Use Of Antiangiogenic Therapy Research Articles

Abstract 5908: Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate

Abstract Rare cancers are defined as cancers with an annual incidence rate lower than 15/100,000 by the National Cancer Institute. Despite what the terminology may suggest, rare cancers collectively are neither very rare, accounting for about a quarter of all cancers, nor less deadly than other forms of cancer. In fact, the comparative lack of research and case studies of rare cancers compared to other forms of cancer provides both an obstacle and a unique opportunity when it comes to drug development. While finding adequate animal models and cell lines to study the disease may be more difficult, the development of innovative treatment options for rare cancers is often incentivized by the Orphan Drug Act, accelerating approval from the FDA and acting as a gateway to approval for other indications. One such rare cancer is angiosarcoma, a rare cancer that originates from the endothelium. Angiosarcoma represents about 1% of total sarcomas and can develop anywhere in the body but occurs mainly in the breast, liver, or skin of the head and neck area. Angiosarcoma is characterized by a high metastasis rate of 16% to 44%, which results in a dismal prognosis, with overall survival ranging from 6 to 16 months. Considering the high reoccurrence rate and high metastatic potential of angiosarcoma, chemotherapeutic options seem to be the obvious choice. However, mainstream chemotherapies have failed to have long-term therapeutic effects. Another approach is the use of anti-angiogenic therapy, which proved effective but was unable to lead to a complete response. Herein, we describe a novel endothelial cell-targeting therapy option for the treatment of angiosarcoma. Previously, we have discovered Doppel, a 23 kDa GPI-anchored protein that is expressed specifically in the endothelium of tumor-associated blood vessels, except for the testis. Considering the fact that angiosarcoma is a rapidly growing tumor of endothelial origin, we hypothesized that Doppel might be a viable target for both the detection and treatment of angiosarcoma. We subsequently developed an antibody-drug conjugate to Doppel by conjugating a human antibody to MMAE using a unique linker, KGDEVD. When tested on xenografts of the angiosarcoma cell lines KU-CAS3 and KU-CAS5, the tumors responded extremely well to anti-Doppel ADC treatment. Most surprisingly, even tumors exceeding 1 cm^3 went into complete remission after 6 doses of the ADC. Thus, we delved deeper into the mechanism of action behind the ADC. ADC internalization was demonstrated using confocal microscopy. Apoptosis assays show that the ADC is capable of inducing apoptosis and caspase 3 expression in angiosarcoma cells, a crucial step in the activation of the KGDEVD linker. In-vitro toxicity assays of the ADC against KU-CAS3 show an IC50 value of 7.94 nM, much lower compared to normal endothelial cell lines. Citation Format: Byoungmo Kim, Ha Kyeong Lee, Youngro Byun, Yoon Gun Ko, Sang Yoon Kim. Angiosarcoma growth inhibition by targeting Doppel, a specific endothelial marker, with an antibody drug conjugate [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 5908.

Therapeutic potential of vasculogenic mimicry in urological tumors.

Angiogenesis is an essential process in the growth and metastasis of cancer cells, which can be hampered by an anti-angiogenesis mechanism, thereby delaying the progression of tumors. However, the benefit of this treatment modality could be restricted, as most patients tend to develop acquired resistance during treatment. Vasculogenic mimicry (VM) is regarded as a critical alternative mechanism of tumor angiogenesis, where studies have demonstrated that patients with tumors supplemented with VM generally have a shorter survival period and a poorer prognosis. Inhibiting VM may be an effective therapeutic strategy to prevent cancer progression, which could prove helpful in impeding the limitations of lone use of anti-angiogenic therapy when performed concurrently with other anti-tumor therapies. This review summarizes the mechanism of VM signaling pathways in urological tumors, i.e., prostate cancer, clear cell renal cell carcinoma, and bladder cancer. Furthermore, it also summarizes the potential of VM as a therapeutic strategy for urological tumors.

Варианты антиангиогенной терапия субретинальных кровоизлияний на фоне возрастной макулодистрофии

Purpose. To evaluate the effectiveness of various options for anti-angiogenic therapy in patients with subretinal hemorrhage (SRH) by of age-related macular degeneration (AMD). Material and methods. A total of 15 patients (15 eyes) with SRH by of AMD were treated. The mean duration of a hemorrhage from its onset to the start of treatment was 18.8 ± 10.0 days. The size of the SRH varied from 0.5 to 5 DD. The best corrected visual acuity (BCVA) before treatment varied from hand movement near the face to 0.1. Patients underwent the following treatment options for SRH: 1) anti-VEGF intravitreal injection (IVI) – 8 (53.3%); 2) IVI anti-VEGF + IVI prourokinase + IVI ophthalmic gas (SF6, C2F6) – 7 (46.7%). The average follow-up period for patients after treatment was 10.8 ± 6.3 months. Results and discussion. With the maximum follow-up period after the treatment in 2nd group it was possible to achieve hemorrhage displacement: partial – in 2 (58%) patients, complete – in 5 (71.5%) patients. At the maximum follow-up period, an improvement in BCVA in comparison with the preoperative one was observed in 8 (53.3%) cases, no dynamics – in 4 (26.7%) cases, and negative dynamics – in 3 (20%) cases. All patients underwent anti-VEGF therapy after the start of SRH treatment. Conclusions. The data obtained indicate that the use of antiangiogenic therapy of SRH by of AMD has positive results in improving BCVA and reducing the volume of hemorrhage. The choice of treatment method is determined by the size and duration of the existence of the SRH. It is necessary to continue anti-VEGF therapy in all patients after the start of treatment with SRH by of AMD. Keywords: submacular hemorrhage, age-related macular degeneration, pneumodislocation, anti-VEGF inhibitors, tissue plasminogen activator

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

Vascular anomalies represent a diverse group of disorders classified broadly as malformations or tumors and include the second most common hereditary bleeding disorder worldwide, hereditary hemorrhagic telangiectasia (HHT). Patients with HHT and other vascular anomalies suffer morbid consequences of these diseases, including bleeding, thrombosis, anemia, localized intravascular coagulation, tissue overgrowth, infections, and other complications. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis, and the treatments for vascular anomalies are rapidly evolving. Recent discoveries have elucidated the molecular basis of a number of common and uncommon vascular anomalies. HHT occurs due to mutations in the transforming growth factor beta (TGF‐β) pathway, resulting in vascular endothelial growth factor excess. Complex vascular anomalies including Klippel‐Trénaunay syndrome (KTS) and arteriovenous malformation (AVM) may occur due to mutations in the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. The discovery of the pathophysiologic mechanisms driving these diseases has led to improved phenotype–genotype correlation and the opportunity to target molecular pathways with medical therapies. Therefore, targeted agents have quickly become a standard of care in the treatment of vascular disorders (particularly HHT). Herein, we provide a case‐based approach to the use of antiangiogenic therapies including bevacizumab and pazopanib for the treatment of bleeding in HHT and the use of mammalian target of rapamycin (sirolimus), PIK3CA (alpelisib), and MEK (trametinib) inhibitors in the treatment of complex vascular anomalies.

TAZ promotes vasculogenic mimicry in gastric cancer through the upregulation of TEAD4.

Vasculogenic mimicry (VM) is a unique blood supply pattern in malignant tumors that is closely associated with metastasis and poor prognosis. The Hippo signaling effector TAZ is upregulated in several cancers, promoting cancer proliferation and metastasis. This study aimed to identify the function of TAZ and its regulatory mechanism in promoting VM in gastric cancer (GC). The expression of TAZ and TEAD4 and their correlations with overall survival and VM-related markers were analyzed in 228 cases of GC. The regulatory mechanism of TAZ and its interaction with TEAD4 in epithelial-mesenchymal transition (EMT) and VM were investigated in vitro and in vivo. TAZ was highly expressed in GC samples and was associated with shorter patient survival time. TAZ expression was positively correlated with TEAD4 and VM in patients with GC. TAZ enhanced the migration and invasion capacity of GC cells through EMT in vitro and upregulated the expression of VM-associated proteins, including VE-cadherin, MMP2, and MMP9, thus promoting VM formation. Overexpression of TAZ accelerated the growth of subcutaneous xenograft and promoted VM formation in vivo. Co-immunoprecipitation assays showed that TAZ can directly bind to TEAD4, and in vitro experiments showed that this binding mediates the function of TAZ in regulating EMT and VM formation in GC. TAZ promotes GC metastasis and VM by upregulating TEAD4 expression. Our findings expand the role of TAZ in VM and provide new theoretical support for the use of antiangiogenic therapy in the treatment of advanced GC.

Systemic Antiangiogenic Therapies for Bleeding in Hereditary Hemorrhagic Telangiectasia: A Practical, Evidence-Based Guide for Clinicians.

Management of bleeding in hereditary hemorrhagic telangiectasia (HHT), the second most common hereditary bleeding disorder in the world, is currently undergoing a paradigm shift. Disease-modifying antiangiogenic therapies capable of achieving durable hemostasis via inducing telangiectasia regression have emerged as a highly effective and safe modality to treat epistaxis and gastrointestinal bleeding in HHT. While evidence to date is incomplete and additional studies are ongoing, patients presently in need are being treated with antiangiogenic agents off-label. Intravenous bevacizumab, oral pazopanib, and oral thalidomide are the three targeted primary angiogenesis inhibitors, with multiple studies describing both reassuring safety and impressive effectiveness in the treatment of moderate-to-severe HHT-associated bleeding. However, at present there is a paucity of guidance in the literature, including the published HHT guidelines, addressing the practical aspects of antiangiogenic therapy for HHT in clinical practice. This review article and practical evidence-based guide aims to fill this unaddressed need, synthesizing published data on the use of antiangiogenic agents in HHT, relevant data for their use outside of HHT, and expert guidance where evidence is lacking. After a brief review of principles of bleeding therapy in HHT, guidance on hematologic support with iron and blood products, and alternatives to antiangiogenic therapy, this article examines each of the aforementioned antiangiogenic agents in detail, including patient selection, initiation, monitoring, toxicity management, and discontinuation. With proper, educated use of antiangiogenic therapies in HHT, patients with even the most severe bleeding manifestations can achieve durable hemostasis with minimal side-effects, dramatically improving health-related quality of life and potentially altering the disease course.

An overview of resistance to chemotherapy in osteosarcoma and future perspectives.

Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

Safety and efficacy review of aflibercept for the treatment of metastatic colorectal cancer

ABSTRACT Introduction Anti-angiogenic drugs are an efficacious class of therapy in the treatment of patients with metastatic colorectal cancer (mCRC). Aflibercept, a vascular endothelial growth factor (VEGF) trap which binds the angiogenic factors VEGF-A, VEGF-B, and placental growth factor (PIGF) is approved in combination with FOLFIRI chemotherapy following progression after an oxaliplatin-containing regimen. Areas covered This report provides a review of the practice-changing clinical studies which have established the use of anti-angiogenic therapy as second-line therapy in mCRC including aflibercept with FOLFIRI (5FU, leucovorin, irinotecan). This review also evaluates aflibercept with other chemotherapy regimens as well as efficacy and safety data from real-world studies. Expert opinion Aflibercept in combination with FOLFIRI chemotherapy is an established safe and efficacious regimen for the treatment of mCRC as second-line chemotherapy. Although several toxicities have been described, the majority are either low grade or manageable by drug cessation and supportive therapies. For optimal outcomes, patient selection and close observation of toxicities is essential.

Breast MRI for Evaluation of Response to Neoadjuvant Therapy.

Neoadjuvant therapy is increasingly being used to treat early-stage triple-negative and human epidermal growth factor 2-overexpressing breast cancers, as well as locally advanced and inflammatory breast cancers. The rationales for neoadjuvant therapy are to shrink tumor size and potentially decrease the extent of surgery, to serve as an in vivo test of response to therapy, and to reveal prognostic information for the patient. MRI is the most accurate modality to demonstrate response to therapy and to help ensure accurate presurgical planning. Changes in lesion diameter, volume, and enhancement are used to predict complete response, partial response, or nonresponse to therapy. However, residual disease may be overestimated or underestimated at MRI. Fibrosis, necrotic tumors, and residual benign masses may be causes of overestimation of residual disease. Nonmass lesions, invasive lobular carcinoma, hormone receptor-positive tumors, nonconcentric shrinkage patterns, the use of antiangiogenic therapy, and late-enhancing foci may be causes of underestimation of residual disease. In patients with known axillary lymph node metastasis, neoadjuvant therapy may be followed by targeted axillary dissection to avoid the potential morbidity associated with an axillary lymph node dissection. Diffusion-weighted imaging, radiomics, machine learning, and deep learning methods are under investigation to improve MRI accuracy in predicting treatment response.©RSNA, 2021.

A comprehensive analysis of factors related to carmustine/bevacizumab response in recurrent glioblastoma.

Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM. In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status. Median follow-up was 18.6months, overall RR to the combination was 56.3%, and median PFS was 9.0months (95% CI 8.0-9.9). OS from time of diagnosis was 21.0months (95% CI 13.2-28.7) and from starting BCNU/Bev it was 10.7months (95% CI 9.5-11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%). BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.

Histological changes secondary to use of anti-angiogenic therapy after interruption of vasa vasorum flow in the descending aorta: results in a porcine model.

BackgroundAnti-angiogenic regulators may have therapeutic implications for onset and progression of atherosclerosis.ObjectivesTo demonstrate histological changes secondary to the use of bevacizumab in the aorta of pigs after interruption of flow in the vasa vasorum.MethodsTwelve pigs were divided into two groups. The intercostal arteries of the descending aorta were dissected and ligated and wrapped with a polyvinyl chloride membrane. The treatment group received an intravenous dose of bevacizumab. After 15 days, the animals were euthanized and the aorta removed. Histological slides were prepared for control and treatment groups and for non-manipulated areas and analyzed for degree of angiogenesis, injury, inflammation, and intimal thickening. Data were expressed as mean (SD) of scores and groups were compared using the Mann-Whitney test. The Poisson distribution was used to calculate 95% confidence intervals for mean scores, in order to determine effect statistics.ResultsBevacizumab had adverse effects on all treated pigs. The analysis using a Scale of Magnitudes for Effect Statistics showed a trend toward a decrease in angiogenesis [0.58 (1.79/-0.63)] and injury [0.55 (1.76/-0.66)] and an increase in inflammation [0.67 (1.89/-0.55)] with threshold moderate effects. There was no difference in intimal thickening [0 (1.19/-1.19)].ConclusionsThe medication exhibited a trend toward reduced angiogenesis and injury, but no reduction in the inflammatory process or intimal thickening of the aortic wall. These findings are in disagreement with studies that correlate neovascularization with increased migration of inflammatory cells. Bevacizumab exhibited toxicity in the porcine model.

Anti-angiogenic therapy for high-grade glioma.

Anti-angiogenic therapy for high-grade glioma.

Binding of \u03b1v\u03b23 Integrin-Specific Radiotracers Is Modulated by Both Integrin Expression Level and Activation Status

PurposeMolecular imaging of αvβ3 integrin has exhibited real potential to guide the appropriate use of anti-angiogenic therapies. However, an incomplete understanding of the factors that influence binding of αvβ3 integrin-specific radiotracers currently limits their use for assessing response to therapy in cancer patients. This study identifies two fundamental factors that modulate uptake of these radiotracers.ProceduresExperiments were performed in prostate cancer (PC3) and glioblastoma (U87MG) cells, which differentially express αvβ3 integrin. αvβ3 integrin-specific radiotracers were used to investigate the effect of manipulating αvβ3 integrin expression or activation in cellular binding assays. β3 integrin and αvβ3 integrin expression were measured by western blotting and flow cytometry, respectively. The effect of select pharmacological inhibitors on αvβ3 integrin activation and expression was also determined.ResultsRadiotracer binding was proportional to αvβ3 integrin expression when it was decreased (β3 knock-down cells) or increased, either using pharmacological inhibitors of cell signalling or by culturing cells for different times. Studies with both small molecule and arginine–glycine–aspartic acid (RGD)-based radiotracers revealed increased radiotracer binding after activation of αvβ3 integrin with Mn2+ or talin head domain. Moreover, inhibition of fundamental signalling pathways (mitogen-activated protein kinase kinase (MEK), Src and VEGFR2) decreased radiotracer binding, reflecting reduced αvβ3 integrin activity.ConclusionBinding of small molecule ligands and radiolabelled RGD peptides is modulated by expression and activation status of αvβ3 integrin. αvβ3 integrin-specific radiotracers can provide otherwise inaccessible information of the effect of signalling pathways on αvβ3 integrin. This has significant implications for assessing response to anti-angiogenic therapies in clinical studies.

Tumor angiogenesis revisited: Regulators and clinical implications.

Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases.

Targeting the vasculature in hepatocellular carcinoma treatment: Starving versus normalizing blood supply.

Traditional treatments for intermediate or advanced stage hepatocellular carcinoma (HCC) such as transarterial chemoembolization (TACE) and anti-angiogenesis therapies were developed to starve tumor blood supply. A new approach of normalizing structurally and functionally abnormal tumor vasculature is emerging. While TACE improves survival in selected patients, the resulting tumor hypoxia stimulates proliferation, angiogenesis, treatment resistance and metastasis, which limits its overall efficacy. Vessel normalization decreases hypoxia and improves anti-tumor immune infiltrate and drug delivery. Several pre-clinical agents aimed at normalizing tumor vasculature in HCC appear promising. Although anti-angiogenic agents with vessel normalizing potential have been trialed in advanced HCC with modest results, to date their primary intention had been to starve the tumor. Judicious use of anti-angiogenic therapies is required to achieve vessel normalization yet avoid excessive pruning of vessels. This balance, termed the normalization window, is yet uncharacterized in HCC. However, the optimal class, dose and schedule of vascular normalization agents, alone or in combination with other therapies needs to be explored further.

Clinical and radiological features driving patient selection for antiangiogenic therapy in non-small cell lung cancer (NSCLC)

BackgroundThe use of antiangiogenic therapy in non-small cell lung cancer (NSCLC) requires thorough evaluation of patient characteristics in order to avoid potential safety issues, particularly pulmonary haemorrhage (PH). The aim of this consensus by a panel of experts was to identify important criteria for the selection of patients with NSCLC who would benefit from antiangiogenic therapy.MethodsRadiologists and oncologists were selected for the expert panel. The nominal group technique (NGT) and the Delphi questionnaire were used for consensus generation. The NGT consisted of four steps, the result of which was used to set the Delphi questionnaire. A final report was generated based on the opinions of the experts from the panel.ResultsAn extremely important prerequisite for the evaluation of an antiangiogenic therapeutic approach in patients with NSCLC was thorough clinical and radiological analysis of the relationships between tumour and vascular or anatomical structures (performed in close co-operation by oncologists and radiologists). The panel identified major parameters to be considered before the use of antiangiogenic treatment, collectively agreeing on the relevance of tumour cavitation, vascular infiltration, endobronchial growth and thromboembolism for chest tumour sites, and of the presence of aneurysms, extra-thoracic bleeding, brain metastases or thrombi for extra-thoracic sites. Moreover, a structured report containing information not only on the tumour but also on the general vascular status is essential to guide the treatment choice The experts agreed that tumour localization in the absence of vessel infiltration, cavitation, and the use of antiplatelet therapy are relevant parameters to be assessed, but their presence should not necessarily exclude a patient from receiving antiangiogenic therapy.ConclusionClose co-operation between oncologists and radiologists in the diagnosis, treatment selection, and assessment of response is essential for ensuring therapeutic appropriateness in the NSCLC setting. It should be noted that neither the use of antiplatelet therapy nor tumour localisation are to be considered as contraindications to antiangiogenic treatment.

Endothelial Cell Hypertrophy and Microvascular Proliferation in Meningiomas Are Correlated with Higher Histological Grade and Shorter Progression-Free Survival.

Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p < 0.0001, p = 0.0004, and p = 0.0003, respectively). ECH and MVP but not CD105 immunoreactivities were significantly correlated with a shorter progression-free survival time (PFS) (p = 0.017, p = 0.021, and p = 0.137, respectively). In Cox multivariate analysis, ECH was an independent predictor of shorter PFS (p = 0.028). Therefore, ECH and MVP are markers of shorter PFS in meningiomas and are significantly correlated with grade. These findings give insight into the use of anti-angiogenic therapies. Further studies are needed to determine whether these markers could allow us to identify patients who could benefit from anti-angiogenic therapies.

Changes in PlGF and MET-HGF expressions in paired initial and recurrent glioblastoma.

Angiogenesis is one of the key features of glioblastoma (GB). However, the use of anti-angiogenic therapies directed against vascular endothelial growth factor (VEGF) is limited by primary or acquired resistance. MET/HGF and PlGF signaling are involved in potential alternative escape mechanisms to VEGF pathway. Our objective was to explore the potential changes of MET/HGF and PlGF expression, comparing initial diagnosis and recurrence after radiotherapy-temozolomide (RT/TMZ). Paired frozen tumors from both initial and recurrent surgery after radio-chemotherapy were available for 28 patients. RNA expressions of PlGF, MET, and HGF genes were analyzed by RT-qPCR. PlGF expression significantly decreased at recurrence (p = 0.021), and expression of MET showed a significant increase (p = 0.011) at recurrence. RNA expressions of MET and HGF significantly correlated both at baseline and recurrence (baseline: p = 0.005; recurrence: p = 0.019). Evolutive profile (increasing versus decreasing expression at recurrence) of MET was associated with PFS (p = 0.002) and OS (p = 0.022) at recurrence, while the evolutive profile of HGF was associated with PFS at relapse (p = 0.049). Recurrence of GB after chemo-radiation could be associated with a variation in PlGF and MET expression. These results contribute to suggest a modification of the GB angiogenic process between initial diagnosis and recurrence.

Interplay between Molecular Imaging and Tumor Modeling of Anti-Angiogenic Therapies

Molecular imaging plays a crucial role in oncology, as it can unveil dynamics of biological processes before and during therapy. Angiogenesis is one of the key tumor hallmarks. Use of anti-angiogenic therapies, particularly those targeting the VEGF pathway, is a common treatment strategy. However, clinical outcomes have been rather disappointing. One of the key phenomena in response to anti-angiogenic therapies is the so-called “angiogenic flare”, rapid rebound of tumors after therapy cessation or during treatment breaks. In addition, prolonged exposure to anti-angiogenic agents leads to build-up of treatment resistance. A series of clinical trials using advanced molecular imaging techniques will be presented that has helped explaining the observed angiogenic flare, giving insights into potential treatment strategies.Tumor modeling helps “bridging the scales” between molecular processes (biological foundations of tumor growth and response to therapies), and observed molecular imaging (phenotypic expression in vivo). We have used tumor modeling based on patient-specific molecular imaging input to investigate potential mechanisms leading to treatment failures. Interplay between molecular imaging-driven clinical trials and tumor modeling will be presented as a role-model for better understanding of clinically observed phenomena and as a guiding tools to guide more successful future treatment strategies.

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma.

The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma (HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.