Targeted anti-angiogenesis therapy for advanced osteosarcoma.

To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients.

The potential of lenvatinib in breast cancer therapy.

Breast cancer, as a highly prevalent cancer among women, is one of the main causes of female mortality due to cancer. There is a need for more treatment options to improve the survival time of breast cancer patients. Metastasis to distant organs is a standard indicator of advanced breast cancer and a primary cause of breast cancer mortality, making the control of breast cancer metastasis crucial. Targeted therapy, with its advantages of precision, high effectiveness, and minimal side effects, has garnered significant attention as a hot research topic in breast cancer treatment. Among these therapies, anti-angiogenic therapy aim to inhibit tumor angiogenesis, control tumor growth, and reduce metastasis. Additionally, anti-angiogenic therapy can restructure the tumor vasculature, enhancing the effectiveness of other anti-cancer drugs. Lenvatinib, an orally available small molecule multi-targeted tyrosine kinase inhibitor, exerts its anti-tumor effects mainly by inhibiting tumor angiogenesis and tumor cell proliferation. It has been approved for the treatment of thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. Due to its multi-targeted nature, lenvatinib not only has direct anti-tumor effects but also possesses immunomodulatory activity, which can enhance the tumor immune response. This makes it a promising candidate for a broad range of cancers. Recent studies have explored the role of lenvatinib in breast cancer, including its various mechanisms of action and its use as a monotherapy or in combination to control breast cancer progression. This review will summarize the molecular mechanisms and research progress of lenvatinib in breast cancer treatment, discussing its potential applications and therapeutic prospects in managing breast cancer.

Pericytes recruited by CCL28 promote vascular normalization after anti-angiogenesis therapy through RA/RXRA/ANGPT1 pathway in lung adenocarcinoma.

BACKGROUND: It has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure. METHOD: Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC-MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter. RESULTS: Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells. CONCLUSION: We reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.

The anti-angiogenic and anti-vasculogenic mimicry effects of GN25 in endothelial and glioma cells.

BACKGROUND AND PURPOSE: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM. EXPERIMENTAL APPROACH: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways. KEY RESULTS: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures. CONCLUSION AND IMPLICATIONS: This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.

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Objective: Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. Methods: First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. Results: The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. Conclusion: RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

Mechanisms of angiogenesis in tumour.

Angiogenesis is essential for tumour growth and metastasis. Antiangiogenic factor-targeting drugs have been approved as first line agents in a variety of oncology treatments. Clinical drugs frequently target the VEGF signalling pathway during sprouting angiogenesis. Accumulating evidence suggests that tumours can evade antiangiogenic therapy through other angiogenesis mechanisms in addition to the vascular sprouting mechanism involving endothelial cells. These mechanisms include (1) sprouting angiogenesis, (2) vasculogenic mimicry, (3) vessel intussusception, (4) vascular co-option, (5) cancer stem cell-derived angiogenesis, and (6) bone marrow-derived angiogenesis. Other non-sprouting angiogenic mechanisms are not entirely dependent on the VEGF signalling pathway. In clinical practice, the conversion of vascular mechanisms is closely related to the enhancement of tumour drug resistance, which often leads to clinical treatment failure. This article summarizes recent studies on six processes of tumour angiogenesis and provides suggestions for developing more effective techniques to improve the efficacy of antiangiogenic treatment.

Efficacy and outcome analysis: Combination of Endostar and chemotherapy as a neoadjuvant treatment of stage IIIA/IIIB squamous cell lung cancer.

Patients with stage IIIA/IIIB squamous non-small cell lung cancer (SqCLC) are particularly challenging to treat with a poor 5-year survival rate and new treatment strategies are needed. In the present study, a retrospective, single-center study was conducted to explore the efficacy and safety of Endostar combined with chemotherapy as the neoadjuvant treatment in patients with stage IIIA/IIIB SqCLC. A total of 27 patients with locally advanced SqCLC treated with Endostar combined with chemotherapy as neoadjuvant therapy from January 1, 2017 to December 31, 2019 at the Zhejiang Cancer Hospital (Hangzhou, China) were included. Short-term efficacy, rate of surgical resection, long-term outcome and adverse events were analyzed. After treatment with Endostar combined with chemotherapy, 37% of the patients underwent surgery and the radical resection rate was 90%. The objective response rate was 63% for the total population and 80% for patients who received surgery. Of note, 100% of the patients achieved disease control after treatment with Endostar combined with chemotherapy. In patients who underwent surgical resection, postoperative pathology showed that 100% of the patients achieved pathological downstaging. Furthermore, 1 (10%) patient showed a pathological complete response after surgery. The median progression-free survival was 13.5 months and overall survival was 27.9 months for the total cohort. The most common adverse events (AEs) were anemia (69.4% of patients), followed by hypertension (29.6% of patients). Most of the AEs were grade 1-2 and only 4 patients (14.8%) developed grade 3-4 AEs. Endostar combined with chemotherapy was well-tolerated and showed promising efficacy in patients with stage IIIA/IIIB SqCLC. Further prospective studies are warranted to explore its value as a neoadjuvant therapy.

The application and research progress of anti-angiogenesis therapy in tumor immunotherapy.

Tumor immunotherapy, as the focus of scientific research and clinical tumor treatment in recent years, has received extensive attention. Due to its remarkable curative effect and fewer side effects than traditional treatments, it has significant clinical benefits for the treatment of various advanced cancers and can improve cancer patient survival in the long term. Currently, most patients cannot benefit from immunotherapy, and some patients may experience tumor recurrence and drug resistance even if they achieve remission overcome. Numerous studies have shown that the abnormal angiogenesis state of tumors can lead to immunosuppressive tumor microenvironment, which affects the efficacy of immunotherapy. Actually, to improve the efficacy of immunotherapy, the application of anti-angiogenesis drugs to normalize abnormal tumor vessel has been widely confirmed in basic and clinical research. This review not only discusses the risk factors, mechanisms, and effects of abnormal and normalized tumor angiogenesis state on the immune environment, but summarizes the latest progress of immunotherapy combined with anti-angiogenic therapy. We hope this review provides an applied reference for anti-angiogenesis drugs and synergistic immunotherapy therapy.

Clinical efficacy of PD-1 inhibitor combined with radiotherapy in a multi-drug resistant patient with liver metastasis from gastric cancer.

A 54-year-old male was diagnosed with extensive liver metastasis and small nodule metastasis in the lungs from gastric adenocarcinoma [Her-2 (-)]. The patient achieved significant partial response (PR) after chemotherapy combined with anti-angiogenesis therapy but developed progressive disease (PD) after 5 months. Then, the chemotherapeutic and anti-angiogenic drugs were replaced. Meanwhile, the delivery route of some chemotherapeutic drugs was changed, and some chemotherapeutic drugs were given via transcatheter arterial chemoembolization (TACE) to achieve PR, and PD developed after 3 months of remission maintenance. During chemotherapy combined with anti-angiogenesis, the application of programmed cell death-1 (PD-1) inhibitor achieved PR again and maintained for 5 months before disease progression. The progression of the lesions in the left lobe of the liver and the hepatic hilar lymph nodes was significant. Hence, chemotherapy was terminated and gamma stereotactic body radiation therapy (SBRT) was performed on left lobe lesions and hilar lymph nodes. The lesions both inside and outside the radiation field regressed significantly, reaching PR and abscopal effects. The immune-related adverse events (irAEs) occurred, including erythema and black and luster hair. The abscopal effects of lesion reduction in the radiation field and the enhancement of the immune function stimulated by radiation are a highlight of the combination of radiation and immunotherapy. In the end, the patient died of gastrointestinal failure, with overall survival of 18 months.

Long-term survival with anlotinib as a front-line treatment in an elderly NSCLC patient: A case report.

Background: Half of the population of non-small cell lung cancer (NSCLC) patients are older than 70 years and have limited therapeutic options due to poor tolerance and being excluded in most clinical trials. Anlotinib hydrochloride, a novel oral multi-target tyrosine kinase inhibitor, has been approved for the standard third-line treatment for NSCLC in China. Herein we report an elderly NSCLC patient without any driver gene mutations who was undergoing anlotinib as a front-line treatment and who achieved long-term survival. Case summary: The 77-year-old male patient was admitted to the hospital for chest tightness after engaging in physical activity for a week. The patient has been diagnosed with stage IIIB driver gene-negative squamous cell lung carcinoma. After that, he was treated with anlotinib for 2 years and 10 months from the first diagnosis until the last disease progression. Briefly, anlotinib combined with platinum-based chemotherapy was performed as the first-line therapy over six cycles. After 6 more cycles of anlotinib monotherapy maintenance, disease progression occurred. Then, anlotinib combined with tegafur was administered as a salvage treatment, and the disease was controlled again. After 29 cycles of anlotinib combined with tegafur regimens, the disease progressed finally. The patient achieved a total of 34 months of progression-free survival after anlotinib was used as the front-line treatment. He is still alive with a good performance status now (performance status score: 1). Conclusion: This patient achieved long-term survival using anlotinib as a front-line regimen combined with chemotherapy.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study.

The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

Recent advances of nanomaterial-based anti-angiogenic therapy in tumor vascular normalization and immunotherapy.

Anti-angiogenesis therapy and immunotherapy are the first-line therapeutic strategies for various tumor treatments in the clinic, bringing significant advantages for tumor patients. Recent studies have shown that anti-angiogenic therapy can potentiate immunotherapy, with many clinical trials conducted based on the combination of anti-angiogenic agents and immune checkpoint inhibitors (ICIs). However, currently available clinical dosing strategies and tools are limited, emphasizing the need for more improvements. Although significant progress has been achieved, several big questions remained, such as how to achieve cell-specific targeting in the tumor microenvironment? How to improve drug delivery efficiency in tumors? Can nanotechnology be used to potentiate existing clinical drugs and achieve synergistic sensitization effects? Over the recent few years, nanomedicines have shown unique advantages in antitumor research, including cell-specific targeting, improved delivery potentiation, and photothermal effects. Given that the applications of nanomaterials in tumor immunotherapy have been widely reported, this review provides a comprehensive overview of research advances on nanomaterials in anti-angiogenesis therapy, mainly focusing on the immunosuppressive effects of abnormal tumor vessels in the tumor immune microenvironment, the targets and strategies of anti-angiogenesis nanomedicines, and the potential synergistic effects and molecular mechanisms of anti-angiogenic nanomedicines in combination with immunotherapy, ultimately providing new perspectives on the nanomedicine-based synergy between anti-angiogenic and immunotherapy.

Drug-related adverse events potentially predict the efficacy of apatinib on advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs).  METHODS: This analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib. RESULTS: Patients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p < 0.001) had significantly better OS than those without corresponding AEs, and the appearance of HFS (p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS. CONCLUSION: Among all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.

Low-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8+T cells.

PURPOSE: Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy. METHODS: We tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy. RESULTS: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1. CONCLUSION: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

Patients undergoing immunotherapy always exhibit a low-response rate due to tumor heterogeneity and immune surveillance in the tumor. Angiogenesis plays an important role in affecting the status of tumor-infiltrated lymphocytes by inducing hypoxia and acidosis microenvironment, suggesting its synergistic potential in immunotherapy. However, the antitumor efficacy of singular anti-angiogenesis therapy often suffers from failure in the clinic due to the compensatory pro-angiogenesis signaling pathway. In this work, classic injectable thermosensitive PLGA-PEG-PLGA copolymer was used to construct a platform to co-deliver CA4P (vascular disruptive agent) and EPI for inducing immunogenic cell death of cancer cells by targeting the tumor immune microenvironment. Investigation of 4T1 tumor-bearing mouse models suggests that local administration of injectable V+E@Gel could significantly inhibit the proliferation of cancer cells and prolong the survival rate of 4T1 tumor-bearing mouse models. Histological analysis further indicates that V+E@Gel could effectively inhibit tumor angiogenesis and metastasis by down-regulating the expression of CD34, CD31, MTA1 and TGF-ß. Moreover, due to the sustained release kinetics of V+E@Gel, its local administration relieves the immune surveillance in tumor tissues and thus induces a robust and long-lasting specific antitumor immune response. Overall, this work provides a new treatment strategy through the mediation of the tumor immune microenvironment by vascular disruption to fulfill enhanced chemotherapy and immunotherapy.

Case report: Two novel intergenic region-ALK fusions in non-small-cell lung cancer resistant to alectinib: A report of two cases.

Background: The anaplastic lymphoma kinase (ALK) mutation, also known as the diamond mutation in non-small-cell lung cancer (NSCLC), has been treated with tremendous success since it was first reported in 2007. Alectinib, a second generation ALK-Tyrosine kinase inhibitor (TKI), has been reported to have significantly longer progression- free survival (PFS) than first generation ALK inhibitors in untreated ALK positive NSCLC. However, the clinical efficacy of ALK-TKIs on rare ALK fusions remains unclear. In recent years, with the popularity of next-generation sequencing (NGS) technology, an increasing number of novel ALK fusion partners have been reported, but the responses are heterogeneous among different ALK fusions. Considering the inconsistent reactions, the clinical efficacy of ALK-TKIs in rare ALK gene fusions remains to be evaluated in more cases. Methods: To seek for individualized therapy, the tumor tissues acquired during biopsy were sent for genomic testing by NGS based on a 139-gene panel and a 425-gene panel in a centralized clinical testing center (GENESEEQ Technology Inc, Nanjing, China). See Supplementary Material for more details about the methods for DNA-based NGS, RNA-based NGS. Results: We present two cases of patients with lung adenocarcinoma harboring two novel Intergenic Region (IGR)-ALK rearrangements detected by DNA sequencing, which had limited clinical response to ALK-TKIs but showed sensitivity to chemotherapy combined with bevacizumab therapy in patient 2, with a PFS of over 1 year up till the last follow-up assessment. Conclusions: In summary, our cases emphasize the need for comprehensive molecular analysis of different ALK fusion partners at the DNA level to formulate accurate treatment strategies and provide a certain therapeutic reference for these two types of novel IGR-ALK fusions.

Next-Generation Anti-Angiogenic Therapies as a Future Prospect for Glioma Immunotherapy; From Bench to Bedside.

Glioblastoma (grade IV glioma) is the most aggressive histopathological subtype of glial tumors with inordinate microvascular proliferation as one of its key pathological features. Extensive angiogenesis in the tumor microenvironment supplies oxygen and nutrients to tumoral cells; retains their survival under hypoxic conditions; and induces an immunosuppressive microenvironment. Anti-angiogenesis therapy for high-grade gliomas has long been studied as an adjuvant immunotherapy strategy to overcome tumor growth. In the current review, we discussed the underlying molecular mechanisms contributing to glioblastoma aberrant angiogenesis. Further, we discussed clinical applications of monoclonal antibodies, tyrosine kinase inhibitors, and aptamers as three major subgroups of anti-angiogenic immunotherapeutics and their limitations. Moreover, we reviewed clinical and preclinical applications of small interfering RNAs (siRNAs) as the next-generation anti-angiogenic therapeutics and summarized their potential advantages and limitations. siRNAs may serve as next-generation anti-angiogenic therapeutics for glioma. Additionally, application of nanoparticles as a delivery vehicle could increase their selectivity and lower their off-target effects.

Monitoring cancer cell surface receptor expression during anti-angiogenesis therapy in vivo.

Concurrent administration of cancer therapeutics with tumor vasculature targeting treatment has been shown to improve overall survival in multiple human cancer types, as such combinations aim to destroy different compartments of tumors. Anti-angiogenesis therapeutics designed to inhibit tumor induced vessel sprouting have also been shown to re-model the tumor vasculature through a transient vessel normalization effect, which leads to improved perfusion of oxygen and drug in tumor. However, the effects that this normalized vasculature has on the availability of cancer receptor, such as EGFR, is unknown. Herein, we examined the use of MRI-PAFT to estimate cancer surface receptor availability in response to anti-angiogenesis therapy, using MRI-coupled paired agent fluorescence tomography. Bevacizumab treated tumors showed increase in RA compared to control tumors, but this was not statistically significant.

Efficacy of Combination Docetaxel and Nintedanib in Advanced Non-Small Cell Lung Cancer in Thailand: A Multicenter Study.

INTRODUCTION: The mainstay systemic treatment for non-oncogenic addictive advanced stage non-small cell lung cancer is chemotherapy. Anti-angiogenic agents are additive compounds that enhance disease control and lead to improvement of overall survival benefit. Recently PD-(L)1 blockage, a checkpoint inhibitor, has been adopted as another line of treatment. A sequential strategy to enhance the efficacy of combination docetaxel and nintedanib after immunotherapy, correlated with genomic mutation, has been explored. METHOD: A retrospective cohort study of 56 patients from 8 centers in Thailand who received combination docetaxel and nintedanib via the Thai nintedanib Named Patient Use program was conducted. Demographic characteristics, treatment details, and treatment responses were retrieved from medical records. RESULTS: The majority of patients were male (62.5%) with adenocarcinoma subtype (88%). Thirty-five percent had sensitizing EGFR mutation. Combination docetaxel and nintedanib was given as second to fourth line of treatment. Median PFS of docetaxel/nintedanib was 5.6 months [95% CI 4.8-6.9]. Median OS of the entire cohort was 22.5 months [95% CI 20.2-31.1]. Among them, only four patients received this combination after immunotherapy which limited the validity of efficacy analysis. Median PFS of those four patients was 7.9 months [range 5.2-9.1] which was slightly higher than the remaining cohort (median PFS 4.5 months, 95% CI: 4.0-6.0, p-value 0.09). Among the adenocarcinoma subtype, a relapse-time of platinum-doublet chemotherapy of more than 6 months was solely indicated as a benefit of combination docetaxel/nintedanib treatment compared to the relapse-time of platinum-doublet chemotherapy of less than 6 months by multivariate HR of PFS 0.32 [95% CI: 0.14-0.68, p-value 0.003]. CONCLUSION: Combination docetaxel and nintedanib provided more benefit in relapse-time of platinum-doublet chemotherapy of more than 6 months in advanced stage adenocarcinoma lung cancer. Neither EGFR nor ALK alteration influenced the outcome of treatment.