Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for "REnal Cell cancer treatment with Oral RAD001 given Daily"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.
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PMID:Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. 2062 46

Well-differentiated neuroendocrine tumors (NETs) of the jejunum, ileum, and appendix are also collectively known as midgut carcinoids. Similar to NETs in general, the diagnosed incidence of the midgut NETs is on the rise. Their presenting symptoms vary depending on stage and primary site. Local-regional NETs often present with vague and nonspecific symptoms. Classic carcinoid syndrome is more likely to appear in patients with advanced disease. Local-regional NETs of the small bowel should be resected whenever possible. With the exception of small well-differentiated NETs of the appendix, NETs of the midgut have substantial risk of relapse after resection and need to be followed for at least 7 years.Metastatic/advanced NETs of the midgut are incurable. Optimal management requires a multidisciplinary approach. Somatostatin analogs are effective in the management of carcinoid syndrome. Octreotide long-acting release has also recently been shown to delay disease progression. Liver-directed therapy and surgical debulking can improve quality of life in selected patients. Pivotal phase 3 studies with bevacizumab targeting vascular endothelial growth factor and everolimus targeting mTOR (mammalian target of rapamycin) are ongoing and may lead to improved outcome. Further studies of novel approaches such as peptide receptor radiotherapy are also warranted.
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PMID:The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. 2066 73

The authors review the most important clinical aspects of carcinoid tumors. Carcinoid tumors originating in neuroendocrine cells are rare, usually slowly-growing neoplasms, however, they may present as aggressive and rapidly progressing tumors. Epidemiologic data indicates that their prevalence is gradually increasing, which may be explained, at least in part, by the development and wider use of advanced diagnostic methods. A considerable proportion of patients with neuroendocrine tumors are symptom-free, whereas others may have carcinoid syndrome or symptoms of other endocrine syndromes. Early diagnosis may be established by the measurement of biochemical markers (serum chromogranin A, urinary 5-hydroxyindoleacetic acid) and advanced localization methods. A considerable number of patients are diagnosed at the late stages of the disease; in these cases surgical cure is not possible but surgical and/or interventional radiologic procedures which reduce tumoral mass should be still considered. The most effective drugs for symptomatic treatment of carcinoid tumors are somatostatin analogues; in addition to their beneficial effect on clinical symptoms they may stabilize tumor growth for many years and, less frequently, may produce tumor regression. The use of chemotherapeutic agents is considered in patients with aggressive, rapidly growing and advanced tumors; initial findings with temozolomide and thalidomide in clinical trials raise the possibility that these chemotherapeutic agents may prove to be new therapeutic options. Radioisotope-labeled peptide receptor therapy with 131 I-MIBG, 90 Y-DOTA-TOC or 177 Lu-DOTA-TOC may offer a highly effective option for patients with progressive and advanced stage of neuroendocrine tumors. Initial observations obtained in clinical trials with some tyrosine kinase inhibitors, antibodies against tyrosine kinases, and with inhibitors of mammalian target of rapamycin (mTOR) support the possibility that at least some of these new agents may have a role in future treatment options in patients with advanced neuroendocrine tumors.
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PMID:[Carcinoid tumors]. 2104 39

Well- to moderately differentiated neuroendocrine tumors (NET) are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. For patients with localized NET, surgical resection remains the mainstay of treatment. Surgical resection of hepatic metastases or hepatic artery embolization may also be beneficial in patients with hepatic-predominant metastatic disease. Symptoms of hormonal excess, such as carcinoid syndrome and syndromes associated with functional pancreatic NET, can be effectively treated with somatostatin analogs. Systemic treatment options for patients with advanced NET have been limited. Treatment with the somatostatin analog octreotide has been shown to improve progression-free survival in patients with advanced midgut carcinoid tumors, and the potential antiproliferative effect of somatostatin analogs in patients with other NET subtypes is currently under investigation. Patients with advanced pancreatic NET may also respond to treatment with streptozocin or temozolomide-based therapy. In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with the mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, sunitinib or everolimus should now be considered as therapeutic options in patients with advanced pancreatic NET. Initial phase II studies have also suggested activity associated with VEGF pathway and mTOR inhibitors in patients with advanced carcinoid tumors. Future studies will likely further define the role of these agents in the advanced carcinoid patient population.
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PMID:New treatment options for patients with advanced neuroendocrine tumors. 2143 92

Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.
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PMID:Safety and efficacy of everolimus in adult patients with neuroendocrine tumors. 2225 54

Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a challenge. Liver-directed therapies are a consideration in patients with liver-dominant disease. Somatostatin analogs (SSTa) are routinely used to control hormone-mediated symptoms (carcinoid syndrome), but the identification of systemic agents with antitumor efficacy has proven difficult. Aside from octreotide for small bowel carcinoid (which is associated with delayed progression), no treatment has proven antitumor activity. Chemotherapy seems to be of limited value. The role of interferon is also controversial; it is typically used after failure of octreotide. Peptide receptor radionuclide therapy may have activity in patients with SST receptor-expressing tumors, but randomized controlled trials are lacking. Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor [VEGF] and mammalian target of rapamycin [mTOR] signaling pathways), but none has been definitively validated in carcinoid. Everolimus is associated with a trend toward improved progression-free survival in patients with progressive carcinoid, but is not approved for this indication. Therefore, a serious unmet need remains for additional therapeutic strategies for patients with advanced disease. Several avenues are under study, including the use of novel SSTa; VEGF and mTOR inhibitors; and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Moving forward, optimizing patient selection based on clinical features or biomarkers holds promise for identifying individuals most likely to benefit from therapy.
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PMID:Systemic therapy for advanced carcinoid tumors: where do we go from here? 2267 20

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, whose incidence and prevalence are increasing. The clinical behavior of NEN is variable, ranging from well-differentiated slow growing tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. The term carcinoid is commonly used for the more benign variants of these neoplasms. Most frequently, carcinoids have their origin in the small intestine, followed by in the lung and other sites. Some of these tumors are associated with the carcinoid syndrome. The use of somatostatin analogs has revolutionized the clinical management of patients with carcinoids. However, although symptomatic relief and stabilization of tumor growth for various periods of time are observed in many patients treated with somatostatin analogs, tumor regression is rare. Currently, there is no other powerful antiproliferative agent available for carcinoids. Mammalian target of rapamycin (mTOR), a main protein kinase in the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations of the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NEN, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of carcinoids. However, further clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting, these drugs might be most usefully applied.
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PMID:Inhibition of mTOR in carcinoid tumors. 2288 6

"Carcinoids" are mostly slow-growing neuroendocrine neoplasms (NENs) with low proliferative activity. A wide range of therapeutic options with variable efficacy exist, including locoregional ablative strategies. Thereafter, some patients may not require medical therapy for years depending on the rate of progression or recurrence. However, the majority of patients require systemic treatment and therein lies the dilemma, since no antiproliferative agent is currently approved for carcinoids. Somatostatin analogs (SSAs), and to a lesser extent interferon-alpha, are standard therapy for carcinoids associated with the carcinoid syndrome. These drugs have some antiproliferative efficacy. SSAs rarely lead to tumor remission but may modestly prolong time to tumor progression. Chemotherapy is of limited value in carcinoids with low proliferation indices but may be useful in higher grade tumors. Peptide receptor-targeted radionuclide therapy may be of benefit and is mostly used after medical therapies fail. However, it is considered an investigational modality. More recently, targeted drugs such as mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenics have been investigated. Objective remissions are rare. Their value remains to be rigorously elucidated. Increased efficacy requires a better understanding of the underlying tumor biology and identification of molecular pathological criteria to allow appropriate preselection of candidates for targeted therapies.
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PMID:Systemic therapeutic options for carcinoid. 2339 Nov 16

The prevalence of intestinal neuroendocrine tumours, also known as carcinoid tumours, has increased significantly over the past three decades. Tumours of the distal small intestine (midgut) are often indolent, but are characterized by a high potential to metastasize to the small-bowel mesentery and liver. Patients with distant metastases are prone to development of the carcinoid syndrome, a constellation of symptoms which includes flushing, diarrhoea, and valvular heart disease. The carcinoid syndrome is caused by secretion of serotonin and other vasoactive substances into the systemic circulation. Treatment options for metastatic intestinal NETs have expanded in recent years. Of particular importance has been the development of somatostatin-analogue therapies. Somatostatin analogues were originally introduced for palliation of the carcinoid syndrome; however recent clinical trials have demonstrated that they can exert an inhibitory effect on tumour growth. Other novel agents targeting the VEGF and mTOR pathways have recently been evaluated in phase III trials, however their role in the management of small-intestinal NETs remains controversial. This article examines the biological characteristics of small intestinal NETs, summarizes current guidelines on classification, staging and grading, and reviews developments in locoregional and systemic therapy.
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PMID:Neuroendocrine tumours of the small intestine. 2358 17

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, increases progression-free survival in patients with advanced neuroendocrine tumours. Patients with neuroendocrine tumours and symptomatic carcinoid have inferior health-related quality of life than those without symptoms. We aimed to evaluate the effect of everolimus on symptomatic control of neuroendocrine tumours. Fifteen patients with metastatic neuroendocrine disease pre-treated with depot octreotide received combination everolimus and octreotide (midgut = 8, pancreatic = 3, other = 4). Reasons for initiation of everolimus were progressive disease (PD) by response evaluation criteria in solid tumours (n = 5), worsening syndromic symptomology (n = 5), or both (n = 5). Symptomatic and objective response and toxicity were evaluated using standard criteria. 7/10 patients who were syndromic had improvements in symptomology, with a mean duration of symptom control 13.9 months (range 1-39). All 10 symptomatic patients had non pancreatic neuroendocrine (pNET) primaries, and with everolimus, 6/10 had reduced stool frequency, 3/7 had a reduction of asthenia, and 5/7 had reduced frequency and severity of flushing. Sixty percent of patients experienced any grade toxicities, including the following: 40% grade 1/2 stomatitis, 7% grade 3/4 stomatitis, 20% grade 1/2 rash, 13% diarrhoea, and one case of pneumonitis. In this cohort of 15 patients, we demonstrated that 70% of non pNET individuals with common carcinoid syndrome symptoms resistant to depot octreotide had improvement in these symptoms on institution of everolimus, with meaningful durations of symptom control. Although this data is observational, to our knowledge, this represents the largest analysis of carcinoid syndrome control with combined everolimus and octreotide.
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PMID:Symptomatic Control of Neuroendocrine Tumours with Everolimus. 2624 86


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