Antimetastatic activity of (arene)ruthenium(II) complex of 4-aryl-4H-naphthopyran.

Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.

In vivo interaction screening reveals liver-derived constraints to metastasis.

It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology2 and fluorescence niche labelling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2-semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.

Decoding the interplay between genetic and non-genetic drivers of metastasis.

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.

Therapies After Progression on Enfortumab Vedotin and Pembrolizumab: Navigating Second-line Options for Metastatic Urothelial Carcinoma in the New Treatment Landscape.

There is no clear standard-of-care treatment for patients with metastatic urothelial carcinoma following progression on enfortumab vedotin and pembrolizumab, although multiple regimens are available, including platinum-based chemotherapy, sacituzumab govitecan, and erdafitinib for selected patients. Clinical trials will be important in informing decisions on the best treatment.

An Overview on the Emerging Role of the Plasma Protease Inhibitor Protein ITIH5 as a Metastasis Suppressor.

Most cancers are not detected until they have progressed to the point of becoming malignant and life-threatening. Chemotherapy and conventional medicines are often ineffective against cancer. Although we have made significant progress, new conceptual discoveries are still required to investigate new treatments. The role of metastasis suppressor genes as a therapeutic option for limiting tumor progression and metastasis has been on the anvil for some time. In this review, we discuss the role of ITIH5 as a metastasis suppressor gene and catalog its involvement in different cancers. We further shed light on the mode of action of ITIH5 based on the available data. The review will provide a new perspective on ITIH5 as an anti-metastatic protein and hopefully serve as an impetus for future studies towards the application of ITIH5 for clinical intervention in targeting metastatic cancers.

Recently reported cell migration inhibitors: Opportunities and challenges for antimetastatic agents.

Antimetastatic agents are highly desirable for cancer treatment because of the severe medical challenges and high mortality resulting from tumor metastasis. Having demonstrated antimetastatic effects in numerous in vitro and in vivo studies, migration inhibitors present significant opportunities for developing a new class of anticancer drugs. To provide a useful overview on the latest research in migration inhibitors, this article first discusses their therapeutic significance, targetable proteins, and developmental avenues. Subsequently it reviews over 20 representative migration inhibitors reported in recent journals in terms of their inhibitory mechanism, potency, and potential clinical utility. The relevance of the target proteins to cellular migratory function is focused on as it is crucial for assessing the overall efficacy of the inhibitors.

Rapid Reduction of CEA and Stable Metastasis in an NRAS-mutant Rectal-Cancer Patient Treated With FOLFIRI and Bevacizumab Combined With Oral Recombinant Methioninase and a Low-Methionine Diet Upon Metastatic Recurrence After FOLFIRI and Bevacizumab Treatment Alone.

BACKGROUND/AIM: The choice of chemotherapy agents for RAS-mutant colorectal cancer is limited, and prognosis is poor compared to RAS-wild-type colorectal cancer. The purpose of the present study was to evaluate the effectiveness of methionine restriction combined with chemotherapy in a patient with NRAS-mutant rectal cancer. PATIENTS AND METHODS: A 59-year-old female was diagnosed with lung-metastatic recurrence of NRAS-mutant rectal cancer two and a half years after resection of the primary tumor. She started chemotherapy, which consisted of fluorouracil, irinotecan (FOLFIRI), and bevacizumab, in October 2020. Eight months later, stereotactic body radiation therapy (SBRT) was performed to treat the lung metastases. She stopped chemotherapy at this point and had blood tests and computed tomography (CT) scans regularly. Her CEA level increased to 139.91 ng/ml and her lung metastasis became larger by September 2022. Therefore, she was reintroduced to FOLFIRI and bevacizumab in October 2022, and also started a low-methionine diet and oral recombinant methioninase (o-rMETase) as a supplement. RESULTS: After starting the combination therapy with o-rMETase, a low-methionine diet, FOLFIRI, and bevacizumab, blood CEA levels very rapidly decreased and were almost within the normal limits five months later. CT findings showed the lung metastasis did not grow. CONCLUSION: Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.

Pharmacological targeting of netrin-1 inhibits EMT in cancer.

Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1-7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFß1 administration8,9-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.

Histone deacetylase inhibitors inhibit lung adenocarcinoma metastasis via HDAC2/YY1 mediated downregulation of Cdh1.

Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Local Therapeutics for the Treatment of Oligo Metastatic Prostate Cancer.

PURPOSE OF REVIEW: Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies are increasingly utilized in the early treatment of the disease, particularly in patients with oligometastatic prostate cancer (OMPC). OMPC represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC. RECENT FINDINGS: To date, there are three utilized forms of local therapy for OMPC: cryoablation, radiation therapy, and cytoreductive prostatectomy. Cryoablation can be utilized for the total ablation of the prostate and has shown promising results in patients with OMPC either in combination with ADT or with ADT and systemic chemotherapy. Radiation therapy along with ADT has demonstrated improvement in progression-free survival. The STAMPEDE Arm G, PEACE-1, and the HORRAD clinical trials have investigated radiation therapy for mPCa compared to standard of care versus systemic therapy with varying results. Cytoreductive radical prostatectomy (CRP) in conjunction with ADT has also been proposed in the management of OPMC with promising results from case-control and retrospective studies. Currently there are larger controlled trials investigating CRP for OPMC including the SIMCAP, LoMP, TRoMbone, SWOG 1802, IP2-ATLANTA, g-RAMPP, and FUSCC-OMPCa trials. Given the novel nature of local treatments for OPMC, treatment selection is still controversial and requires long-term follow-up and randomized clinical trials to aid patient and clinician decision making.

Zhuidu Formula suppresses the migratory and invasive properties of triple-negative breast cancer cells via dual signaling pathways of RhoA/ROCK and CDC42/MRCK.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuidu Formula (ZDF) is composed of triptolide, cinobufagin and paclitaxel, which are the active ingredients of Tripterygium wilfordii Hook. F, dried toad skin and Taxus wallichiana var. chinensis (Pilg) Florin, respectively. Modern pharmacological studies show that triptolide, cinobufagin, and paclitaxel are well-known natural compounds that exert anti-tumor effects by interfering with DNA synthesis, inducing tumor cell apoptosis, and inhibiting the dynamic balance of the tubulin. However, the mechanism by which the three compounds inhibit triple-negative breast cancer (TNBC) metastasis is unknown. OBJECTIVE: The objective of this investigation was to examine the inhibitory essences of ZDF on the metastasis of TNBC and elucidate its potential mechanism. MATERIALS AND METHODS: Cell viability of triptolide (TPL), cinobufagin (CBF), and paclitaxel (PTX) on MDA-MB-231 cells was assessed employing a CCK-8 assay. The drug interactions of the three drugs on MDA-MB-231 cells were determined in vitro utilizing the Chou-Talalay method. MDA-MB-231 cells were identified for migration, invasion and adhesion in vitro through the implementation of the scratch assay, transwell assay and adhesion assay, respectively. The formation of cytoskeleton protein F-actin was detected by immunofluorescence assay. The expressions of MMP-2 and MMP-9 in the supernatant of the cells were determined by ELISA analysis. The Western blot and RT-qPCR were employed to explore the protein expressions associated with the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. The anti-tumor efficacy of ZDF in vivo and its preliminary mechanism were investigated in the mouse 4T1 TNBC model. RESULTS: The results demonstrated that ZDF could significantly reduce the viability of the MDA-MB-231 cell, and the combination index (CI) values of actual compatibility experimental points were all less than 1, demonstrating a favorable synergistic compatibility relationship. It was found that ZDF reduces RhoA/ROCK and CDC42/MRCK dual signaling pathways, which are responsible for MDA-MB-231cell migration, invasion, and adhesion. Additionally, there has been a significant reduction in the manifestation of cytoskeleton-related proteins. Furthermore, the expression levels of RhoA, CDC42, ROCK2, and MRCKß mRNA and protein were down-regulated. ZDF significantly decreased the protein expressions of vimentin, cytokeratin-8, Arp2 and N-WASP, and inhibited actin polymerization and actomyosin contraction. Furthermore, MMP-2 and MMP-9 levels in the high-dose ZDF group were decreased by 30% and 26%, respectively. ZDF significantly reduced the tumor volume and protein expressions of ROCK2 and MRCKß in tumor tissues without eliciting any perceptible alterations in the physical mass of the mice, and the reduction was more pronounced than that of the BDP5290 treated group. CONCLUSION: The current investigation demonstrates that ZDF exhibits a proficient inhibitory impact on TNBC metastasis by regulating cytoskeletal proteins through the dual signaling pathways of RhoA/ROCK and CDC42/MRCK. Furthermore, the findings indicate that ZDF has significant anti-tumorigenic and anti-metastatic characteristics in breast cancer animal models.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFß. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond.

Colorectal cancer (CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide. Despite advances in therapeutic regimens, the number of patients presenting with metastatic CRC (mCRC) is increasing due to resistance to therapy, conferred by a small population of cancer cells, known as cancer stem cells. Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC. Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC, and these include vascular endothelial growth factor, epidermal growth factor receptor, human epidermal growth factor receptor-2, mitogen-activated extracellular signal-regulated kinase, in addition to immune checkpoints. Currently, there are several ongoing clinical trials of newly developed targeted agents, which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy. In this review, we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC. Furthermore, we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies, in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.

Molecular predictors of metastasis in patients with prostate cancer.

INTRODUCTION: Prostate cancer is a serious threat to the health of older adults worldwide. The quality of life and survival time of patients sharply decline once metastasis occurs. Thus, early screening for prostate cancer is very advanced in developed countries. The detection methods used include Prostate-specific antigen (PSA) detection and digital rectal examination. However, the lack of universal access to early screening in some developing countries has resulted in an increased number of patients presenting with metastatic prostate cancer. In addition, the treatment methods for metastatic and localized prostate cancer are considerably different. In many patients, early-stage prostate cancer cells often metastasize due to delayed observation, negative PSA results, and delay in treatment time. Therefore, the identification of patients who are prone to metastasis is important for future clinical studies. AREAS COVERED: this review introduced a large number of predictive molecules related to prostate cancer metastasis. These molecules involve the mutation and regulation of tumor cell genes, changes in the tumor microenvironment, and the liquid biopsy. EXPERT OPINION: In next decade, PSMA PET/CT and liquid biopsy will be the excellent predicting tools, while 177 Lu- PSMA-RLT will be showed excellent anti-tumor efficacy in mPCa patients.

Pegylated liposomal doxorubicin (Duomeisu®) monotherapy in patients with HER2-negative metastatic breast cancer heavily pretreated with anthracycline and taxanes: a single-arm, phase II study.

PURPOSE: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. METHODS: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. RESULTS: Of 44 enrolled patients (median age, 53.5 years; range, 34-69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3-4.1) and median OS was 15.0 months (95% CI 12.1-17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. CONCLUSION: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.

Engineered Macrophages-Based uPA-Scavenger Load Gemcitabine to Prompt Robust Treating Cancer Metastasis.

The majority of cancer patients die of metastasis rather than primary tumors, and most patients may have already completed the cryptic metastatic process at the time of diagnosis, making them intractable for therapeutic intervention. The urokinase-type plasminogen activator (uPA) system is proved to drive cancer metastasis. However, current blocking agents such as uPA inhibitors or antibodies are far from satisfactory due to poor pharmacokinetics and especially have to face multiplex mechanisms of metastasis. Herein, an effective strategy is proposed to develop a uPA-scavenger macrophage (uPAR-MΦ), followed by loading chemotherapeutics with nanoparticles (GEM@PLGA) to confront cancer metastasis. Interestingly, significant elimination of uPA by uPAR-MΦ is demonstrated by transwell analysis on tumor cells in vitro and enzyme-linked immunosorbent assay detection in peripheral blood of mice with metastatic tumors, contributing to significant inhibition of migration of tumor cells and occurrence of metastatic tumor lesions in mice. Moreover, uPAR-MΦ loaded with GEM@PLGA shows a robust antimetastasis effect and significantly prolonged survival in 4T1-tumor-bearing mice models. This work provides a novel living drug platform for realizing a potent treatment strategy to patients suffering from cancer metastasis, which can be further expanded to handle other tumor metastasis markers mediating cancer metastasis.

Integrating radium-223 therapy into the management of metastatic prostate cancer care: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Few life-prolonging treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). This article provides an overview of the current systemic treatments available for mCRPC and reviews studies that investigate the optimal timing for the use of radium-223. The aim is to illustrate possible systemic treatment sequences to maximize benefit from radium-223 therapy. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER & HOW IS IT TREATED?: Prostate cancer is called mCRPC when it spreads to organs outside of the prostate (such as the lymph nodes, bones, liver, or lungs) and no longer responds to hormonal therapy. There are several treatment options available for mCRPC, such as abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, olaparib, rucaparib, sipuleucel-T, and 177Lu-PSMA. It is important to understand the risks and benefits associated with each treatment and whether current use may have an impact on future treatment options, including eligibility in certain clinical trials. Maintaining bone health is also an important part of prostate cancer care. WHAT IS RADIUM-223?: Radium-223 is a radioactive molecule that releases strong radiation within a very small range around itself. It mainly travels to the bone where the prostate cancer has spread and kills the cancer cells in that area. Results from a clinical study named ALSYMPCA showed that men who received radium-223 lived longer in addition to having less bone pain. The most common side effects of radium-223 are nausea, vomiting, and diarrhea. Radium-223 minimally suppresses the bone marrow, which means that it slightly reduces the levels of red and white blood cells.

Early evaluation of liver metastasis using spectral CT to predict outcome in patients with colorectal cancer treated with FOLFOXIRI and bevacizumab.

PURPOSE: Early evaluation of the efficacy of first-line chemotherapy combined with bevacizumab in patients with colorectal cancer liver metastasis (CRLM) remains challenging. This study used 2-month post-chemotherapy spectral computed tomography (CT) to predict the overall survival (OS) and response of CRLM patients with bevacizumab-containing therapy. METHOD: This retrospective analysis was performed in 104 patients with pathologically confirmed CRLM between April 2017 and October 2021. Patients were treated with 5-fluorouracil, leucovorin, oxaliplatin or irinotecan with bevacizumab. Portal venous phase spectral CT was performed on the target liver lesion within 2 months of commencing chemotherapy to demonstrate the iodine concentration (IoD) of the target liver lesion. The patients were classified as responders (R +) or non-responders (R -) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at 6 months. Multivariate analysis was performed to determine the relationships of the spectral CT parameters, tumor markers, morphology of target lesions with OS and response. The differences in portal venous phase spectral CT parameters between the R + and R - groups were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of spectral CT parameters. RESULTS: Of the 104 patients (mean age ± standard deviation: 57.73 years ± 12.56; 60 men) evaluated, 28 (26.9%) were classified as R + . Cox multivariate analysis identified the iodine concentration (hazard ratio [HR]: 1.238; 95% confidence interval [95% CI]: 1.089-1.408; P < 0.001), baseline tumor longest diameter (BLD) (HR: 1.022; 95% CI: 1.005-1.038, P = 0.010), higher baseline CEA (HR: 1.670; 95% CI: 1.016-2.745, P = 0.043), K-RAS mutation (HR: 2.027; 95% CI: 1.192-3.449; P = 0.009), and metachronous liver metastasis (HR: 1.877; 95% CI: 1.179-2.988; P = 0.008) as independent risk factors for patient OS. Logistic multivariate analysis identified the IoD (Odds Ratio [OR]: 2.243; 95% CI: 1.405-4.098; P = 0.002) and clinical N stage of the primary tumor (OR: 4.998; 95% CI: 1.210-25.345; P = 0.035) as independent predictor of R + . Using IoD cutoff values of 4.75 (100ug/cm3) the area under the ROC curve was 0.916, sensitivity and specificity were 80.3% and 96.4%, respectively. CONCLUSIONS: Spectral CT IoD can predict the OS and response of patients with CRLM after 2 months of treatment with bevacizumab-containing therapy.