Inhibition Of Tumor Angiogenesis Research Articles

Traditional Chinese Medicine for Cancer Treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

PH-responsive drug-loaded peptides enhance drug accumulation and promote apoptosis in tumor cells

The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising.

Screening and construction of nanobodies against human CD93 using phage libraries and study of their antiangiogenic effects.

Cluster of Differentiation 93 (CD93) plays an important role in angiogenesis and is considered an important target for inhibiting tumor angiogenesis, but there are currently no therapeutic antibodies against CD93 in the clinic. Thus, we describe the screening of novel nanobodies (Nbs) targeting human CD93 from a phage library of shark-derived Nbs. Screening and enrichment of phage libraries by enzyme-linked immunosorbent assay (ELISA). Anti-CD93 Nbs were purified by expression in E. coli. The binding affinity of anti-CD93 Nbs NC81/NC89 for CD93 was examined by flow cytometry (FC) and ELISA. The thermal stability of NC81/NC89 was examined by ELISA and CD spectroscopy. Afterward, the anti-angiogenic ability of NC81/NC89 was examined by MTT, wound healing assay, and tube formation assay. The expression level of VE-cadherin (VE-Ca) and CD93 was detected by Western Blot (WB). The binding sites and binding forms of NC81/NC89 to CD93 were analyzed by molecular docking. The anti-CD93 Nbs were screened in a phage library, expressed in E. coli, and purified to >95% purity. The results of FC and ELISA showed that NC81/NC89 have binding ability to human umbilical vein endothelial cells (HUVECs). The results of ELISA and CD spectroscopy showed that NC81/NC89 retained the ability to bind CD93 at 80°C and that the secondary structure remained stable. In vitro, the results showed that NC81 and NC89 significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) as well as tube formation on Matrigel. Western Blot showed that NC81 and NC89 also inhibited the expression of VE-Ca thereby increasing vascular permeability. It was found during molecular docking that the CDR regions of NC81 and NC89 could be attached to CD93 by strong hydrogen bonds and salt bridges, and the binding sites were different. We have successfully isolated NC81 and NC89, which bind CD93, and both Nbs significantly inhibit angiogenesis and increase vascular permeability. These results suggest that NC81 and NC89 have potential clinical applications in angiogenesis-related therapies.

Metronomic Chemotherapy for Pediatric Refractory Solid Tumors: A Retrospective Single-Center Study.

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage.

Pre-coating cRGD-modified bovine serum albumin enhanced the anti-tumor angiogenesis of siVEGF-loaded chitosan-based nanoparticles by manipulating the protein corona composition

Chitosan-based nanoparticles inevitably adsorb numerous proteins in the bloodstream, forming a protein corona that significantly influences their functionality. This study employed a pre-coated protein corona using cyclic Arg-Gly-Asp peptide (cRGD)-modified bovine serum albumin (BcR) to confer tumor-targeting capabilities on siVEGF-loaded chitosan-based nanoparticles (CsR/siVEGF NPs) and actively manipulated the serum protein corona composition to enhance their anti-tumor angiogenesis. Consequently, BcR effectively binds to the nanoparticles' surface, generating nanocarriers of appropriate size and stability that enhance the inhibition of endothelial cell proliferation, migration, invasion, and tube formation, as well as suppress tumor proliferation and angiogenesis in tumor-bearing nude mice. Proteomic analysis indicated a significant enrichment of serotransferrin, albumin, and proteasome subunit alpha type-1 in the protein corona of BcR-precoated NPs formed in the serum of tumor-bearing nude mice. Additionally, there was a decrease in proteins associated with complement activation, immunoglobulins, blood coagulation, and acute-phase responses. This modification resulted in an enhanced impact on anti-tumor angiogenesis, along with a reduction in opsonization and inflammatory responses. Therefore, pre-coating of nanoparticles with a functionalized albumin corona to manipulate the composition of serum protein corona emerges as an innovative approach to improve the delivery effectiveness of chitosan-based carriers for siVEGF, targeting the inhibition of tumor angiogenesis.

MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non‐small cell lung cancer

AbstractBackgroundAngiogenesis plays an important role in the occurrence and development of non‐small cell lung cancer (NSCLC). The atypical mitogen‐activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.MethodsAdult male C57BL/6 wild‐type mice were randomly divided into the control group and p‐siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.ResultsWe found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c‐Jun n‐terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.ConclusionOur results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

Abstract LB447: Drug delivery and efficacy testing using vascularized tumor-on-a-chip

Abstract The inhibition of tumor angiogenesis is considered a promising strategy to impede cancer progression, as the vasculature associated with tumors plays a crucial role in supplying blood and facilitating metastasis. Therefore, the in vitro replication of vascularized tumors is essential for comprehending cancer pathology and discerning the mechanisms governing tumor cell proliferation, metastasis, and response to pharmaceutical interventions. In this study, we fabricated vascularized tumor-on-a-chip to recapitulate the pathological features of solid tumors. We first developed hybrid spheroids consisting of tumor and endothelial cells, resulting in self-assembled intratumoral vessels. This approach enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed of only cancer cells. RNA sequencing analysis revealed that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behaviors, such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Notably, we successfully induced both lymphangiogenesis and angiogenesis around the tumor hybrid spheroids by promoting interstitial flow. In summary, our findings demonstrated that vascularized tumor-on-a-chip reproduces various characteristics of vascularized tumors. Consequently, our model stands as a valuable platform for investigating interactions between within tumor microenvironments and exploring therapeutic strategies in cancer. Citation Format: Da-Hyun Kim. Drug delivery and efficacy testing using vascularized tumor-on-a-chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB447.

In situ assembly FeS2-tetrathiomolybdate nanosheets for imaging-guided tumor vascular collapse and amplified catalytic therapy

Catalytic therapy has recently gained considerable attention as a novel tumor microenvironment (TME)-responsive treatment. While conventional nano-catalysts have demonstrated the ability to induce the death of tumor cells through oxidative damage via the generation of reactive oxygen species (ROS), their therapeutic efficacy is impeded by several factors, including limited tissue penetration depth and suboptimal catalytic efficiency. Herein, the FeS2-tetrathiomolybdate (FeS2-TTM) nanosheet was synthesized via in-situ self-assembled in the specific redox TME using metal precursors of divalent iron and tetrathiomolybdate, and these metal precursors could easily enter tumor cells through vascular penetration to avoid the blood-brain barrier. This nanosheet has been proved to possess peroxidase (POD)-like catalytic activity, which overcomes the limitations of traditional nanoparticals by the bimetallic electron transfer effect in the TME to amplify the catalytic treatment effect. Importantly, it retains the chelating copper characteristics of TTM, and inhibits tumor angiogenesis by depriving the necessary copper in cells and angiogenesis, resulting in vascular embolization to cause tumor blood vessels to collapse. Additionally, it can also act as a nanoprobe that supports both real-time fluorescence imaging monitoring and T1/T2 dual-modality magnetic resonance imaging (MRI). As a promising nanomaterial, this new type of in-situ self-assembled nanosheet provides more varieties for the construction of an integrative platform of tumor diagnosis and treatment.

Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment.

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

Abstract 6817: Control of breast cancer via pro-resolving mediators

Abstract Tumor recurrence is the principal cause of mortality in breast cancer, yet the underlying mechanisms are not well understood. Anti-estrogen therapy, including tamoxifen, reduces tumor burden by inducing apoptosis and necrosis of cancerous tissue. The resulting cellular debris may stimulate tumor growth by disrupting inflammation resolution and creating pro-inflammatory and pro-tumorigenic microenvironments. Compared to estrogen receptor (ER)-positive breast cancer, ER-negative behaves aggressively, and patients have a poor prognosis due to the lack of treatment options. Here, we demonstrate that breast tumor cells killed by cytotoxic anti-estrogen therapy or chemotherapy (“tumor cell debris”) stimulate primary tumor growth when co-injected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering a macrophage-derived pro-inflammatory and pro-angiogenic “cytokine storm.” Thus, tumor cell debris is a critical risk factor for aggressive breast cancer growth. To assess whether stimulating the clearance of debris would impact breast cancer progression in vivo, we utilized maresin 1 (MaR1), maresin conjugates in tissue regeneration (MCTR1, MCTR2) and protectin conjugates in tissue regeneration (PCTRs), which are specialized pro-resolving lipid autacoid mediators (SPMs). We treated established models of ER-positive (EO771) and negative (4T1) breast cancer. Each maresin sharply reduced tumor growth in debris-stimulated and spontaneous (e.g. MMTV-PyMT) breast cancer models at nanogram concentrations without toxicity. Notably, PCTR1 inhibited orthotopic triple-negative (4T1) growth and proliferation compared to chemotherapy (paclitaxel) or immunotherapy (anti-cytotoxic T-lymphocyte-associated protein 4, CTLA4). Similarly, PCTR1 alone or in combination with chemotherapy (paclitaxel) reduced gene expression and protein levels of pro-angiogenic factor CXCL12/SDF1 in the ER-negative (4T1) tumor microenvironment. In ER-positive (EO771), a triple combination of PCTR1, chemotherapy (paclitaxel), and immunotherapy (anti-CTLA4) treatment potentiated the immune checkpoint blockade. Maresins also stimulated macrophage phagocytosis of therapy-generated breast tumor cell debris, inhibited tumor angiogenesis, and dampened a therapy-induced cytokine storm, including TNF-α, MIP-2/CXCL2, CCL2/MCP-1, IL- 1ra/IL-1F3, and G-CSF. Expression of SPM receptors (e.g. resolvin D1 (RvD1) receptor ALX/FPR2, resolvin D2 (RvD2) receptor GPR18, maresin 1 (MaR1) receptor LGR6, and resolvin E1 (RvE1) receptor ChemR23) were specifically identified in breast cancer tissue. Taken together, the maresin and protectin pathway mediators may represent a new therapeutic approach to stimulate the resolution of inflammation in breast cancer. Citation Format: Sarina A. Virani, Michael Gillespie, Haixia Yang, Diane R. Bielenberg, Mark W. Kieran, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Control of breast cancer via pro-resolving mediators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6817.

Abstract 1211: Biomarker analysis of pembrolizumab and ramucirumab neoadjuvant therapy for PD-L1-positive stage IB-IIIA lung cancer: EAST ENERGY trial

Abstract Background: Neoadjuvant treatments with novel combination immunotherapies for resectable non-small cell lung cancer (NSCLC) are being developed. Combination therapy with antiangiogenic agents and anti-PD-1/PD-L1 antibody has shown enhanced antitumor effects. EAST ENERGY is a single-arm multicenter phase 2 trial of neoadjuvant pembrolizumab and ramucirumab in patients with PD-L1-positive stage IB-IIIA NSCLC (NCT04040361). In this study, we aimed to identify biomarkers that predicts the efficacy of the neoadjuvant therapy. Furthermore, we aimed to elucidate the effect of the neoadjuvant therapy on the tumor microenvironment (TME). Methods: Patients enrolled in the EAST ENERGY trial (n=24) for whom pre- and post-treatment specimens were available (n=20) were included in this study. RNA-sequencing and multiplex immunohistochemistry (mIHC) were used to examine the association between the immunological phenotype of the TME and major pathological response (MPR), and changes in the TME before and after treatment. Results: MPR was achieved in 50.0% (12/24) of patients. Biomarker analyses with RNA-sequencing revealed that high expression of cancer-associated genes, and upregulation of interferon-gamma and interferon-alpha response in pre-treatment tumor were associated with MPR (q value<0.001). mIHC in pre-treatment samples revealed that abundance of CD8+ T cells in the pre-treatment TME was associated with MPR (p=0.039). On the other hand, infiltration of immunosuppressive cells such as Treg or M2-macrophages were not associated with resistance for the treatment (p=0.836, 0.639, respectively). Next, to clarify the effect of the neoadjuvant therapy on the TME, comparative analyses of pre- and post-treatment samples was performed. In gene set enrichment analysis, the neoadjuvant therapy enhanced gene set associated with interferon-gamma response (q value=0.051). Furthermore, angiogenesis-related gene set were downregulated after the treatment (q value=0.090). mIHC analyses revealed that the number of CD8+ T cells in the TME was significantly increased after the neoadjuvant therapy (p<0.001). Notably, Tregs/CD8+ T cells ratio and the number of M2-macrophage in the TME were significantly decreased after the neoadjuvant therapy (p=0.032, 0.003, respectively). Conclusion: In the neoadjuvant therapy with pembrolizumab and ramucirumab, immune-activated status before treatment serves as a potential biomarker for predicting treatment response. Moreover, combining ramucirumab with pembrolizumab reduced immunosuppressive cells in the TME and inhibited tumor angiogenesis. These results suggest that this combination therapy modifies the TME and augments antitumor immunity. Larger clinical trial is warranted to assess the efficacy of neoadjuvant therapy with ramucirumab and pembrolizumab in patients with PD-L1-positive NSCLC. Citation Format: Kotaro Nomura, Shogo Kumagai, Shohei Koyama, Keiju Aokage, Yoshihisa Shimada, Kiyotaka Yoh, Masashi Wakabayashi, Miki Fukutani, Hideki Furuya, Tomohiro Miyoshi, Kenta Tane, Joji Samejima, Tetsuro Taki, Takuo Hayashi, Jun Matsubayashi, Genichiro Ishii, Norihiko Ikeda, Hiroyoshi Nishikawa, Masahiro Tsuboi. Biomarker analysis of pembrolizumab and ramucirumab neoadjuvant therapy for PD-L1-positive stage IB-IIIA lung cancer: EAST ENERGY trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1211.

Abstract 2732: NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor microenvironment

Abstract The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is detected on leukocytes, epithelia and endothelia, and involved in cell adhesion through homophilic or heterophilic binding. In various gastrointestinal cancers, NSCLC (non-small cell lung cancer), and melanoma, CEACAM1 is highly expressed on tumor cells and tumor stroma, with its levels increasing as the disease progresses. Notably, CEACAM1 has been found to dampen T and NK cell functions while promoting tumor angiogenesis and metastasis. In this study, we present NB203, a novel CEACAM1/VEGF bispecific antibody developed using Neologics CEACAM-plus, a bifunctional molecule engineering platform designed to target and modulate the tumor microenvironment (TME). NB203 effectively accumulated in the TME and hindered the homophilic or heterophilic interactions of CEACAM1. It demonstrated a significant enhancement in T cell activities and NK cell-mediated killing of CEACAM1-expressing tumor cells, and the inhibition of tumor cell migration and polyploidy through macrophages. More importantly, NB203 was specifically designed to impede tumor angiogenesis. It exhibited an increased binding capacity to both CEACAM1 and VEGF in pro-angiogenic TME, and undermined intratumoral vessel maturation by blocking VEGF and negatively regulating myeloid cell-dependent tumor angiogenesis. In summary, our preclinical data indicate that NB203 exhibits effective anti-tumor activity by mediating NK and cytotoxic T cell activities, improving the immune-suppressive TME, and suppressing tumor angiogenesis. The use of NB203 holds promise in overcoming resistance to anti-VEGF therapy and substantially improving the safety of therapeutic targeting of angiogenesis in cancer treatment. Citation Format: Jinyu Dong, Binbin Wang, Dong Wang, Jie Ni, Tingting Bu, Haojie Wang, Bishnu Nayak, Baiyang Wang, Xin Dong, Yu Zhang. NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2732.

Abstract 3045: PPAR-α antagonist enhances immunotherapy and anti-angiogenic therapy to inhibit murine renal cancer

Abstract Peroxisome proliferator activated receptor alpha (PPARα) is a transcription factor and master regulator of fatty acid oxidation. PPARα ligands modulate the switch between co-activator and co-repressor transcription complexes at PPARα-controlled target genes. In addition, PPARα has been shown to transrepress NF-κB signaling and inhibit angiogenesis. Renal cell carcinoma (RCC) expresses high levels of PPAR-α and is a highly angiogenic cancer. Current frontline treatments for RCC include chemotherapy, anti-angiogenics, and immunotherapy but are limited by the immune suppressive state of the tumor microenvironment. TPST-1120 is a novel PPARα antagonist for the treatment of cancer patients that binds in the ligand binding domain, positioning the AF-2 activation helix in an inactive conformation. The inactive conformation has a lower affinity for co-activator motifs and reduces activation of PPARα regulated genes. In a CHO-based reporter cell line, TPST-1120 potently competed against the PPARα-specific agonist GW7647 (IC50 = 36 nM at 20 nM GW7647) and an endogenous PPARα agonist oleoylethanolamide (OEA; IC50 = 15 nM at 30 µM OEA). Furthermore, in an enzyme fragment complementation assay, we demonstrated that TPST-1120 inhibited agonist-induced binding of PPARα to MED1 by destabilizing the co-activator complex thereby stabilizing the inactive conformation of PPAR-α. In a murine model of renal cell adenocarcinoma (RENCA), TPST-1120 treatment for 12 days (30 mg/kg qd) reduced tumor growth by 52% as a monotherapy (p<0.0001). Consistent with these findings, TPST-1120 inhibited tumor angiogenesis and proliferation as quantified by Ki67 levels. Combination treatment with current frontline therapeutics resulted in synergistic tumor inhibition of 74% with anti-PD1 (200 ug Q3D for 12 days) and 81% with cabozantinib (15 mg/kg QD for 15 days) (p<.0001). Flow cytometry-based analysis of tumors demonstrated increased CD8+ T cell infiltration in the TME as well as decreases in M2 and elevations in M1 macrophages. Importantly, we demonstrate that TPST-1120 can reverse an immunosuppressive class of immune cells to promote anti-tumor immunity and anti-angiogenesis in kidney cancer in the absence of overt toxicity. These data support advancement of TPST-1120 into RCC. Citation Format: Michael Gillespie, Valerie Chen, Isabella Howard, Keira Smith, Dave Freund, Nathan Standifer, Dara Burdette, Thomas W. Dubensky, Sam Whiting, Dipak Panigrahy. PPAR-α antagonist enhances immunotherapy and anti-angiogenic therapy to inhibit murine renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3045.

Advances in tumor vascular growth inhibition.

Tumor growth and metastasis require neovascularization, which is dependent on a complex array of factors, such as the production of various pro-angiogenic factors by tumor cells, intercellular signaling, and stromal remodeling. The hypoxic, acidic tumor microenvironment is not only conducive to tumor cell proliferation, but also disrupts the equilibrium of angiogenic factors, leading to vascular heterogeneity, which further promotes tumor development and metastasis. Anti-angiogenic strategies to inhibit tumor angiogenesis has, therefore, become an important focus for anti-tumor therapy. The traditional approach involves the use of anti-angiogenic drugs to inhibit tumor neovascularization by targeting upstream and downstream angiogenesis-related pathways or pro-angiogenic factors, thereby inhibiting tumor growth and metastasis. This review explores the mechanisms involved in tumor angiogenesis and summarizes currently used anti-angiogenic drugs, including monoclonal antibody, and small-molecule inhibitors, as well as the progress and challenges associated with their use in anti-tumor therapy. It also outlines the opportunities and challenges of treating tumors using more advanced anti-angiogenic strategies, such as immunotherapy and nanomaterials.

Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer

BackgroundTumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear.MethodsConditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression.ResultsGli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis.ConclusionThe Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.

CPD-002, a novel VEGFR2 inhibitor, relieves rheumatoid arthritis by reducing angiogenesis through the suppression of the VEGFR2/PI3K/AKT signaling pathway

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002′s targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002′s effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.

Targeting STAT3 and NF-κB Signaling Pathways in Cancer Prevention and Treatment: The Role of Chalcones.

Chalcones are a type of natural flavonoid compound that have been found to possess promising anticancer properties. Studies have shown that chalcones can inhibit the growth and proliferation of cancer cells, induce apoptosis, and suppress tumor angiogenesis. In addition to their potential therapeutic applications, chalcones have also been studied for their chemopreventive effects, which involve reducing the risk of cancer development in healthy individuals. Overall, the anticancer properties of chalcones make them a promising area of research for developing new cancer treatments and preventative strategies. This review aims to provide a thorough overview of the central studies reported in the literature concerning cancer prevention and the treatment of chalcones. Although chalcones target many different mechanisms, the STAT and NF-κB signaling pathways are the ones this review will focus on, highlighting the existing crosstalk between these two pathways and considering the potential therapeutic opportunities for chalcone combinations.

Antiangiogenic Therapeutic mRNA Delivery Using Lung-Selective Polymeric Nanomedicine for Lung Cancer Treatment.

Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.

Comparison of intravesical chemotherapy regimens after radical nephroureterectomy for upper tract urothelial carcinoma and analysis of risk factors for postoperative recurrence.

Upper tract urothelial carcinoma (UTUC) is a relatively rare but aggressive type of urologic cancer that includes renal pelvic tumors and ureteral tumors with a poor prognosis. Full-length nephroureterectomy plus sleeve bladder resection is the standard treatment for the disease, but patients are prone to recurrence of bladder tumors after surgery. Intravesical infusion therapy is the main means to prevent the recurrence and progression of bladder cancer. Epirubicin and gemcitabine are widely used in clinical practice as first-line or salvage therapy for intravesical chemotherapy; however, the efficacy of these agents is rarely discussed. The purpose of this study was to investigate the effects of epirubicin and gemcitabine on the occurrence of bladder cancer after radical nephroureterectomy for UTUC and to analyze the risk factors affecting the recurrence of postoperative bladder cancer. A total of 215 patients with diagnosed UTUC and treated in our hospital from June 2019 to August 2021 were retrospectively selected as the research subjects, and they were divided into an observation group (120 cases) and a control group (95 cases) according to different treatment methods. The patients in the control group were treated with epirubicin, while those in the observation group received gemcitabine. All patients were followed up by telephone or outpatient examination for 12 months to record the occurrence of adverse reactions. The occurrence of bladder cancer was recorded at 3 months, 6 months, and 12 months after the surgery. According to the occurrence of bladder cancer after surgery, the patients were divided into a bladder cancer group (63 cases) and a non-bladder cancer group (152 cases). Multivariate Logistic regression analysis was used to analyze the risk factors of bladder cancer after surgery. The total incidence of adverse reactions in the control group was 49.47%, which was higher than that in the observation group with 15.00% (p<0.01). The incidence of bladder tumors in the observation group and the control group was 0.00% and 2.11% at 3 months, 5.00% and 8.42% at 6 months, 13.33% and 15.79% at 12 months, without significant difference (p>0.05). After 12 months of perfusion, the levels of acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in the two groups were significantly lower than those before perfusion (p<0.05). In the observation group, the levels of these three factors were slightly decreased compared with those in the control group, without a significant difference (p>0.05). Between the bladder cancer and non-bladder cancer groups, there were significant differences in tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer (p<0.05). The above indexes were all risk factors for postoperative bladder cancer (p<0.05). Epirubicin and gemcitabine reduced the occurrence of bladder cancer and effectively inhibited tumor angiogenesis after radical nephroureterectomy for UTUC. The tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer were risk factors for postoperative bladder cancer.

A meta‑ and bioinformatics analysis of maspin expression levels influencing the prognosis of patients with breast cancer.

Maspin is a serine protease inhibitor that is encoded by the human SERPINB5 gene. As a tumor inhibitor, it can inhibit the growth of tumor cells, increase adhesion between tumor cells and inhibit tumor angiogenesis. In the present study, a meta- and bioinformatics analysis was performed through the PubMed and China National Knowledge Infrastructure databases including entries added until up to March 20, 2023. It was found that compared with normal breast tissue, maspin expression was downregulated in breast cancer tissue. Maspin expression was negatively associated with lymph node metastasis. According to Kaplan-Meier plotter, it was found that lower maspin expression was negatively associated with the overall and distant metastasis-free survival rate of patients with estrogen receptor-positive, luminal A and grade 2 breast cancer. High expression of maspin was also positively associated with the relapse-free survival rate of patients of the luminal A subtype. Low maspin expression was positively associated with the post-progression and distant metastasis-free survival rate of the progesterone receptor-negative subtype. According to the GEPIA database, SERPINB5 mRNA expression was higher in normal than breast cancer tissues and negatively correlated with the TNM stage. High expression of maspin was also positively associated with the overall survival rate. In the UALCAN database, it was found that the mRNA and promoter methylation levels of SERPINB5 were higher in normal than in breast cancer tissues. These findings suggest that the expression of maspin may serve as a potential marker to indicate the occurrence, subsequent progression and even prognosis of breast cancer.