 0.270 ± 0.012), demonstrated efficient drug entrapment (60.32 ± 2.24%), and exhibited rapid release kinetics, with 90.21 ± 2.16% of the drug release within 8 h. In vitro studies using A549 lung cancer cells demonstrated superior cellular uptake and cytotoxicity of Cur-CD-loaded liposomes compared to curcumin alone (Cur-Suspension), achieving IC50 values of 0.093 ± 0.011 µg/ml and 0.016 ± 0.006 µg/ml, respectively.ConclusionThis research underscores C. aurantifolia as a viable natural source for green CD synthesis. The obtained CDs with red fluorescence emission, optimized through reaction conditions and excitation wavelengths, hold promise for enhanced biological applications, particularly in the realm of lung cancer therapy. The findings advocate for further exploration and refinement of citrus-based CDs as versatile theranostic agents, capitalizing on their sustainable origins and potent biomedical properties. The combination of citrus-derived CDs with curcumin loaded into liposomal formulations represents a potent theranostic strategy for lung cancer treatment, leveraging the unique properties of CDs and their potential for targeted and effective therapy.Graphical abstract

Reactive Oxygen Species-Regulated Conjugates Based on Poly(jasmine) Lactone for Simultaneous Delivery of Doxorubicin and Docetaxel

In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer–drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were conjugated onto novel poly(jasmine lactone) based copolymer via a thioketal (TK) linker. In addition, a photosensitizer (chlorin e6) was attached to the polymer, which served as a reactive oxygen species generator to cleave the TK linker. The conjugate is readily self-assembled into micelles less than 100 nm in size. Micelles demonstrate a notable increase in their ability to cause cell death when exposed to near-infrared (NIR) light on MDA-MB-231 breast cancer cells. The increase in cytotoxicity is higher than that observed with the combination of free DOX and DTX. The accumulation of DOX in the nucleus after release from the micelles (laser irradiation) was also confirmed by confocal microscopy. In the absence of light, micelles did not show any toxicity while the free drugs were found toxic irrespective of the light exposure. The obtained results suggest the targeted drug delivery potential of micelles regulated by the external stimuli, i.e., NIR light.

Sendai virus-mediated RNA delivery restores fertility to congenital and chemotherapy-induced infertile female mice.

Current infertility treatment strategies focus on mature gametes, leaving a significant proportion of cases with gamete progenitors that stopped complete differentiation. On the other hand, recent advancements in next-generation sequencing have identified many candidate genes that may promote maturation of germ cells. Although gene therapy has shown success in mice, concerns about the integration of DNA vectors into oocytes hinder clinical applications. Here, we present the restoration of fertility in female mice through Sendai virus (SeV)-mediated RNA delivery. Ovaries lacking Kitl expression exhibit only primordial follicles due to impaired signaling to oocytes expressing the KIT tyrosine kinase. Despite SeVs being immunogenic and larger than the blood-follicle barrier, the administration of Kitl-expressing SeVs reinitiated oogenesis in genetically infertile mice that have only primordial follicles, resulting in the birth of normal offspring through natural mating. This virus also effectively addressed iatrogenic infertility induced by busulfan, a widely used cancer chemotherapy agent. Offspring born through SeV administration and natural mating displayed normal genomic imprinting patterns and fertility. Since SeVs pose no genotoxicity risk, the successful restoration of fertility by SeVs represents a promising approach for treating congenital infertility with somatic cell defects and protecting fertility of cancer patients who may become infertile due to loss of oocytes during cancer therapy.

Targeted Delivery of Circular Single-Stranded DNA Encoding IL-12 for the Treatment of Triple-Negative Breast Cancer.

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.

NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.Graphical

Selpercatinib prior to radioactive iodine for pediatric papillary thyroid carcinoma

Abstract Objectives We introduced selpercatinib prior to radioactive iodine therapy prior to radioactive iodine therapy (RAI) for pediatric papillary thyroid cancer (PTC) to enhance the tumorical effects of RAI. Case presentation PTC has an excellent prognosis but is commonly associated with local and distant metastases. Successful complete response to the current standard of care, thyroidectomy with lymph node resection and RAI, is achieved in only a small minority of cases with metastases. The direct effect of tyrosine kinase inhibitors (TKIs) on tumor regression has been confirmed in several randomized controlled studies, while the increased RAI uptake has been reported in small case series, but typically TKIs are currently reserved third-line. Selpercatinib is a TKI that specifically has a durable effect in RET-fusion positive malignancies. We describe a 10-year-old Hispanic girl with metastatic PTC treated with total thyroidectomy and extensive lymph node resection. Evaluation for relevant genetic drivers of the malignancy revealed a strong overexpression of the RET tyrosine kinase domain indicative of a RET gene fusion. Selpercatinib 120 mg twice daily given orally was initiated prior to the initial dose of RAI to achieve further tumor regression by a direct cytostatic effect and then secondarily enhancement of RAI uptake. Minimal side effects occurred, specifically intermittent mild skin rashes that resolved. Resolution of distal lung metastases was noted on CT imaging. RAI was then administered 9 months afterward, with ultimately achievement of a low thyroglobulin level 1.0 ng/mL 11 months after RAI. Conclusions In conclusion, selpercatinib given prior to the initial dose of adjunctive RAI for RET-fusion positive PTC is a well-tolerated intervention that further reduces tumor burden and potentially enhances the tumorcidal effects of RAI.

Presenting decision-relevant numerical information to Dutch women aged 50-70 with varying levels of health literacy: Case example of adjuvant systemic therapy for breast cancer.

If communicated adequately, numerical decision-relevant information can support informed and shared decision making. Visual formats are recommended, but which format supports patients depending on their health literacy (HL) levels for specific decisions is unclear. The aim of this study is to investigate: 1) the effect of survival rates and side-effects presentation formats on comprehension and 'feeling informed'; 2) differential effects among women with higher/lower HL, with adjuvant systemic breast cancer therapy as case example. Two online experiments among women from the Dutch population without a history of breast cancer were conducted. Experiment 1 had a 3 (survival rate format: text block-bar graph-icon array) x 2 (HL: low-high) between-subjects design. Experiment 2 had a 5 (side-effects format: no probability information-probability information in numbers with or without a visualisation-probability information in numbers with or without a visualisation accompanied by a description of the side-effects) x 2 (HL: low-high) design. Primary outcomes were comprehension and feeling informed (Experiment 2 only). Formats were previously designed in co-creation with patients. In Experiment 1, presentation format did not affect gist or verbatim comprehension. Higher HL was associated with higher gist comprehension. Experiment 2 showed an interaction between presentation format and HL on 'feeling informed'. When provided with visualised probability information without a description of the side-effects, women with lower HL felt better informed than women with higher HL. Visual formats did not enhance comprehension of survival rate information beyond a well-designed text block format. However, none of the formats could overcome HL differences. When designing decision-relevant information, visualisations might not necessarily provide an advantage over structured numerical information for both patients with lower and higher HL. However, a deeper understanding of presenting side-effect information is warranted.

Efficacy and safety of rechallenge with [177Lu]Lu-PSMA-I&T radioligand therapy in metastatic castration resistant prostate cancer.

The purpose of this study was to evaluate the safety and outcome of rechallenge [177Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [177Lu]Lu-PSMA radioligand therapy(PRLT). We retrospectively included 18 patients who underwent rechallenge with [177Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [68Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii)ECOG performance status 0-1.Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [68Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [68Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death. Patients were initially treated with a median of 5 cycles (range 4-7) and were rechallenged after a median of 9 months (range 3-13). Each patient received a median of 4 (range 2-7) rechallenge cycles (median cumulative activity 26.1GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14-44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI,14.3-43.7 months) for the initial treatment and 11 months (95%CI,8.1-13.8 months) for the first rechallenge course. More than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.