Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles (original) (raw)
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Theranostics, 2018
Metastatic clear-cell renal cell carcinoma (ccRCC) affects thousands of patients worldwide each year. Antiangiogenic therapy has been shown to have beneficial effects initially, but resistance is eventually developed. Therefore, it is important to accurately track the response of cancer to different therapeutics in order to appropriately adjust the therapy to maximize efficacy. Change in tumor volume is the current gold standard for determining efficacy of treatment. However, functional variations can occur much earlier than measurable volume changes. Contrast-enhanced ultrasound (CEUS) is an important tool for assessing tumor progression and response to therapy, since it can monitor functional changes in the physiology. In this study, we demonstrate how ultrasound molecular imaging (USMI) can accurately track the evolution of the disease and molecular response to treatment.A cohort of NSG (NOD/scid/gamma) mice was injected with ccRCC cells and treated with either the VEGF inhibitor...
International Journal of Molecular Sciences
Standard imaging cannot reliably predict the nature of renal tumors. Among malignant renal tumors, clear cell renal cell carcinoma (ccRCC) is the most common histological subtype, in which the vascular endothelial growth factor 2 (VEGFR-2) is highly expressed in the vascular endothelium. BR55, a contrast agent for ultrasound imaging, consists of gas-core lipid microbubbles that specifically target and bind to the extracellular portion of the VEGFR-2. The specific information provided by ultrasound molecular imaging (USMI) using BR55 was compared with the vascular tumor expression of the VEGFR-2 by immunohistochemical (IHC) staining in a preclinical model of ccRCC. Patients’ ccRCCs were orthotopically grafted onto Nod-Scid-Gamma (NSG) mice to generate patient-derived xenografts (PdX). Mice were divided into four groups to receive either vehicle or axitinib an amount of 2, 7.5 or 15 mg/kg twice daily. Perfusion parameters and the BR55 ultrasound contrast signal on PdX renal tumors wer...
Background: Increased sunitinib exposure (area under the curve) is associated with better outcome in metastatic renal cell cancer. Recommendations for dose modification do not take this into account. A treatment strategy, based on individual patient toxicity, was developed to maximize dose and minimize time without therapy for patients who could not tolerate the standard sunitinib schedule of 50 mg given for 28 days with a 14-day break (50 mg, 28/14). Methods: A single-center retrospective review was conducted on patients with metastatic renal cell cancer treated from October 2005 to March 2010. Dose/schedule modifications (DSM) were done to keep toxicity (hematological, fatigue, skin, and gastrointestinal) at rgrade 2. DSM-1 was 50 mg, 14 days on/7 days off with individualized increases in days on treatment. DSM-2 was 50 mg, 7 days on/7 days off with individualized increase in days on treatment. DSM-3 was 37.5 mg with individualized 7-day breaks. DSM-4 was 25 mg with individualized 7-day breaks. Multivariable analysis was performed for outcome as a function of patient and treatment variables. Results: Overall, 172 patients were included in the analysis. Most patients had clear cell histology (79.1%) with sunitinib given as a first-line therapy in 59%. The DSM-1 and 2 and DSM-3 and 4 groups had a progression-free survival (PFS) (10.9–11.9 mo) and overall survival (OS) (23.4–24.5 mo) that was significantly better than the PFS (5.3 mo; P o 0.001) and OS (14.4 mo; P ¼ 0.03 and 0.003) for the standard schedule (50 mg, 28/14). DCE-US in a subset of patients showed that maximum antiangiogenic activity was achieved after 14 days on therapy. Conclusions: Individualized sunitinib scheduling based on toxicity may improve PFS and OS. This hypothesis is supported by several other respective data that are reviewed. A confirmatory prospective trial is ongoing. r
IEEE transactions on bio-medical engineering, 2018
Functional and molecular changes often precede gross anatomical changes, so early assessment of a tumor's functional and molecular response to therapy can help reduce a patient's exposure to the side effects of ineffective chemotherapeutics or other treatment strategies. Our intent was to test the hypothesis that an ultrasound microvascular imaging approach might provide indications of response to therapy prior to assessment of tumor size. Mice bearing clear-cell renal cell carcinoma xenograft tumors were treated with antiangiogenic and Notch inhibition therapies. An ultrasound measurement of microvascular density was used to serially track the tumor response to therapy. Data indicated that ultrasound-derived microvascular density can indicate response to therapy a week prior to changes in tumor volume and is strongly correlated with physiological characteristics of the tumors as measured by histology (p=0.75). Furthermore, data demonstrated that ultrasound measurements of v...
Molecular Cancer Therapeutics, 2008
Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric ''multitarget quantification'' and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and A v B 3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and A v B 3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and A v B 3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and A v B 3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.
ANALYTICAL AND QUANTITATIVE CYTOPATHOLOGY AND HISTOPATHOLOGY, 2015
Renal cell carcinoma is an aggressive neoplasm, frequently diagnosed incidentally in an advanced stage (local or metastatic). Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases, mainly directed against the angiogenic pathway. Sunitinib is largely used in first-line treatment, but response varies widely among patients. Thus, there is an urgent need to find predictive factors able to determine whether or not a patient would respond to treatment, thereby avoiding unnecessary toxicities. In this report we review the literature focusing on clinical, pathological, and molecular predictive factors currently being studied and more promising to enter clinical practice.
European urology, 2014
The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to significant necrosis without significant reduction in tumour size. In addition, the vascular effects of antiangiogenic therapy may occur long before there is any reduction in tumour size. To perform a systematic review of conventional and novel imaging methods for the assessment of response to targeted agents in RCC and to discuss their use from a clinical perspective. Relevant databases covering the period January 2006 to April 2013 were searched for studies reporting on the use of anatomic and functional imaging techniques to predict response to targeted therapy in RCC. Inclusion criteria were randomised trials, nonrandomised controlled studies, retrospective case series, and cohort studies. Revie...
Anticancer Research, 2013
Aim: To verify whether vascular endothelial growth factor (VEGF) is associated with distant metastasis free survival (DMFS) and Overall Survival (OS) of patients with renal cell carcinoma (RCC) treated with sunitinib. Patients and Methods: We have studied 41 patients with metastatic RCC treated with radical nephrectomy, between 2008 and 2010, and sunitinib. Pathological features were compared with the Memorial Sloan-Kettering Cancer Center (MSKCC) score, DMFS, and with OS, and PFS after first-line therapy. Results: Tumor stage and grade, VEGF expression and H-score correlated with MSKCC score, DMFS, and with OS; VEGF expression correlated with stage and OS. Patients with higher H-score and higher VEGF expression had a significantly shorter survival; OS after first-line sunitinib therapy and PFS correlated with MSKCC score and DMFS but not with VEGF expression and H score. Conclusion: Our data suggest the potential use of tumor cell VEGF expression as a prognostic marker for DMFS and OS, but VEGF does not appear promising as a marker of response to therapy. Renal cell carcinoma (RCC) represents 2-3% of all tumors (1), 80-90% of which are of the clear cell type. Although most patients with early-stage RCC can be cured surgically, approximately 33% present with disease are in an advanced state at diagnosis, and for them, treatment is not curative ; approximately 50% of patients who undergo potentially curative surgical resection for less advanced disease can be expected to develop distant metastases during follow-up (3-6).
BMC medicine, 2016
Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient. We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed. A total of 115 metastases were assessed longitudinally in 27 patient...
Denoised VEGFR2 Expression Relates to Sunitinib Efficacy in Advanced Clear Cell Renal Cell Carcinoma
BJSTR
Personalized biomarkers can facilitate decision making upon multiple therapeutic options in ccRCC. VEGFR2 expression denoised with 37 normal and tumor gene-expressions relates to sunitinib effect whereas raw VEGFR2 expression does not relate to sunitinib effect. Background: Several studies suggested that molecular analysis of patients with advanced clear cell renal cell carcinoma (ccRCC) could indicate whether a patient is susceptible of benefiting from sunitinib in first-line systemic treatment compared to immunotherapies. However, data remain conflicting and no predictive biomarker is validated so far to decipher if sunitinib could still represent a good therapeutic option in first line setting and beyond. Methods: PREDMED® denoised the tumor RNA expression of 37 genes including KDR (encoding VEGFR2) estimated by RT-qPCR, by normalizing it on the expression of normal kidney tissue and cell types. We investigated the performance of PREDMED® VEGFR2-scoring to predict the clinical effect of sunitinib for patients affected by ccRCC. Results: Among the 34 ccRCC patients' samples retrospectively retrieved from the UroCCR project (NCT03293563), high VEGFR2 scores were associated with objective clinical responses under sunitinib treatment and low scores with stable disease or progression with a sensitivity of 86%, a specificity of 67% and an AUC of 72.5% (95%CI[50.1–94.9]; p=0.04). VEGFR2 scores were significantly and positively related to progression-free survival (HR = 0.465; 95%CI[0.221–0.978]; p=0.0311) and overall survival (HR = 0.400; 95%CI[0.192–0.834]; p=0.0134) under sunitinib treatment. In our cohort, raw VEGFR2 expression (before PREDMED® processing) was not related to the above-mentioned outcomes. We describe a gene-expression based algorithm that is accurately related to the effect of sunitinib for patients with ccRCC. We further plan a validation of PREDMED® for combinatorial strategies involving antiangiogenics and immunecheckpoint blockers.