A comparison of robotic and laparoscopic minimally invasive adrenalectomy for adrenal malignancies.

BACKGROUND: Although guidelines recommend open adrenalectomy for most resectable adrenal malignancies, minimally invasive adrenalectomies are performed. Robotic adrenalectomies have become more popular recently, but there is a paucity of literature comparing laparoscopic and robotic resections. METHODS: Patients who underwent a planned minimally invasive adrenalectomy for adrenal malignancies (adrenocortical carcinoma, malignant pheochromocytoma, other carcinoma) were identified in the National Cancer Database. The primary outcome was the conversion rate from minimally invasive to open. Other post-operative outcomes and survival were compared. RESULTS: 416 patients (76.5%) underwent a laparoscopic adrenalectomy and 128 (23.5%) underwent a robotic operation. Demographics and clinical characteristics were similar. Approximately 19% of tumors resected by a minimally invasive approach were > 10 cm. The intra-operative conversion rate was decreased among robotic adrenalectomies relative to laparoscopic on univariate (7.8% vs. 18.3%, p = 0.005) and multivariable (odds ratio 0.39, p = 0.01) analyses. Using marginal standardization, there was a stepwise increase in the conversion rate as tumor size increased (< 5, 5-10, > 10 cm) for laparoscopic (7.5%, 18.0%, 33.2%) and robotic (3.1%, 8.3%, 17.3%) adrenalectomies. Operations which required conversion had a greater margin positivity rate, greater length of stay, and an association with poor overall survival. CONCLUSION: In contrast to most clinical guidelines, minimally invasive adrenalectomies are being performed on large malignant tumors. A laparoscopic approach was associated with a greater conversion rate and subsequent poor outcomes. If a surgeon is not planning an open adrenalectomy, but adrenal malignancy is a possibility, robotic adrenalectomy may be the preferred approach for resectable adrenal tumors.

Reassessing the impact of tumor size on operative approach in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is often a contraindication to minimally invasive adrenalectomy (MIA). We used an administrative data set to analyze postoperative outcomes. We hypothesized that small tumors would have better short- and long-term outcomes, independent of the operative approach. METHODS: The National Cancer Database (2010-2016) identified patients with ACC who underwent adrenalectomy. Tumors were grouped: <5 cm (n = 125), 5-10 cm (n = 431), and >10 cm (n = 443). The primary and secondary outcomes were margin positivity and overall survival, respectively. RESULTS: Nine hundred and ninety-nine patients were analyzed: 37% MIA and 63% open adrenalectomy (OA). As the size increased, the rate of attempted MIA decreased. Larger tumors were associated with conversion to open. Although tumors with local invasion and those which required conversion to open were associated with an increased likelihood of a positive margin, tumor size was not. Although "complete" MIA (vs. OA) and tumor size were not associated with differences in survival, conversion (HR = 1.83, p = .02), positive margins (HR = 1.54, p = .01), and local invasion (HR = 1.84, p < .001) were associated with poor survival. CONCLUSION: Positive margins are associated with poor survival in ACC. Tumors ≥ 5 cm were associated with an increased conversion rate and subsequent increase in margin positivity. MIA may be considered for select patients with small tumors but adequate oncologic resection is critical.

Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer.

Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.

Pediatric thyroid cancer: Socioeconomic disparities and their impact on access to care.

BACKGROUND: Few studies have examined the disparities in access to care for pediatric thyroid cancers. We sought to clarify socioeconomic and patient factors that affect access to care for pediatric differentiated thyroid cancer and aggressive variants of papillary thyroid cancer. METHODS: Using the National Cancer Database, we performed a retrospective study on pediatric differentiated thyroid cancer and aggressive variants of papillary thyroid cancer (2004-2019). Patients were divided into three periods (2004-2008, 2009-2013, 2014-2019) to assess for trends. The χ2 analysis and Kruskal-Wallis test were used to test for independence of groupings for each socioeconomic and disease-related factor. RESULTS: In all, 6,275 patients with pediatric differentiated thyroid cancer and 182 with aggressive variants of papillary thyroid cancer were analyzed. Differentiated thyroid cancer patients with Medicaid (median 18.0 miles) and those from lower-income households (median 21-30 miles) had to travel greater distances for care in recent years (2014-2019). Racial/ethnic disparities were evident; Black and Hispanic patients have higher odds of waiting >30 days for surgery (odds ratio 1.39, 1.49, P < .05, respectively) than White patients. Black patients with differentiated thyroid cancer had a higher risk of mortality compared with White and Hispanic patients (hazard ratio 4.31, 95% confidence interval: 1.95-9.51, P < .05). Nodal positivity was higher in Hispanic patients with differentiated thyroid cancer (60%, P < .05, White patients 51% and Black patients 36%). Socioeconomic factors did not significantly affect survival or nodal positivity in aggressive variants of papillary thyroid cancer. CONCLUSION: This study highlights disparities in access to care and survival outcomes in pediatric differentiated thyroid cancer and aggressive variants of papillary thyroid cancer. Race, income status, and type of insurance all play a role in these disparities. Understanding the complex etiologies and developing interventions to improve access and patient outcomes are crucial.

Association of thyroid, breast and renal cell cancer: a population-based study of the prevalence of second malignancies.

BACKGROUND: Analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results data has shown that the incidence of thyroid cancer is higher in patients with a preexisting malignancy and that the incidence of other malignancies is higher in patients with thyroid cancer. The purpose of this study was to evaluate the prevalence of a second malignancy in patients treated for thyroid, breast or renal cell cancer and determine what associations, if any, exist between these cancers. METHODS: This study utilized the novel data system, Explorys, as its population base. Patient cohorts were constructed using ICD-9 codes, and prevalence rates were obtained for each cancer. Rates of second malignancy were obtained and compared to the baseline prevalence for a particular malignancy. RESULTS: Female thyroid cancer patients had a 0.67- and twofold increase in prevalence of a subsequent breast and renal cell cancer. Female breast and renal cell cancer patients had a twofold and 1.5-fold increase in the prevalence of thyroid cancer, respectively. Male patients with thyroid cancer had a 29- and 4.5-fold increase in prevalence of subsequent breast and renal cell cancer. Male patients with breast and renal cell cancer had an increased prevalence of subsequent thyroid cancer, 19- and threefold, respectively. CONCLUSIONS: Our study demonstrated a bidirectional association between thyroid, breast and renal cancer in both male and female patients. This may have important implications for patient follow-up and screening after treatment of a primary cancer.

Varying impact of patient age on the rising rate of pediatric thyroid cancer: Analysis of NCDB database (2004-2017).

Pediatric thyroid carcinoma is on the rise. We sought to better characterize patient factors associated with this and evaluate for trends based on age groups. Additionally, we examined surgical management over time, and whether it aligns with recommendations made by the American Thyroid Association. Using the National Cancer Database (NCDB), we examined cases of thyroid cancer from 2004 to 2017, ages 1-18 years. We subdivided this cohort by age group: those <10y, 10-15y, and >15y. NCDB query yielded 5,814 cases. The annual proportion of total cases ranged from 3% to 8% for <10y, 31%-40% for 10-15y, and 52%-66% for >15y. 80-90% of cases in all age groups did indeed receive total thyroidectomy which is consistent with ATA guidelines. Our results verify an overall increase in pediatric thyroid cancer cases, occurring mostly in the 10-18 years old age range with the largest year-to-year increases in the >15y group.

Evolution of intra-operative parathyroid hormone and its application in parathyroid surgery.

The history and evolution of parathyroid hormone is a true testament to inter-disciplinary collaboration among anatomists, biochemists and surgeons. The parathyroid glands were the last endocrine glands to be discovered in the mid-1800s. Over the next century, progress in the evaluation of primary hyperparathyroidism, the identification of parathyroid hormone (PTH) and its application for use in the field of parathyroid surgery have led to a significant improvement in surgical cure rates, accompanied by a shift toward minimally invasive surgical options. This chapter provides a historical lens through which we can view these relatively recent advancements, as well as the current role of parathyroid hormone, both with regards to pre-operative localization and intra-operative detection of abnormal glands. Furthermore, we discuss the importance of parathyroid hormone in the management of complex multiglandular disease and reoperative cases, as well as the significance of persistently elevated PTH levels post-parathyroidectomy.

Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.

Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-ß and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.

Outcomes of malignant pheochromocytoma based on operative approach: A National Cancer Database analysis.

BACKGROUND: Malignant pheochromocytoma is often managed with adrenalectomy. Most literature focusing on postoperative outcomes are from single institutions. This study aimed to describe outcomes of adrenalectomy for malignant pheochromocytoma using a national database. We hypothesized that minimally invasive approaches might be associated with improved short-term outcomes but potentially inferior oncologic efficacy. METHODS: Patients who underwent adrenalectomy for malignant pheochromocytoma were identified in the National Cancer Database (2010-2016). Patients were categorized as minimally invasive adrenalectomy or open adrenalectomy. Short- and long-term outcomes were compared. RESULTS: A total of 276 patients underwent adrenalectomy for malignant pheochromocytoma: 50.7% open adrenalectomy and 49.3% minimally invasive adrenalectomy. Demographics were similar, except those who underwent open adrenalectomy had larger tumors compared to minimally invasive adrenalectomy (8.2 cm vs 4.7 cm; P < .001). Tumor size ≥6 cm was associated with a reduced likelihood of minimally invasive adrenalectomy (relative to open adrenalectomy) on multivariable regression (odds ratio = 0.23; P < .001). Open adrenalectomy was associated with longer duration of stay relative to minimally invasive adrenalectomy (6 vs 3 days; P < .001). Rates of positive margins, unplanned readmissions, or 30-/90-day mortalities were similar based on operative approach. Five-year survival rates were similar (open adrenalectomy 74.3%, minimally invasive adrenalectomy 79.1%). There was no association between overall survival and operative approach on multivariable Cox analysis when controlling for tumor size, laterality, and clinicodemographic variables. CONCLUSION: Patients with larger malignant pheochromocytomas were more likely to undergo an open adrenalectomy. With the exception of an increased duration of stay, there was no difference in short- or long-term postoperative outcomes. These data suggest that minimally invasive adrenalectomy appears safe among tumors <6 cm.

Total thyroidectomy is superior to subtotal thyroidectomy for management of Graves' disease in the United States.

BACKGROUND: In the United States, Graves' disease is most commonly treated with radioiodine, yet thyroidectomy remains an important option for correcting hyperthyroidism. In many countries, limited access to thyroid hormone makes subtotal thyroidectomy the procedure of choice. In the United States, where levothyroxine is widely available, we hypothesized that total (TT) or near-total thyroidectomy (NT) is superior to subtotal thyroidectomy (ST) for long-term control of Graves' disease. METHODS: A retrospective review of patients who underwent ST, NT, or TT for Graves' disease between 1990 and 2008 was conducted. Differences in rates of disease recurrence were assessed by analysis of variance (ANOVA). Rates of parathyroid autotransplantation, complications, gland weight, and final pathology were determined. RESULTS: A total of 136 patients with Graves' disease were treated with thyroidectomy. Average age was 36.4 +/- 11.3 years (range: 16-81 years) and 88% were female. From 1990 to 1994, 10 patients underwent ST and 6 had NT. Since then, all patients have undergone TT (n = 120). There was a significantly higher rate of recurrence for ST (30%) compared to NT (0%; P = 0.15) and TT (0%; P < 0.0001). Parathyroid autotransplantation was performed in 36 (26.5%) patients, only 2 of whom underwent ST or NT. Transient postoperative hypocalcemia was more common after TT (P = 0.04). No patient in any group had permanent hypoparathyroidism. Two TT pts had transient recurrent laryngeal nerve palsy. CONCLUSIONS: Subtotal thyroidectomy resulted in 30% long-term failure to correct Graves' hyperthyroidism. We saw no recurrences and no increase in postoperative complications in the TT group. We feel that TT is safe and superior to ST for management of Graves' disease in the United States.

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.

Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.

Parathyroid Cancer: A Review.

Parathyroid cancer is one of the rarest causes of primary hyperparathyroidism and tends to present with more severe symptoms than its more benign counterparts. This article details various aspects of the disease process, including epidemiology, clinical presentation, and a step-wise diagnostic process for parathyroid cancer. This includes laboratory assessments as well as a proposed staging system. The en bloc principle of surgical intervention is detailed, as well as the current role of adjuvant treatments. A general guide to surveillance and the natural history of the disease is also outlined.

Diagnosis and Evaluation of Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, resulting from the autonomous production of parathyroid hormone from 1 or more abnormal parathyroid glands. Disease presentation ranges from asymptomatic to multiorgan involvement (skeletal, renal, neurocognitive, and gastrointestinal). This article outlines the epidemiology, clinical presentation, and diagnostic algorithm for PHPT. Key laboratory assessments are discussed, as are imaging studies for preoperative localization. Indications for surgical intervention are detailed, as are potential indications for surveillance. Sporadic and genetic syndromes associated with PHPT are also described.

Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants.

PURPOSE: Targeting of KIT and platelet-derived growth factor receptor (PDGFR) tyrosine kinases by imatinib is an effective anticancer strategy. However, mutations of the gatekeeper residue (T670 in KIT and T681 in PDGFRbeta) render the two kinases resistant to imatinib. The aim of this study was to evaluate whether sorafenib (BAY 43-9006), a multitargeted ATP-competitive inhibitor of KIT and PDGFR, was active against imatinib-resistant KIT and PDGFRbeta kinases. EXPERIMENTAL DESIGN: We used in vitro kinase assays and immunoblot with phosphospecific antibodies to determine the activity of sorafenib on KIT and PDGFRbeta kinases. We also exploited reporter luciferase assays to measure the effects of sorafenib on KIT and PDGFRbeta downstream signaling events. The activity of sorafenib on interleukin-3-independent proliferation of Ba/F3 cells expressing oncogenic KIT or its imatinib-resistant T670I mutant was also tested. RESULTS: Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRbeta (IC(50) for KIT T670I, 60 nmol/L; IC(50) for PDGFRbeta T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC(50) for KIT D816V, 3.8 micromol/L; IC(50) for PDGFRbeta D850V, 1.17 micromol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRbeta gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation. CONCLUSIONS: Sorafenib might be a promising anticancer agent for patients carrying KIT and PDGFRbeta gatekeeper mutations.

Molecular classification of thyroid nodules by cytology.

OBJECTIVES: Fine needle aspiration (FNA) biopsy of thyroid nodules provides cytologic specimens whose interpretation can direct patients toward either thyroidectomy or observation. Approximately 20% of FNA specimens yield an indeterminate result. Recent studies have characterized differences in gene expression between benign and malignant conditions, most often using whole tissue. Our goal was to determine the feasibility of quantitative polymerase chain reaction (qPCR)-based gene expression analysis in cytologic samples. For five genes shown to be over-expressed in thyroid carcinomas (fibronectin, galectin-3, Met/HGFR, MUC1, and GA733-precursor), we compared expression among pathologic states. STUDY DESIGN: Prospective laboratory analysis of 20 thyroidectomy specimens. METHODS: Routine microscopy was performed. Cytologic samples were obtained from the dominant nodules, and RNA was extracted. Preliminary analysis using fluorometry and reverse-transcriptase (RT)-PCR was performed. Expression levels of the test genes in nodules and from control samples were measured by real-time qPCR. Fold changes in gene expression were compared. RESULTS: Only one specimen did not yield sufficient intact RNA for gene expression analysis. RT-PCR revealed satisfactory RNA recovery in all other specimens. qPCR showed significant over-expression of fibronectin in the papillary carcinomas compared with the goiters (P = .0013), follicular adenomas (P = .0014), and follicular carcinomas (P = .0001). Differences in both fibronectin and MUC1 expression between the follicular carcinomas and the follicular adenomas were also significant (P = .025 and .045, respectively). CONCLUSIONS: Cytologic specimens were a satisfactory source of tissue for qPCR-based gene expression analysis. Both fibronectin and MUC1 were differentially expressed in follicular adenomas and follicular carcinomas, and fibronectin expression differed in papillary carcinomas compared with the other lesions. These results may form the basis of a clinical predictor for lesions with indeterminate or suspicious cytology.

Evaluation and management of incidental thyroid nodules in patients with another primary malignancy.

BACKGROUND: Studies indicate that incidentally discovered thyroid nodules >or=1 cm in size may have a higher rate of malignancy (7% to 29%) than traditionally discovered nodules (5%). We sought to determine the rate of malignancy in incidental thyroid nodules in patients with other malignancies, and examine the accuracy of ultrasound (US) versus computed tomography (CT) in determining nodule size. METHODS: We evaluated 41 patients with history of another known malignancy (gastrointestinal, 23; breast, 11; other, 7) referred with an incidental thyroid nodule. Patients underwent office-based US and biopsy of nodules >or=1 cm. Surgical intervention was based on biopsy results. We compared nodule size at pathology with size seen on CT or US. RESULTS: Thirty-five patients met criteria for biopsy. Of the 35, 20 (57%) had atypical biopsy results warranting resection. Sixteen of those 20 underwent surgery. Pathology yielded 4 papillary thyroid cancers (PTC), 4 microPTC, 2 metastatic cancers, and 7 benign lesions. Ultrasound measurement of nodules compared to size measured at pathology had an r2 correlation value of 0.90 with P value <.0001. CT scan had an r2 value of 0.83 and P value of .005. CONCLUSIONS: Incidental thyroid nodules in patients with another primary malignancy warranted resection in 57%. The rate of malignancy in incidental thyroid nodules was 24%, which is above the expected rate of 5% seen in traditionally discovered nodules. US correlation with nodule size at pathology was excellent and superior to CT scan. Incidentally discovered thyroid nodules >or=1 cm, seen in patients with another malignancy, warrant further evaluation.

BRAF is a therapeutic target in aggressive thyroid carcinoma.

PURPOSE: Oncogenic conversion of BRAF occurs in approximately 44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In papillary thyroid carcinomas, this mutation is associated with an unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a potential therapeutic target for thyroid carcinoma. EXPERIMENTAL DESIGN: We used RNA interference to evaluate the effect of BRAF knockdown in the human anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006 [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit RAF family kinases in a panel of six (V600E)BRAF-positive thyroid carcinoma cell lines and in nude mice bearing ARO cell xenografts. Statistical tests were two sided. RESULTS: Knockdown of BRAF by small inhibitory duplex RNA, but not control small inhibitory duplex RNA, inhibited the mitogen-activated protein kinase signaling cascade and the growth of ARO and FRO cells (P < 0.0001). These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 micromol/L; P < 0.0001), whereas the compound had negligible effects in normal thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001) smaller in nude mice treated with BAY 43-9006 than in control mice. This inhibition was associated with suppression of phospho-mitogen-activated protein kinase levels. CONCLUSIONS: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the (V600E)BRAF mutation and, therefore, BRAF suppression might have therapeutic potential in (V600E)BRAF-positive thyroid cancer.

Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature.

Activating mutations in Ras and B-RAF were identified in several human cancers. In addition, several receptor tyrosine kinases, acting upstream of Ras, were found either mutated or overexpressed in human tumors. Because oncogenic activation of the Ras/RAF pathway may lead to a sustained proliferative signal resulting in tumor growth and progression, inhibition of this pathway represents an attractive approach for cancer drug discovery. A novel class of biaryl urea that inhibits C-RAF kinase was discovered using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). It inhibited MEK and ERK phosphorylation in various cancer cell lines and tumor xenografts and exhibited potent oral antitumor activity in a broad spectrum of human tumor xenograft models. Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling). In phase I and phase II clinical trials, sorafenib showed limited side effects and, more importantly, disease stabilization. This agent is currently being evaluated in phase III clinical trials in renal cell and hepatocellular carcinomas.