Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platinum-based chemotherapy regimens are often recommended for patients with unresectable thymic carcinoma. In more than 60 cases, however, the systemic chemotherapy provides little benefit. In this report, we described a case of advanced KIT- and VEGF-positive thymic carcinoma with liver and lung metastasis. The patient, a 46-year-old man, exhibited a resistance to cisplatin-based chemotherapy, but responded to the treatment with sorafenib, a molecular target-based therapy. After 4 months of sorafenib therapy, his lung and liver metastases as well as the mediastinal tumor shrank dramatically. Moreover, the tumors showed stable disease for at least 9 months. To the best of our knowledge, it is the first report about a response of advanced thymic carcinoma to sorafenib. The preliminary study suggested that molecular target-based therapy could be an alternative treatment to those chemotherapy-refractory patients.
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PMID:Response to sorafenib in cisplatin-resistant thymic carcinoma: a case report. 1884 37

We report a long-term survival case of metastatic breast cancer treated with trastuzumab and paclitaxel. The patient was a 50-year-old female. She underwent left mastectomy with axillary lymphadenectomy for advanced breast cancer with liver metastases. Histological examination showed papillotublar carcinoma, f, T3, ly3, v2, N2 (24/34), histological grade III, ER (-), PgR (-), HER2 (3+). Trastuzumab and paclitaxel was performed. One year after the operation, any lesions of liver were not detected by CT and she was diagnosed as a complete response. No evidence of viable lesions has been found for 7 years. Breast cancer with liver metastases often could be a life threatening, and therefore an optimal chemotherapy should be applied as soon as possible. Trastuzumab and paclitaxel would be one of the optimal chemotherapies for HER2 positive breast cancer.
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PMID:[A long-term survival case of metastatic breast cancer treated with trastuzumab and paclitaxel]. 1910 81

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib. The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.
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PMID:EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up. 1918 17

The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment.
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PMID:Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors. 1929 38

Pancreatic cancer with liver metastases has a poor prognosis and the molecular mechanisms remain unclear. In this study, SW1990HM, a highly metastatic human pancreatic carcinoma line was subcloned from SW1990 by intrasplenic injection. In vivo and in vitro tumorigenicity, metastatic potential, in vitro invasion, cell growth curves, plate efficiency and S-phase cell numbers were higher in SW1990HM cells. Gene expression profiles of SW1990HM and SW1990 cells showed 40 metastasis-related genes expressed with a 3-fold difference. Thirteen of these 32.5% (13/40) were adhesion and extracellular-matrix related and twelve 30% (12/40) were cell growth and proliferation related, such as MMP10, MMP9, MMP7, CDH1, MGAT5, CTNNA1, IGF1, IL8RB, ITGA7, MDM2, MET, SSTR2 and VEGF, which were related to the onset and progression of tumor metastasis. Thus, SW1990HM is an attractive model to study metastasis and identify potential therapeutic targets.
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PMID:Identification of liver metastasis-related genes in a novel human pancreatic carcinoma cell model by microarray analysis. 1937 52

Cetuximab, an anti-EGFR human/mouse chimeric antibody, has just been approved in Japan for patients with EGFR positive unresectable or recurrent colorectal cancer, as monotherapy or in combination with irinotecan. We reported two cases of unresectable or recurrent colorectal cancer effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A51-year-old male suffered from sigmoid colon cancer with synchronous liver metastases. He received cetuximab plus irinotecan combination therapy in the third-line setting. Amonth after the initiation of the chemotherapy, abdominal CT showed tumor shrinkage of liver metastases. Case 2: A57-year-old female suffered from sigmoid colon cancer with metachronous liver, ovarian metastases, ascites and pleural effusion. Her performance status(PS)according to ECOG performance scale was 1, and she complained of dyspnea on exertion. She received cetuximab monotherapy in the fourth-line setting. Five weeks after initiation of chemotherapy, her chest, abdominal and pelvic CT showed tumor shrinkage of the liver metastases and the reduction of both ascites and pleural effusion, together with resolution of her dyspnea on exertion. Before cetuximab administration, we investigated KRAS status on cancer tissue previously resected in the above 2 cases, which showed KRAS wild-type. Cetuximab could be effective for KRAS wild-type colorectal cancer, as well as the previous reports from Western countries.
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PMID:[Two cases of KRAS wild-type unresectable or recurrent colorectal cancer effectively treated by cetuximab after progression of prior chemotherapy]. 1954 25

PURPOSE: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3alpha/beta, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis. EXPERIMENTAL DESIGN: DNA and protein were isolated from dissected frozen melanoma metastases (n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3alpha/beta, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines (n = 58) was analyzed for comparison. RESULTS: BRAF-mutant tumors had higher levels of P-AKT-Ser473 (P = 0.01), P-AKT-Thr308 (P = 0.002), and P-GSK3alpha/beta (P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases. CONCLUSIONS: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538-46).
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PMID:Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma. 1999 8

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.
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PMID:A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases. 2003 67

Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-beta (PDGFR-beta) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-beta, and hTS is better than or close to standards. In a COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.
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PMID:Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents. 2009 23

A case report of a patient with HER2-positive liver metastases of breast cancer. Partial regression was reached during chemotherapy, which was further stabilized by trastuzumab. Resection of the metastases was performed after progression. Capecitabine was started after the occurrence of new multiple lesions; complete regression was reached, which has now lasted over three years with continued capecitabine treatment.
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PMID:[Long-term response of liver metastases of breast cancer to capecitabine--case report]. 2019 74


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