Cancer Therapy Research Articles

Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy.

Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.

Is there a place for surgery in oligometastatic ductal carcinoma of the pancreatic head?

Background: New chemotherapy regimens (gemcitabine / nab-paclitaxel, FOLFIRINOX) have improved overall survival rates in ductal carcinoma, which has renewed the interest in surgical treatment for isolated liver metastases. Aim: To identify the role of surgery in ductal carcinoma of the pancreatic head with liver oligometastases. Methods: We retrospectively analyzed the data from 490 patients with morphologically verified ductal carcinoma of the pancreatic head in two specialized centers, who had undergone pancreatoduodenectomy (PD) from January 2011 to April 2024. In 21 patients, PD was performed simultaneously with liver resection (liver oligometastases were found during the surgery). Results: In the postoperative period after PD with liver resection, compared to that after PD without liver resection, intra-abdominal abscesses were more frequent (4/21 (19.0%) versus 10/469 (2.2%), p = 0.002) and relaparotomy was performed more often by 9.8% [95 confidence interval (CI, Miettinen-Nurminen score method) 0.21–30.3] (3/21 (14.3%) versus 21/469 (4.5%), p = 0.077). The postoperative death rates were comparable (1/21 (4.8%) versus 19/469 (4.1%), p = 0.8). The median overall survival of the patients after PD with liver resection was 11 (95% CI: 6–16) months, and overall 1-, 2-, and 3-year survival rates were 39.2, 16.8 and 7.2%, respectively. In the patients after PD with liver resection without any adjuvant chemotherapy (n = 5), the median overall survival was 6 (95% CI: 5–7) months, and in those with chemotherapy, 13 (95% CI: 6–16) months (p = 0.006). The overall three-year survival of the patients after PD with liver resection and adjuvant chemotherapy was 11.5%. In the patients after PD with liver resection R0, the median overall survival was 13 (95% CI: 6–32) months, with R1 resection 6 (95% CI: 6–7), and with R2 resection 6 (95% CI: 6–7) months (p = 0.021). The median overall survival of patients after PD with liver resection for G1 tumors was 17 (95% CI: 6–32) months. Conclusion: Surgery as a component of combination therapy for oligometastatic pancreatic head cancer can be considered in a certain category of patients with high tumor differentiation grade and mandatory preliminary assessment of the feasibility of R0 surgery and systemic chemotherapy.

Radioiodinated Nanobody immunoPET probe for in vivo detection of CD147 in pan-cancer.

To develop the extracellular matrix metalloproteinase inducer (CD147)-targeting therapeutic strategies, accurate detection of CD147 expression in tumors is crucial. Owing to their relatively low molecular weights and high affinities, nanobodies (Nbs) may be powerful candidates for cancer diagnosis and therapy. In this study, we developed a novel CD147-targeted nanobody radiotracer, [124I]I-NB147, which provides guidance for the noninvasive detection of CD147-overexpressing cancers. CD147 expression in human cancers was detected via immunohistochemistry (IHC) on tissue microarrays (TMAs). Western blot (WB) and flow cytometry were used to screen CD147-positive malignant melanoma (MM), triple-negative breast cancer (TNBC), and pancreatic cancer (PCA) cell lines. The CD147 nanobody (NB147) was labeled with [124I]INa using Iodogen as the oxidizing agent and was purified by the PD-10 column. The physicochemical properties, affinity, metabolic characteristics, biodistribution, and immunoPET imaging of [124I]I-NB147 were evaluated Moreover, [18F]F-FDG was used as a control. Finally, CD147 expression analysis was performed via multiplex immunofluorescence (MxIF) and autoradiography on human cancer specimens and tumor-bearing mice tissues. TMAs results revealed that CD147 is highly expressed in MM, TNBC, and PCA. A CD147-specific nanobody, NB147, was successfully generated with excellent in vitro binding characteristics. [124I]I-NB147 was obtained with high radiochemical yield and purity, and was stable for at least 4h in vitro. WB and FCM revealed that CD147 was positive in A375, MDA-MB-435 and ASPC1 cells, whereas SK-MEL-28, 4T1 and BXPC3 cells presented low expression levels. The radio-ELISA results indicated that [124I]I-NB147 had a high binding affinity to CD147. The uptake of [124I]I-NB147 was significantly different between CD147 high-expression cells and CD147 low-expression cells (P < 0.001). The biological half-life of the distribution and clearance phases were 0.05h and 1.58h, respectively. In CD147-positive tumor models, the [124I]I-NB147 accumulated in A375, MDA-MB-435, and ASPC1 tumors, and the uptake value was significantly higher than that of [18F]F-FDG. Uptake in SK-MEL-28, BXPC3, and 4T1 tumors was not clearly observed. Finally, through autoradiography and histological studies, the correlation analysis between tumor uptake and CD147 expression level was determined. The high expression of CD147 in MM, TNBC, and PCA tissuesand in tumor cells was verified. The CD147 nanobody, NB147 was produced and radiolabeled to obtain the immunoPET probe, [124I]I-NB147, which showed high affinity to CD147 and precise visualization for accurate diagnosis of CD147-expressing lesions in different cancers. These results provide insight into the imaging and binding properties of nanobody NB147 over extended periods of time, reinforcing its potential in developing radionuclide therapies for CD147-positive cancer patients.

Oesophageal cancer.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Deep learning pipeline for accelerating virtual screening in drug discovery.

In the race to combat ever-evolving diseases, the drug discovery process often faces the hurdles of high-cost and time-consuming procedures. To tackle these challenges and enhance the efficiency of identifying new therapeutic agents, we introduce VirtuDockDL, which is a streamlined Python-based web platform utilizing deep learning for drug discovery. This pipeline employs a Graph Neural Network to analyze and predict the effectiveness of various compounds as potential drug candidates. During the validation phase, VirtuDockDL was instrumental in identifying non-covalent inhibitors against the VP35 protein of the Marburg virus, a critical target given the virus's high fatality rate and limited treatment options. Further, in benchmarking, VirtuDockDL achieved 99% accuracy, an F1 score of 0.992, and an AUC of 0.99 on the HER2 dataset, surpassing DeepChem (89% accuracy) and AutoDock Vina (82% accuracy). Compared to RosettaVS, MzDOCK, and PyRMD, VirtuDockDL outperformed them by combining both ligand- and structure-based screening with deep learning. While RosettaVS excels in accurate docking but lacks high-throughput screening, and PyRMD focuses on ligand-based methods without AI integration, VirtuDockDL offers superior predictive accuracy and full automation for large-scale datasets, making it ideal for comprehensive drug discovery workflows. These results underscore the tool's capability to identify high-affinity inhibitors accurately across various targets, including the HER2 protein for cancer therapy, TEM-1 beta-lactamase for bacterial infections, and the CYP51 enzyme for fungal infections like Candidiasis. To sum up, VirtuDockDL combines user-friendly interface design with powerful computational capabilities to facilitate rapid, cost-effective drug discovery and development. The integration of AI in drug discovery could potentially transform the landscape of pharmaceutical research, providing faster responses to global health challenges. The VirtuDockDL is available at https://github.com/FatimaNoor74/VirtuDockDL .

Unleashing the potential of Genistein and its derivatives as effective therapeutic agents for breast cancer treatment.

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. Genistein (Gen), a phytoestrogen soy isoflavone, has emerged as a promising agent in the prevention and treatment of breast cancer due to its ability to function as a natural selective estrogen receptor modulator (SERM). This review explores the multifaceted mechanisms through which Gen and its derivatives exert their anticancer effects, including modulation of the PI3K/Akt signaling pathway, regulation of apoptosis, inhibition of angiogenesis, and impacts on DNA methylation and enzyme functions. We discuss the dual roles of Gen in both enhancing and inhibiting estrogen receptor (ER)-dependent pathways., highlighting its complex interactions with ERα and ERβ. Furthermore, the review examines the synergistic effect of combining Gen with conventional chemotherapeutic agents such as doxorubicin, cisplatin, and selenium, as well as other natural compounds like lycopene. Clinical studies suggest that while isoflavones may not significantly influence breast cancer progression in general, the high consumption of soy isoflavones is associated with reduced recurrence rates in breast cancer survivors. Importantly, Gen's ability to modulate key signaling pathways and enhance the efficacy of existing treatments improves its potential as a valuable adjunct in breast cancer therapy. In conclusion, Gen and its derivatives offer a novel and promising approach for treatment of breast cancer. Continued research into their mechanisms of action and clinical applications will be essential in optimizing their therapeutic potential and translating these findings into effective clinical interventions.

An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells.

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies.

Nanotechnology in healthcare, and its safety and environmental risks.

Nanotechnology holds immense promise in revolutionising healthcare, offering unprecedented opportunities in diagnostics, drug delivery, cancer therapy, and combating infectious diseases. This review explores the multifaceted landscape of nanotechnology in healthcare while addressing the critical aspects of safety and environmental risks associated with its widespread application. Beginning with an introduction to the integration of nanotechnology in healthcare, we first delved into its categorisation and various materials employed, setting the stage for a comprehensive understanding of its potential. We then proceeded to elucidate the diverse healthcare applications of nanotechnology, spanning medical diagnostics, tissue engineering, targeted drug delivery, gene delivery, cancer therapy, and the development of antimicrobial agents. The discussion extended to the current situation surrounding the clinical translation and commercialisation of these cutting-edge technologies, focusing on the nanotechnology-based healthcare products that have been approved globally to date. We also discussed the safety considerations of nanomaterials, both in terms of human health and environmental impact. We presented the in vivo health risks associated with nanomaterial exposure, in relation with transport mechanisms, oxidative stress, and physical interactions. Moreover, we highlighted the environmental risks, acknowledging the potential implications on ecosystems and biodiversity. Lastly, we strived to offer insights into the current regulatory landscape governing nanotechnology in healthcare across different regions globally. By synthesising these diverse perspectives, we underscore the imperative of balancing innovation with safety and environmental stewardship, while charting a path forward for the responsible integration of nanotechnology in healthcare.

Health Disparities and Inequities in the Utilization of Proton Therapy for Prostate Cancer

Our study sought to review and summarize the reported health disparities and inequities in the utilization of proton beam therapy (PBT) for prostate cancer. We queried the PubMed search engine through 12/2023 for original publications examining disparate utilization of PBT for prostate cancer. The query terms included the following: prostate cancer AND proton AND (disparities OR IMRT OR race OR insurance OR socioeconomic OR inequities)”. Studies were included if they involved United States patients, examined PBT in prostate cancer, and addressed health inequities. From this query, 22 studies met the inclusion criteria, comprising 13 population-based analyses, 5 single-institutional analyses, 3 cost/modeling investigations, and 1 survey-based study. The analyses revealed that in addition to age-related and insurance-related disparities, race and socioeconomic status played significant roles in the receipt of PBT. The likelihood of receiving PBT was lower for non-White patients in population-based and single-institution analyses. Socioeconomic metrics, such as higher median income and higher education level, portended an increased likelihood of receiving PBT. Conclusively, substantial age-based, racial, socioeconomic/insurance-related, and facility-associated disparities and inequities existed for PBT utilization in prostate cancer. The identification of these disparities provides a framework to better address these as the utility of PBT continues to expand across the US and globally.

Precise Genotyping Via Surface‐Enhanced Raman Spectroscopy‐Based Optical Sensing Chip for Guiding Targeted Therapy in Lung Cancer

AbstractThe emergence of “precision medicine” marks a notable shift in cancer treatment, moving from a tumor type–oriented approach to a more targeted, gene‐oriented approach. Detecting low‐abundance mutant genes in blood is challenging but crucial for personalized treatment plans. Herein, a novel platform combining catalytic hairpin self‐assembly (CHA)‐mediated self‐calibrating surface‐enhanced Raman spectroscopy (SERS) with a high‐throughput Raman system (CCSPS) was designed. This platform enables ultrasensitive and rapid genotype analysis of gene mutations. The development of CCSPS specifically targets EGFR mutations, which serve as crucial therapeutic targets for precision therapy in lung cancer. This system shows excellent sensitivity and selectivity, capable of detecting multiple EGFR mutations (Del‐19, L858R, and T790M) with a detection limit as low as attomolar levels. Additionally, precise genotyping analysis was successfully conducted on 42 clinical samples using the CCSPS, yielding results consistent with those obtained through next‐generation sequencing. These results underscore the efficacy of the CCSPS in noninvasively identifying circulating tumor DNA (ctDNA) mutations, facilitating immediate therapeutic decision making at the bedside. In summary, the CCSPS is a fast, accurate, versatile, and compact testing system capable of precisely screening individuals who stand to benefit from targeted therapy, thus promoting personalized and precise healthcare.

A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma.

NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell-activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.

Trends in complexity of single-agent and combination therapies for solid tumor cancers approved by the US Food and Drug Administration.

Many FDA-approved cancer therapies, whether as a multiagent combination or as a single agent, have demonstrated only modest clinical benefit. To investigate the drug development landscape, this analysis focuses on whether newly approved drugs are added to existing standards as combination therapy or replace a former drug as monotherapy. A retrospective analysis of package inserts and corresponding trials for the treatment of nonhematology solid tumor malignancies from January 2011 to December 2023 was conducted to categorize an approval as monotherapy or combination therapy. Drug characteristics, treatment indications, study design, approval history, and efficacy results were compared between the 2 cohorts. Among the 292 approval entries and 110 drugs, 193 (66.1%) were monotherapies and 99 (33.9%) were combinations. Combinations, when compared with monotherapies, were more frequently approved as regular than accelerated approval (85 [85.9%] vs 132 [68.4%], P <.01), in the first-line setting (66 [66.7%] vs 69 [35.8%], P <.01), and with overall survival as the criteria (49 [49.5%] vs 40 [20.7%], P <.01). Monotherapies were more likely to be novel drugs compared with combinations (80 [41.5%] vs 14 [14.1%] P <.01). Monotherapies were more likely to be small molecule targeted agents, while combinations were more likely to be immunotherapies (P <.02). There was no difference comparing the time-to-event endpoints and validated clinical benefit scale, but the median response rate of combinations (46%) was higher than monotherapies (34%, P <.01). Given that clinical benefit appears limited in combination therapy compared with monotherapy, drug development could focus on simplifying cancer therapies toward patient-centered paradigms.

The CML experience to elucidate the role of innate T-cells as effectors in the control of residual cancer cells and as potential targets for cancer therapy

Considering the general view that unconventional immune effectors play a major role in antitumor immunity, we recently postulated that the distinct new innate CD8 T-cell pool (co-expressing the transcription factor Eomesodermin and innate markers such as KIR/NKG2A) may counteract tumor cells, and thereby be potential target for cancer therapy. Here, to test this assumption, we used successfully targeted anti-leukemic therapy discontinuation (TFR) in chronic myeloid leukemia (CML). Numerical and functional status of innate CD8 T-cells, iNKT cells and γδ T-cells, in comparison with NK cells, was compared longitudinally between non-relapsed patients (i.e., with &amp;gt; 12 months TFR) and relapsed patients (i.e., who experienced molecular recurrence during the first 12 months after TKI cessation) in a prospective pilot cohort (n=32), starting from treatment discontinuation (D0). Perforin, a key cytotoxic immune player, was expressed in a significantly higher proportion of both innate CD8 T-cell and NK-cell subsets in non-relapsed patients, compared with relapsed patients at D0. In parallel, we assessed the expression of PD-1, an exhaustion marker used as target in cancer therapy. For all T-cell subsets, surface-expression level of PD-1 decreased in non-relapsed patients compared with relapsed patients at D0. This was particularly the case when considering iNKT cells for which surface-expression level of PD-1 even decreased relative to healthy control subjects. Lastly, we found a negative correlation between the proportion of innate CD8 T-cells expressing PD-1 and those expressing perforin in non-relapsed patients at D0. The fact that this was not the case in conventional CD8 T-cells is compatible with a reprogrammed effector profile preferentially targeting innate CD8 T-cells in non-relapsed patients. All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions.

Senescence as a therapeutic target in cancer and age-related diseases.

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

Engineered Platelets for Cancer Therapy

ABSTRACTWhile nanomedicine research shows a great progress in the treatment of cancer, it still faces challenges of tumor recurrence and metastasis. Numerous studies have demonstrated intricate crosstalk between platelets and tumor cells. The re‐education of platelets by tumor cells enables these platelets to provide critical assistance for tumor proliferation, recurrence, and metastasis. Engineered platelets have shown promising potential in the treatment of tumors, postoperative tumor recurrence, and tumor metastasis. Different engineering technologies such as surface modification, gene editing, membrane coating, and loading into hydrogels can produce multifunctional and customized engineered platelets. These engineered platelets inherit the key properties of platelets, including long blood circulation, tumor targeting, and thrombus targeting, and can be stimulated to generate derivatized particles. In this review, we elucidate the critical role of platelets in the complex processes of tumorigenesis and tumor progression and summarize the emerging paradigm of engineered platelets in tumor therapy. The purpose of this review is to comprehensively explore the potential value of engineered platelets toward the clinical treatment of cancer, providing a valuable reference for the further development of engineered platelets and their broader applications in the field of cancer therapy.

A compact X-ray source via fast microparticle streams.

The spatiotemporal resolution of diagnostic X-ray images is limited by the erosion and rupture of conventional stationary and rotating anodes of X-ray tubes from extreme density of input power and thermal cycling of the anode material. Conversely, detector technology has developed rapidly. Finer detector pixels demand improved output from brilliant keV-type X-ray sources with smaller X-ray focal spots than today and would be available to improve the efficacy of medical imaging. In addition, novel cancer therapy demands for greatly improved output from X-ray sources. However, since its advent in 1929, the technology of high-output compact X-ray tubes has relied upon focused electrons hitting a spinning rigid rotating anode; a technology that, despite of substantial investment in material technology, has become the primary bottleneck of further improvement. In the current study, an alternative target concept employing a stream of fast discrete metallic microparticles that intersect with the electron beam is explored by simulations that cover the most critical uncertainties. The concept is expected to have far-reaching impact in diagnostic imaging, radiation cancer therapy and non-destructive testing. We outline technical implementations that may become the basis of future X-ray source developments based on the suggested paradigm shift.

Ashwagandha (Withania somnifera) in Cancer Therapy: Anticancer Activities and Their Mechanisms

Cancers are characterized by rapid development of abnormal cells that multiply uncontrollably, leading to invasive tumors. By 2040, new cancer cases worldwide are expected to reach 30.2 million. In response, research focuses on the anti-cancer properties of ashwagandha (Withania somnifera), used in traditional Indian medicine. Ashwagandha exhibits anti-inflammatory effects by modulating pathways like NF-kB, Nrf2/HO-1, JAK-STAT, MAPK, and NLRP3, reducing cancer-related inflammation. It also has strong antioxidant properties due to compounds like withanolides, increasing antioxidant enzyme activity and reducing oxidative stress, potentially lowering cancer risk. Ashwagandha extract shows cytotoxic effects against cancer cells, inducing apoptosis and arresting cells in the resting phase, leading to DNA damage in cancer cells. It inhibits angiogenesis, the process of forming new blood vessels that supply tumors, through mechanisms such as VEGF inhibition and reduced macrophage infiltration. Additionally, ashwagandha modulates T lymphocytes and cytokine production, enhancing the immune response against cancer, and stimulates NK cell activity, crucial for controlling tumor growth and development. Supplementation with ashwagandha reduces cortisol levels and improves cognitive functions and quality of life in people experiencing stress, potentially lowering cancer risk. Research suggests ashwagandha may be a valuable addition to anti-cancer therapy, acting on various levels of cancer pathogenesis. However, further clinical studies are needed to fully understand its mechanisms of action and to evaluate its efficacy and safety in cancer treatment.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

MRI after focal therapy for prostate cancer: what radiologists must know?

Focal therapy (FT) is a rapidly growing field aiming to minimize the side effects of whole gland treatments in patients with localized prostate cancer and multiparametric MRI plays an important role in patient selection, treatment planning, and post-treatment monitoring. This article reviews the currently available prostate cancer FT techniques, discusses the key imaging findings that affect patient selection and treatment planning, and illustrates the spectrum of expected and abnormal post-treatment MRI findings.

Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.