Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The ‘4-hit’ flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC.
Significance:
Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.
BackgroundThe oncological effectiveness of preoperative radiotherapy for locally advanced colon cancer is unclear. We report a case of pathological complete response in a patient with locally advanced ascending colon cancer after preoperative radiotherapy following failure of chemotherapy.Case presentationA 65-year-old Japanese woman presented with malaise and hematochezia. A computed tomography (CT) revealed a tumor in the ascending colon which seemed to infiltrate the adjacent structures. She was diagnosed with locally advanced ascending colon cancer stages T4b, N2a, M0, and IIIC. We selected modified FOLFOX6 with panitumumab as neoadjuvant chemotherapy. However, we discontinued the chemotherapy after the 8th cycle because of disease progression and severe adverse effects. The patient then underwent radiotherapy of 60 Gy in 30 fractions, resulting in significant tumor size reduction. One month after the radiotherapy, we performed a right hemicolectomy with multivisceral resection without complications. Histopathologically, we found no residual cancer cells in the resected specimen. The patient remains alive and has not required additional therapies for 24 months, as there are no signs of recurrence.ConclusionsThe present case suggests that preoperative radiotherapy might be an effective treatment options for locally advanced colon cancer.
Boerhaave's syndrome is a rare life‐threatening disease that requires prompt intervention. Thoracotomy has traditionally been considered the gold standard approach for treatment, but other minimally invasive approaches have recently been reported. Our institute reported the efficacy of minimally invasive abdominal and left thoracic approach in the treatment of patients with esophagogastric junction cancer and introduced it for the treatment of two patients with Boerhaave's syndrome. We intraoperatively sutured the rupture sites and irrigated the pleural cavity using thoracoscopy. Then, after confirming the absence of intraabdominal contamination, we performed jejunostomy or gastrostomy using laparoscopy. Patients' vital signs remained stable intraoperatively, and their postoperative periods were uneventful with no leakage or stricture. The minimally invasive abdominal and left thoracic approach for Boerhaave's syndrome is convenient and useful as it provides excellent visualization of the thoracic and abdominal cavities with the possibility of quickly switching between views.
<div>Abstract<p>Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a <i>Drosophila</i> model mimicking the genetic signature in PDAC (<i>KRAS</i>, <i>TP53</i>, <i>CDKN2A</i>, and <i>SMAD4</i> alterations), which is associated with the worst prognosis in patients. The ‘<i>4-hit</i>’ flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC.</p>Significance:<p>Development of a <i>Drosophila</i> model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.</p></div>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.