Normalization Of Tumor Vasculature Research Articles

Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo.

Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality?

Simple SummaryDespite substantial theoretical and experimental support for using vascular normalization as cancer therapy, effectively achieving this strategy in the clinic remains complex. In the present paper, we propose a novel potential approach for the induction of tumor vascular normalization, reduction of hypoxia, and improvement of conventional treatment in cancer patients. This approach consists of the pharmacological modulation of a patient’s plasma S1P levels which through a PDGF signaling can enhance tumor vasculature functionality and reduce hypoxia. This approach is proposed following a clinical observation in pancreatic adenocarcinoma patients and pre-clinical data in different in vivo tumor models, and is supported by a review of the literature describing the biological role of S1P in vascular functionality regulation.Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer.

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches.

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

PH-responsive nanomedicine co-encapsulated with Erlotinib and chlorin e6 can enable effective treatment of triple negative breast cancer via reprogramming tumor vasculature

High expression of epidermal growth factor receptor (EGFR) involved in promoting tumor proliferation, hypoxia, and many others has found to be associated with poor prognosis of diverse cancers including triple negative breast cancer (TNBC). The newest progresses have indicated that anti-EGFR chemotherapy could reinforce various cancer treatments by normalizing the abnormal tumor vasculature to improve tumor oxygenation, but suffers from severe side effects owing to the constitutive expression of EGFR in normal tissues. Herein, we develop a pH-responsive nanomedicine simultaneously loaded of Erlotinib, an inhibitor of EGFR tyrosine kinase, and chlorin e6 (Ce6), a photosensitizer, via the CaCO3-assistant emulsion method. The obtained Erlotinib-Ce6-loaded CaCO3 nanoparticles (ECCaNPs) show pH-responsive release of payloads and efficient tumor accumulation, thus enable the normalization of tumor vasculature to improve intratumoral oxygenation and decrease tumor growth by inhibiting EGFR/extracellular regulated protein kinases (ERK)/ AKT serine/threonine kinase 1 (AKT) axis. ECCaNPs together with light exposure can collectively suppress the growth of TNBC cell-line-derived and patient-derived xenograft mouse models through combined chemo- & photodynamic therapy. This study highlights that anti-EGFR chemotherapy programmed tumor vasculature could thereby enhance the therapeutic efficacy of oxygen-consuming cancer treatments, offering a promising strategy to figure out efficient combination cancer treatments to benefit TNBC patients.

Endocrine and Neuroendocrine Tumors Special Issue-Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Simple SummaryIn the past decade, the landscape of cancer treatment has radically changed after the introduction of immunotherapy. Adrenocortical carcinoma and metastatic pheochromocytoma/paraganglioma are rare cancers with limited responses to traditional cancer treatments. The use of immunotherapy against these cancers has yielded a few responses when used alone or in combination with other drugs. We reviewed the current literature to summarize the role of immunotherapy in these rare cancers.Adrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials.

Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BackgroundSignaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage.MethodsIn this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification.ResultsBD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells.ConclusionsThese data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Conquering the Hypoxia Limitation for Photodynamic Therapy.

Photodynamic therapy (PDT) has aroused great research interest in recent years owing to its high spatiotemporal selectivity, minimal invasiveness, and low systemic toxicity. However, due to the hypoxic nature characteristic of many solid tumors, PDT is frequently limited in therapeutic effect. Moreover, the consumption of O2 during PDT may further aggravate the tumor hypoxic condition, which promotes tumor proliferation, metastasis, and invasion resulting in poor prognosis of treatment. Therefore, numerous efforts have been made to increase the O2 content in tumor with the goal of enhancing PDT efficacy. Herein, these strategies developed in past decade are comprehensively reviewed to alleviate tumor hypoxia, including 1) delivering exogenous O2 to tumor directly, 2) generating O2 in situ, 3) reducing tumor cellular O2 consumption by inhibiting respiration, 4) regulating the TME, (e.g., normalizing tumor vasculature or disrupting tumor extracellular matrix), and 5) inhibiting the hypoxia-inducible factor 1 (HIF-1) signaling pathway to relieve tumor hypoxia. Additionally, the O2 -independent Type-I PDT is also discussed as an alternative strategy. By reviewing recent progress, it is hoped that this review will provide innovative perspectives in new nanomaterials designed to combat hypoxia and avoid the associated limitation of PDT.

Bevacizumab-Induced Tumor Vasculature Normalization and Sequential Chemotherapy in Colorectal Cancer: An Interesting and Still Open Question.

Bevacizumab is a recombinant fully humanized IgG1 targeting the Vascular Endothelial Growth Factor A (VEGF-A). The rationale of its use in oncology relies on the critical role of VEGF-A-induced neo-angiogenesis in the growth of many solid tumors (1–3). Since its discovery, many evidences suggested that it did not display direct antitumor action but rather contributes to improve the effects of associated chemotherapy. In fact, following bevacizumab administration, intratumoral vessels become morphologically more organized, and hypoxia and interstitial fluid pressure reduce (“vasculature normalization”); as a consequence, chemotherapy drug delivery into tumor masses ameliorates (4). Avallone et al. published the first randomized phase III study (OBELICS study) comparing the sequential administration of bevacizumab before standard oxaliplatin-based chemotherapy versus a traditional concomitant regimen in metastatic colorectal cancer (CRC) (5). The intent was to optimize bevacizumab and chemotherapy association by administering the chemotherapy in the “normalization window” and ameliorate the antitumor effects. The “normalization window” is the time window during which the anarchist texture of tumor vasculature becomes macroscopically more linear and less dense (1–4) ( Figure 1 ). The authors fail to meet the primary end-point based on a difference in objective response rate (ORR) between the two arms. The odds ratio of response for experimental (ORR: 56.5%) versus standard arm (ORR: 57.4%) was 0.96 (95% CI: 0.55–1,68, P=0.89). We would add insights and prompt discussion making hypotheses on the causes of failure. This is important for scientific discussion and for planning future trials. Open in a separate window Figure 1 Schematic representation of the “normalization window” of anti-angiogenic treatment of tumor masses during time and space.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake.

Simple SummaryIn order for solid tumors to grow, they need to develop new blood vessels in order to support their increasing metabolic requirements. To facilitate the novel vessel formation, the tumor initiates an aggressive pro-angiogenic program. As a result of the aggressive angiogenesis, blood vessels form very rapidly and are often malformed and dysfunctional. There is a reduction in perfusion to the tumor, and often the tumors exhibit significant areas of tumor hypoxia. This review paper discusses the pro-tumorigenic environment induced by tumor hypoxia and how this can be targeted through normalization of the tumor vasculature. Here, we review tumor angiogenesis, the development of a hypoxic phenotype, and how this contributes to sustained tumorigenesis and resistance to therapy. We further discuss the potential of vascular normalization to reduce tumor hypoxia and facilitate uptake and efficacy of a variety of therapies.A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area.

CD93 Blockade Stabilizes Tumor Vasculature to Improve Therapy Response.

CD93/IGFBP7 pathway disruption normalizes tumor vasculature and increases immune infiltration.

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

Abstract 424: An effective treatment for recurrent and inoperable anaplastic thyroid carcinoma using sintilimab and anlotinib: A case report

Abstract Introduction: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and rapid spreading cancers. None of the existing therapies is optimum and most ATC patients experience rapid recurrence. The median overall survival (OS) of ATC patients is about 5 months. Here, we report an ATC patient, who experienced rapid recurrence after operation, achieved OS of 9 months by applying a novel strategy of combining anti-angiogenic agent, anlotinib with immunotherapeutic drug, sintilimab. Case presentation: The female ATC patient was 78 years old. On September 24, 2019, she had total thyroidectomy of the left lobe and isthmus due to a 4.7 cm × 4.2 cm lump in the left anterior cervical region. The mass was diagnosed as anaplastic thyroid cancer (pT3Nx). Immunohistochemistry and molecular testing analysis of the tumor showed the tumor proportion score of programmed death-ligand 1 <1% (PD-L1-negative), tumor mutation burden of 1.88 mut/Mb (TMB-low), microsatellite stable, and mutations of BAI1, CDKN1A, EIF1AX, HRAS, IKBKB, and TP53. One month after the surgery, the tumor (3.3 cm × 1.5 cm) reappeared accompanied by metastases in right lung and sigmoid colon, which deemed her ineligible for another surgery. The patient rejected the use of chemo- or radio-therapy. Since no effective therapies were available, a novel combo strategy was used for this patient: anti-angiogenic agent anlotinib orally 12 mg per day and 2-week on/1-week off; and the immunotherapeutic agent, sintilimab, administrated with 200 mg once every 3 weeks. 2.5 months after the treatment, the recurrent tumor was reduced to 2.5 cm × 1.8 cm, and no lesions were found in the lung and colons. The patient continued to take sintilimab and anlotinib and the disease was under control. During treatment, no adverse reactions were observed. However, she died in May 2020 of abnormal thyroid function. Partial response (PR) and OS of 9 months were achieved. Discussion: In this case, the novel anti-angiogenic drug anlotinib was chosen because it was proven to be safe and effective in treating multiple cancers without targeted mutations. Although the patient did not have positive indicators for immunotherapy (PD-L1 negative/TMB-low), we added sintilimab for the previous evidences of synergistic effect of anti-angiogenic drugs and immunotherapy in other cancers. Anti-angiogenic drug could increase the expression of immune cell markers including PD-L1; moreover, normalized tumor vasculature could increase the infiltration of immune cells. Here, our case provides supportive evidence for using this combination in the treatment of ATC patients. Conclusion: This case showed relatively good prognosis after using anti-angiogenic agent, anlotinib, and immunotherapeutic drug, sintilimab, suggesting a new direction in treating recurrent and inoperable ATC patients, and also providing a new way for cancer patients with PD-L1 negative/TMB-low. Citation Format: Shiheng Zhang, Yuntong Liu, Jiamin Luo, Yu Fang, Tonghui Ma, Xiaoyan Zhang, Wei Guan. An effective treatment for recurrent and inoperable anaplastic thyroid carcinoma using sintilimab and anlotinib: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 424.

Bifunctional Therapeutic Peptide Assembled Nanoparticles Exerting Improved Activities of Tumor Vessel Normalization and Immune Checkpoint Inhibition.

The effectiveness of cancer immunotherapy is impaired by the dysfunctional vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic immune cells help to have immune resistance in tumor tissue. Structural and functional normalization of abnormal tumor vasculature provide vessels for more perfusion efficiency and drug delivery that result in alleviating the hypoxia in the tumor site and increasing infiltration of antitumor T cells. Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune checkpoint blocking peptide (D PPA) is designed and characterized. FSEC peptide is known to be involved in vessel normalization of tumors in vivo. D PPA is an inhibitory peptide of the PD-1/PD-L1 immune checkpoint pathway. The peptide amphiphile nanoparticle sets out to test whether simultaneous modulation of tumor vasculature and immune systems in the tumor microenvironment has a synergistic effect on tumor suppression. Increased intratumoral infiltration of immune cells following vascular normalization, and simultaneously blocking the immune checkpoint function of PD-L1 reactivates effective immune responses to the tumors. In summary, the current study provides a new perspective on the regulation of tumor vessel normalization and immunotherapy based on functional peptide nanoparticles as nanomedicine for improved therapeutic purposes.

Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy

BackgroundBiglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear.MethodsBiglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively.ResultsBreast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice.ConclusionOur results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.

Repurposing Chloroquine Analogs as an Adjuvant Cancer Therapy.

Drug repurposing is emerging as an attractive strategy with lower attrition rate, lower cost and shorter timeframe than traditional drug discovery methods. Chloroquine (CQ) and its analogs are old drugs originally indicated for malaria treatment. Serendipitous discovery in early years revealed its anti-inflammatory properties, thus allowing its repositioned use in autoimmune diseases. Recent evidence also suggested its potential therapeutic use for anticancer therapy. This article reviews the molecular mechanisms, clinical evaluation and recent patents of CQ analogs in cancer therapy. Literature and patent searches were conducted using PubMed database and Google Patent/ USPTO Patent Search database, respectively. The keywords including "chloroquine", "hydroxychloroquine", "chloroquine analogs", "chloroquine derivatives", "repurposing", "autophagy", and "cancer" were used. CQ analogs have been reported to elicit their anticancer effects by modulating autophagy, inducing apoptosis, eliminating cancer stem cells, normalizing tumor vasculature and modulating antitumor immunity. As documented by recent patents and clinical trials, CQ analogs have been repurposed as an adjuvant therapy and combined with other anticancer agents for synergistic enhancement of treatment efficacy. However, most clinical trials on CQ only demonstrated modest improvement in anti-cancer efficacy. Given that CQ loses its anticancer activity in acidic and hypoxic environment within a tumor, novel CQ analogs and/or their formulations are under active investigation to improve their physicochemical properties and biological activity. On the other hand, identification of new biomarkers for better patient selection has been advocated in future trials in order to realize the repurposing of CQ analogs for cancer treatment in a personalized manner.

Phase I with expansion clinical trial of seleno-l-methionine (SLM) in combination with axitinib in patients with relapsed clear cell renal cell carcinoma (ccRCC): Bench to bedside.

322 Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .

Sialic acid-modified mesoporous polydopamine induces tumor vessel normalization to enhance photodynamic therapy by inhibiting VE-cadherin internalization

Tumor hypoxia do harm to the therapeutic efficiency of photodynamic therapy (PDT) since sufficient local O2 concentration is necessary for the generation of toxic singlet O2 (1O2). Herein, a sialic acid-PEG-modified mesoporous polydopamine nanoparticle dual loaded with indocyanine green and 3PO-loaded (SPMI/3) was fabricated. Owing to the specific combination between sialic acid and E-selectin overexpressed on the inflammatory endothelial cells around tumors, SPMI/3 demonstrated a 1.39-fold higher accumulation than that of the PMI/3-treated group. After laser irradiation, SPMI/3 revealed a potent anti-tumor efficacy due to the combination therapy of PDT and photothermal therapy in the early stage of treatment. Later, thanks to the overexpression of vascular endothelial growth factor induced by PDT, the slowly released 3PO from SPMI/3 reduced by 65.20% endocytosis of VE-cadherin compared to the PBS group. Accordingly, SPMI/3 normalized tumor vessels by increasing laminin and pericyte coverage, contributing to the decreased vascular permeability and improved tissue hypoxia. All these improvements contributed to the normalized tumor vasculature and inhibition of metastasis. In conclusion, this finding provides a novel strategy to enhance PDT therapy via tumor vessel normalization.

Remodeling the homeostasis of pro- and anti-angiogenic factors by Shenmai injection to normalize tumor vasculature for enhanced cancer chemotherapy

Ethnopharmacological relevanceNormalization of the tumor vasculature can enhance tumor perfusion and the microenvironment, leading to chemotherapy potentiation. Shenmai injection (SMI) is a widely used traditional Chinese herbal medicine for the combination treatment of cancer in China. Aim of this studyThis study aimed to investigate whether SMI can regulate tumor vasculature to improve chemotherapy efficacy and identify the underlying mechanism. Materials and methodsThe antitumor effect of SMI combined with 5-florouracil (5-FU) was investigated in xenograft tumor mice. Two-photon microscopy, laser speckle contrast imaging and immunofluorescence staining were used to investigate the effects of SMI on tumor vasculature in vivo. The mRNA and protein expression of pro- and anti-angiogenic factors were measured by Q-PCR and ELISA. Histone acetylation and transcriptional regulation were detected by Western blot and ChIP assay. ResultsSMI promoted normalization of tumor microvessels within a certain time window, which was accompanied by enhanced blood perfusion and 5-FU distribution in tumors. SMI significantly increased the expression of antiangiogenic factor angiostatin and decreased the pro-angiogenic factors VEGF, FGF and PAI-1 by day 10. SMI combined with neoadjuvant chemotherapy in colorectal cancer patients also showed a significant increase in angiostatin and decrease in VEGF and FGF in surgically resected tumors when compared to the neoadjuvant chemotherapy group. Further in vitro and in vivo studies revealed that SMI downregulated VEGF, FGF and PAI-1 mRNA expression by inhibiting histone H3 acetylation at the promoter regions. The enhanced production of angiostatin was attributed to the regulation of the plasminogen proteolysis system via SMI-induced PAI-1 inhibition. ConclusionSMI can remodel the homeostasis of pro- and anti-angiogenic factors to promote tumor vessel normalization, and thus enhance drug delivery and anti-tumor effect. This study provides additional insights into the pharmacological mechanisms of SMI on tumors from the perspective of vascular regulation.