Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.41 (isocitrate dehydrogenase)
 3,101 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy. Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition.
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PMID:Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review. 2807 32

Biliary tract cancer (BTC) is a disease entity comprising diverse epithelial tumors with features of cholangiocyte differentiation, and it includes cholangiocarcinoma (CCA) and gallbladder cancer (GBC). Depending on its anatomical location, cholangiocarcinoma is categorized as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Nearly two-thirds of patients with biliary tract cancer present with advanced disease at diagnosis and in 68-86% of resections the cancer eventually recurs either locoregionally or at a distance. Chemotherapy is the first-line therapy for advanced or recurrent BTC. With the development of next-generation sequencing (NGS)-guided molecular targeted therapy, more options are available for treatment of advanced BTC. Chemotherapy, and especially a triplet regimen based on gemcitabine/cisplatin/nab-paclitaxel, has had the most significant effect, and fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) combined with bevacizumab is promising. Molecular targeted therapy should be based on genome sequencing and appears essential to precision medicine. Fibroblast growth factor receptor (FGFR) inhibitors and isocitrate dehydrogenase (IDH) inhibitors are promising emerging targeted therapies mainly for iCCA. Other targeted therapies such as anti-human epidermal growth factor receptor-2 (HER2) therapies, MEK inhibitors, BRAF inhibitors, and poly ADP ribose polymerase (PARP) inhibitors had tentatively displayed efficacy. Further evaluations of combination strategies in particular are needed. An immune checkpoint inhibitor (ICI) alone is less efficacious, but an ICI in addition to chemotherapy or radiotherapy has resulted in a response according to many case series. However, ICIs are still being evaluated in several ongoing studies. Combination therapies have garnered attention because of interactions between signaling pathways of carcinogenesis in BTC.
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PMID:Systemic treatment of advanced or recurrent biliary tract cancer. 3283 Jan 66