Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma.

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.

Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression.

Autophagy may play a critical role in colon cancer stem cells (CCSCs)-related cancer development. Here, we investigate whether accumulation of infection/injury-induced CCSCs due to impaired autophagy influences colon cancer development and progression. When Apc++ mice were infected with Citrobacter rodentium (CR; 109CFUs), we discovered presence of autophagosomes with increases in Beclin-1, LC3B and p62 staining during crypt hyperplasia. Apc1638N/+ mice when infected with CR or subjected to CR+AOM treatment, exhibited increased colon tumorigenesis with elevated levels of Ki-67, ß-catenin, EZH2 and CCSC marker Dclk1, respectively. AOM/DSS treatment of Apc1638N/+ mice phenocopied CR+AOM treatment as colonic tumors exhibited pronounced changes in Ki-67, EZH2 and Dclk1 accompanied by infiltration of F4/80+ macrophages, CD3+ lymphocytes and CD3/ß-catenin co-localization. Intestinal and colonic tumors also stained positive for migrating CSC markers CD110 and CDCP1 wherein, colonic tumors additionally exhibited stromal positivity. In tumors from CR-infected, CR+AOM or AOM/DSS-treated Apc1638N/+ mice and surgically-resected colon tumor/metastatic liver samples, significant accumulation of p62 and it's co-localization with LC3B and Dclk1 was evident. ApcMin/+ mice when infected with CR and BLT1-/-;ApcMin/+ mice, exhibited similar co-localization of p62 with LC3B and Dclk1 within the tumors. Studies in HCT116 and SW480 cells further confirmed p62/Dclk1 co-localization and Chloroquin/LPS-induced increases in Dclk1 promoter activity. Thus, co-localization of p62 with Dclk1 may hamper Dclk1's elimination to impact colon cancer development and progression.

Morbidity and mortality of synchronous hepatectomy with cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

BACKGROUND: Liver resection in conjunction with partial colectomy for colon cancer is considered acceptable treatment for isolated metastasis to the liver. This method is unstudied in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for carcinomatosis due to colon cancer and high grade appendiceal cancer. METHODS: A retrospective chart review included patients from 2005 to 2016 undergoing CRS/HIPEC. Cancers other than colorectal adenocarcinoma and high grade appendiceal carcinoma were excluded. Patients were divided into hepatectomy and non-hepatectomy groups. Data was collected by chart review from electronic medical records to assess morbidity and mortality, as well as oncologic outcomes of included patients. RESULTS: The average patient age, length of stay, and sex were similar between groups. For those in the hepatectomy group, 80% underwent minor hepatectomy, and 20% underwent major hepatectomy. The comprehensive complication index (CCI) scores ranged from 0 (no complications), to 100 (death). The average CCI between study groups was similar (27.29 vs. 17.41, P=0.09). Hepatectomy was associated with a higher rate of Clavien-Dindo classifications (CDCs) of III or greater. Complications included pressor requirement, renal failure, blood transfusions, TPN, pleural effusions and leaks requiring drain placement, respiratory failure, UTI, new onset atrial fibrillation, wound infections, and death. CONCLUSIONS: Patients who underwent CRS/HIPEC and hepatectomy for colorectal and high grade appendiceal carcinomatosis had more severe complications at similar rates to non-hepatectomy patients. Complication rates should be considered when selecting patients for aggressive surgical intervention.