Therapy For Advanced Cancer Research Articles

Observational study of the efficacy and safety of first-line osimertinib and later treatments for uncommon epidermal growth factor receptor-activating mutation-positive advanced non-small cell lung cancer.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations, including both sensitizing and T790M resistance mutations. Its real-world efficacy against uncommon EGFR mutations remains under-researched. The REIWA study, a multicentric, prospective, observational study conducted in Japan from September 2018 to August 2020, enrolled patients with advanced or recurrent EGFR mutation-positive NSCLC receiving osimertinib. Data on clinical outcomes, safety, disease progression, and subsequent treatments were collected for patients with uncommon EGFR mutations. Of 583 patients receiving osimertinib, 39 (6.7%) had an uncommon EGFR mutation. The present study included 32 of these patients after excluding seven patients with an exon 20 insertion mutation. The overall objective response rate was 53.1% [95% confidence interval (CI): 36.4-69.1], and the disease control rate was 78.1% (95% CI: 61.0-89.3). The median progression-free survival was 9.4months (95% CI: 5.0-20.0), and the median overall survival (OS) was 21.8 (95% CI: 14.4-NA) months. Notably, patients with an exon21 L861Q mutation had a significantly longer OS than those with an exon18 G719X mutation, the respective values being 37.8 and 9.7months (hazard ratio: 0.29; 95% CI: 0.10-0.85; P=0.02). The rate of grade 3 or worse adverse events was 10.3%. Seven out of 32 (21.9%) patients showed progression involving only the central nervous system. Osimertinib demonstrated efficacy and tolerability in the clinical setting in patients with uncommon EGFR mutation-positive NSCLC.

Efficacy and safety of PD-1 and PD-L1 inhibitors in advanced colorectal cancer: a meta-analysis of randomized controlled trials

BackgroundPD-1 and PD-L1 inhibitors have emerged as promising therapies for advanced colorectal cancer (CRC), but their efficacy and safety profiles require further evaluation. This meta-analysis aims to assess the efficacy and safety of PD-1/PD-L1 inhibitors in this patient population.MethodsA systematic review and meta-analysis were conducted following PRISMA guidelines, with data sourced from PubMed, Embase, CENTRAL, Web of Science, and CNKI up to August 3, 2024. Nine randomized controlled trials (RCTs) involving 1680 patients were included. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), while safety was assessed through adverse events (AEs) and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CIs).ResultsOverall, the meta-analysis showed that PD-1/PD-L1 inhibitors did not significantly extend OS (MD = 0.86, 95% CI: -0.55, 2.27), but they significantly improved PFS (MD = 2.53, 95% CI: 0.92, 4.15). Additionally, PD-1/PD-L1 inhibitors did not significantly increase the ORR compared to controls (RR = 1.19, 95% CI: 0.99, 1.44). In terms of safety, PD-1/PD-L1 inhibitors did not significantly increase the incidence of overall AEs. Subgroup analysis further indicated that PD-1 inhibitors significantly improved OS (MD = 1.24, 95% CI: 0.20, 2.29) and PFS (MD = 6.27, 95% CI: 0.56, 11.97), while PD-L1 inhibitors did not have a significant impact on these outcomes. Additionally, PD-L1 inhibitors were associated with a higher risk of grade ≥ 3 AEs (RR = 1.29, 95% CI: 1.07, 1.57), a risk not observed with PD-1 inhibitors.ConclusionPD-1 inhibitors significantly improve PFS and OS in advanced CRC, making them a preferable option over PD-L1 inhibitors, which show limited efficacy and a higher risk of severe AEs. These findings support prioritizing PD-1 inhibitors in clinical practice for this patient group, while caution is warranted with PD-L1 inhibitors due to their safety concerns.Trial registrationPROSPERO (CRD42024611696).

Metallic nanoparticles for tumor microenvironment modulation

Cancer is a complex, multifaceted disease influenced by genetic predispositions, lifestyle factors such as nutrition, exercise, and toxin exposure, as well as environmental conditions. A key element in cancer initiation, progression, metastasis, and therapeutic response is the tumor microenvironment (TME). Within the TME, immune cells like T cells, B cells, and immunoglobulins have a profound and direct impact on the growth and spread of tumor cells. As a result, effective regulation of the TME has become crucial for successful cancer treatment. Metal nanoparticles (MNPs), ranging from 1 to 100 nanometers, have shown great potential as agents for modulating the TME, delivering drugs, and improving cancer diagnostics. This discussion explores both the internal and external components of the TME, focusing on how MNPs influence the microenvironment. We highlight their targeting mechanisms and interactions with immune responses and tumor-associated inflammation. Due to their unique properties, MNPs offer distinct advantages in cancer therapy, and their range of applications continues to expand. This review underscores the potential of MNPs as a promising material in the future of cancer treatment.

Upconversion Nanoparticle-Anchored Metal-Organic Framework Nanostructures for Remote-Controlled Cancer Optogenetic Therapy.

Optogenetics, a revolutionary technique utilizing light-sensitive proteins to control cellular functions with high spatiotemporal precision, presents a promising avenue for disease treatment; however, its application in cancer therapy remains constrained by limited research. Herein, we introduce a pioneering strategy for remote-controlled optogenetic cancer therapy, synergistically merging optogenetics with ion therapy, which incorporates ion self-supply, in situ ion channel construction, and near-infrared (NIR) light-activated ion therapy, facilitating remote and noninvasive manipulation of cellular activities in deep tissues and living animals. We report the facile synthesis of water-dispersible upconversion nanoparticle (UCNP)-metal-organic framework (MOF) nanohybrids capable of effectively delivering plasmid DNA to cancer cells, thereby enabling the in situ expression of photoactivatable cation channels. The pH-responsive MOF components serve as a reservoir for metal cations, which are released in the acidic microenvironment of tumors, while the UCNP components function as remote-controlled transducers, converting near-infrared (NIR) light into visible light to activate the cation channels and allowing the cancer influx of released metal cations for ion therapy. The proposed remote-controlled cancer optogenetic therapy demonstrates its effectiveness across multiple tumor models, including subcutaneous colon tumors, subcutaneous breast tumors, and orthotopic breast tumors. This study represents a significant step toward the realization of optogenetics in clinics, with substantial potential for advancing cancer therapy.

Efficacy and Safety of Zolbetuximab in Gastric Cancer.

Gastric cancer remains a major global health concern with high incidence and mortality rates, particularly in East Asia. Patients often have poor outcomes due to limited treatment efficacy. Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2)-overexpressed in 50% to 80% of gastric cancers-demonstrates promise by initiating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in CLDN18.2-positive cells. In clinical trials, zolbetuximab with chemotherapy improved progression-free survival (PFS) and overall survival (OS). The FAST trial showed a median OS increase from 8.4 months to 13.2 months (HR, 0.72; P < .01). The SPOTLIGHT trial found PFS extended to 11.0 months vs. 8.9 months (HR, 0.73; P = .0024) with OS reaching 18.2 months in the zolbetuximab arm. The GLOW trial also confirmed efficacy, with median OS improving from 12.16 months to 14.39 months (HR, 0.771; P = .0118). Zolbetuximab's targeted action, combined with manageable adverse effects, positions it as a promising therapy for advanced gastric cancer.

Early Integration of Palliative Care into Oncology Practice: Is It Still a Mirage?

Abstract For over a decade, “early integration” has become a slogan in the palliative care (PC) community. The care of cancer patients requires improvement, and the studies on the early integration of PC reveal its deficits in the oncological practice. Unmet needs in physical, psychological, spiritual, or social care need to be addressed. A “collusion of hope” in cancer treatment delays appropriate end-of-life care and complicates bereavement. Communicating prognosis and comprehending survival and discussion on measures to enhance the quality of life frequently do not occur simultaneously. Early collaboration between an oncologist and a PC specialist for those with advanced cancer improves symptoms and reduces aggressive cancer care at the end of life without shortening survival. Within the changing care environment and increasing time limitations, the multidimensional needs of a patient on therapy for advanced cancer will increase. A holistic approach to the patient and the family hence requires a multi-professional team. Consensus around palliative quality indicators is in its infancy and is often governed by cost-effectiveness. This is a real crunch for already resource-poor settings.

Acute hyperglycemic hyperosmolar syndrome associated with capivasertib, a new, oral targeted therapy for advanced breast cancer

Acute hyperglycemic hyperosmolar syndrome associated with capivasertib, a new, oral targeted therapy for advanced breast cancer

Summary of Evidence on Nutritional Management for Patients Undergoing Chemotherapy.

This paper aims to consolidate the most robust evidence on nutritional strategies for patients undergoing chemotherapy, offering evidence-based guidance for clinical practice. The review highlights critical evidence gaps in nutritional therapy for advanced gastric cancer (AGC) patients undergoing systemic therapy, integrating findings from both prospective and retrospective studies. According to the "6S" evidence resource pyramid model, clinical decision-making tools, guidelines, expert consensus, and systematic reviews on nutritional management for chemotherapy patients were systematically retrieved from national and international databases. The methodological quality of the selected literature was evaluated using AGREE II for guidelines, the JBI Evidence-Based Healthcare Center's standards for systematic reviews, and expert consensus developed by evidence-based practice experts. A total of 47 articles were analyzed, consisting of 12 guidelines, 12 expert consensus statements, and 23 systematic reviews. The findings were categorized into five dimensions: interdisciplinary collaboration, nutritional screening and assessment, nutritional requirements, nutritional therapy, and discharge and follow-up, resulting in the identification of 62 pieces of relevant evidence. The study provides comprehensive, evidence-based recommendations for nutritional management in chemotherapy patients. Application of the evidence should be adapted to specific clinical scenarios, patient conditions, preferences, and expert judgment to ensure both feasibility and relevance in clinical practice. This review consolidates diverse nutritional management strategies into a unified framework, addressing evidence gaps in AGC under systemic therapy. Integrating prospective and retrospective studies with interdisciplinary insights provides evidence-based recommendations to enhance patient care through personalized and standardized approaches.

Single-cell multiomics reveals simvastatin inhibits pan-cancer epithelial-mesenchymal transition via the MEK/ERK pathway in XBP1+ mast cells

Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation.

Nanocarriers for Delivery of Anticancer Drugs: Current Developments, Challenges, and Perspectives

Cancer, the most common condition worldwide, ranks second in terms of the number of human deaths, surpassing cardiovascular diseases. Uncontrolled cell multiplication and resistance to cell death are the traditional features of cancer. The myriad of treatment options include surgery, chemotherapy, radiotherapy, and immunotherapy to treat this disease. Conventional chemotherapy drug delivery suffers from issues such as the risk of damage to benign cells, which can cause toxicity, and a few tumor cells withstand apoptosis, thereby increasing the likelihood of developing tolerance. The side effects of cancer chemotherapy are often more pronounced than its benefits. Regarding drugs used in cancer chemotherapy, their bioavailability and stability in the tumor microenvironment are the most important issues that need immediate addressing. Hence, an effective and reliable drug delivery system through which both rapid and precise targeting of treatment can be achieved is urgently needed. In this work, we discuss the development of various nanobased carriers in the advancement of cancer therapy—their properties, the potential of polymers for drug delivery, and recent advances in formulations. Additionally, we discuss the use of tumor metabolism-rewriting nanomedicines in strengthening antitumor immune responses and mRNA-based nanotherapeutics in inhibiting tumor progression. We also examine several issues, such as nanotoxicological studies, including their distribution, pharmacokinetics, and toxicology. Although significant attention is being given to nanotechnology, equal attention is needed in laboratories that produce nanomedicines so that they can record themselves in clinical trials. Furthermore, these medicines in clinical trials display overwhelming results with reduced side effects, as well as their ability to modify the dose of the drug.

Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment1-7. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting8. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer.

In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.

Talazoparib for the Treatment of Metastatic Castration-resistant Prostate Cancer

Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD+ binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib’s role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.

Efficacy of neoadjuvant therapy and lymph node dissection in advanced gallbladder cancer without distant metastases: a SEER database analysis.

To investigate the effectiveness of neoadjuvant therapy and lymph node dissection(LND) on overall survival (OS) in patients with stage III/IV gallbladder cancer without distant metastases. Data from 101 patients who received neoadjuvant therapy followed by surgery combined with adjuvant chemotherapy, and 1412 patients who received direct surgical treatment followed by adjuvant chemotherapy, were collected from the SEER database from 2004 to 2020. Patients were divided into group A (neoadjuvant therapy) and group B (direct surgery) based on the treatment modality. A total of 202 cases were obtained after propensity score matching, with 101 cases in each group (A and B). Cox unifactorial and multifactorial analyses were performed to identify independent risk factors for patients with advanced cholecystic carcinoma, and the Kaplan-Meier method was used to analyze overall survival (OS). The Cox proportional hazards model was used to investigate the effect of different subgroups on OS in both patient groups. Further survival analyses were conducted to determine whether lymph node dissection(LND) was beneficial for patients receiving neoadjuvant therapy for gallbladder cancer. Cox univariate analysis showed that marital status, AJCC stage, number of LND, tumor size, and treatment modality were associated with OS (P<0.05). Cox multifactorial regression analysis indicated that AJCC stage, LND, tumor size, and treatment modality were independent risk factors for OS in patients with non-metastatic advanced gallbladder cancer (P<0.05). Survival curves demonstrated that the OS in group A was longer than in group B (median OS: 30 months vs. 14 months, P<0.001). Subgroup analysis indicated that neoadjuvant therapy had a consistent effect on the OS of patients with advanced gallbladder cancer, improving both survival time and outcomes. Survival curves indicated that lymph node dissection was not significant in group A patients (p>0.05) but was significant in group B (p<0.05). Neoadjuvant therapy can improve the OS of patients with non-metastatic stage III/IV gallbladder cancer and is an independent risk factor affecting prognosis; however, the significance of lymph node dissection in these patients still needs further study.

Gold nanostars and nanourchins for enhanced photothermal therapy, bioimaging, and theranostics.

Photothermal therapy (PTT), a recently emerging method for eradicating tumors, utilizes hyperthermia induced by photo-absorbing materials to generate heat within cancer cells. Gold nanoparticles (AuNPs) have gained reliability for in vitro and in vivo applications in PTT due to their strong light absorbance, stability, and biocompatibility. Yet, their potential is limited by their spherical shape, impacting their size capabilities, electromagnetic enhancement effects, and localized surface plasmon resonance (LSPR). Anisotropic shapes have been tested and implemented in this treatment to overcome the limitations of spherical AuNPs. Nanostars (AuNSs) and nanourchins (AuNUs) offer unique properties, such as increased local electron density, improved catalytic activity, and an enhanced electromagnetic field, which have proven to be effective in PTT. Additionally, these shapes can easily reach the NIR-I and NIR-II window while exhibiting improved biological properties, including low cytotoxicity and high cellular uptake. This work covers the critical characteristics of AuNS and AuNUs, highlighting rough surface photothermal conversion enhancement, significantly impacting recent PTT and its synergy with other treatments. Additionally, the bioimaging and theranostic applications of these nanomaterials are discussed, highlighting their multifaceted utility in advanced cancer therapies.

CRISPR/Cas9 system: a novel approach to overcome chemotherapy and radiotherapy resistance in cancer.

Cancer presents a global health challenge with rising incidence and mortality. Despite treatment advances in cancer therapy, radiotherapy and chemotherapy remained the most common treatments for all types of cancers. However, resistance phenotype in cancer cells leads to unsatisfactory results in the efficiency of therapeutic strategies. Therefore, researchers strive to propose effective solutions to overcome treatment failure, which requires a deep knowledge of treatment-resistant mechanisms. The progression and occurrence of tumors can be attributed to gene mutation. Over the past decade, the emergence of clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) genome editing has revolutionized cancer research. This versatile technology enables cancer modeling, manipulation of specific DNA sequences, and genome-wide screening. CRISPR/Cas9 is an effective tool for identifying radio- and chemoresistance genes and offering potential adjunctive treatments to overcome tumor recurrence after chemo- and radiotherapy. This article aims to explain the potential of the CRISPR/Cas9 system in improving the effectiveness of chemo- and radiotherapy and ultimately overcoming treatment failure.

Enhancing lung cancer growth inhibition with calcium ions: Role of mid- and high-frequency electric field pulses

Calcium electroporation (CaEP) involves the combination of calcium ions with electroporation, which is induced by pulsed electric fields (PEFs). This study explores the application of high-frequency unipolar nanosecond pulsed electric fields (nsPEFs: 8–14 kV/cm, 200 ns, 10 kHz, 100 kHz, 1 MHz repetition frequency pulse bursts, n = 100) and their potential in inhibiting lung cancer cell growth. As a reference, standard microsecond range parametric protocols were used (100 µs x 8 pulses). Methods included cell permeability quantification through Yo-Pro-1 uptake, cell viability assays, immunofluorescence studies for apoptosis and EMT markers, analysis of cell death types depending on repetition frequency pulse bursts. We determined the susceptibility of human lung cancer to electric pulses, characterized the efficacy of CaEP, and investigated cell death types depending on repetition frequency pulse bursts. We have shown that adding calcium ions to the applied nsPEF protocol increases cytotoxicity. Additionally, the use of these electroporation parameters can modulate key cellular processes, such as the epithelial-mesenchymal transition and apoptosis, as indicated by changes in the expression of markers such as E-cadherin, N-cadherin, BCL-2, and p53. Changes in cell morphology over time were observed using holotomographic microscopy. The study provides insights into the modulation of key cellular processes, indicating that nsPEF technology could improve the outcomes of conventional cancer treatments through enhanced efficacy and potentially mitigating drug resistance mechanisms. The promising results advocate for further research to optimize nsPEF protocols for clinical application, highlighting the potential of electrical fields in advancing cancer therapy.

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.

LOXL1 promotes gastric cancer progression by β-catenin-cyclinD mediated proliferation

Although much progress has been made in chemotherapy or target therapy for advanced gastric cancer, the prognosis is still poor. It is necessary to screen biomarkers for early diagnosis and prognosis prediction. However, the prognostic value of LOX family in gastric cancer and the underlying molecular mechanisms for promoting the progression of gastric cancer remains unclear. Among five members of LOX family, LOXL1 was the unique independent prognostic risk factor. The nomogram established based on the expression of LOXL1 and other clinical parameters could predict the overall survival rate of gastric cancer. Knockdown (KD) of LOXL1 decreased cell proliferation and led to G1 phase arrest in gastric cells. According to GSEA analysis that LOXL1 was positively correlated with the WNT signaling pathway, in vitro experiment proved that LOXL1-KD reduced the phosphorylation level of β-catenin and the expression of the downstream G1 phase checkpoint CCND1. In conclusion, LOXL1 has been identified as a potential risk prognostic biomarker for gastric cancer by promoting gastric cancer proliferation via WNT/β-catenin/cyclinD1 pathway.

Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer.

Background/Objectives: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer. This may be due to the elevated level of immunosuppression observed in prostate cancer, which remains largely refractory to immune checkpoint blockade. Methods: We developed a vaccine targeting AR-V7, a common isoform associated with treatment resistance, and demonstrated its ability to elicit AR-V7-specific immunity and enable anti-tumor responses against AR-V7+ cancers in subcutaneous tumor models. Results: Our studies also revealed that AR-V7 expression conferred an immune suppressive phenotype that was significant in a non-AR-dependent prostate cancer model. Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Conclusions: Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.