Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1855645 (KPC)
 1,473 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with KRAS mutated colorectal cancer (CRC) represent a cohort with unmet medical needs, with limited options of FDA-approved therapies. Representing 40-45% of all CRC patients, they are considered ineligible to receive anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Although several mouse models of CRC have been developed during the past decade, one genetically resembling the KRAS mutated CRC is yet to be established. In this study C57 BL/6 mice with truncated adenomatous polyposis coli (APC) floxed allele was crossed with heterozygous KRAS floxed outbred mice to generate an APCf/f KRAS+/f mouse colony. In another set of breeding, APC floxed mice were crossed with CDX2-Cre-ERT2 mice and selected for APCf/f CDX2-Cre-ERT2 after the second round of inbreeding. The final model of the disease was generated by the cross of the two parental colonies and viable APC f/f KRAS +/f CDX2-Cre-ERT2 (KPC: APC) were genotyped and characterized. The model animals were tamoxifen (TAM) induced to generate tumors. Micro-positron emission tomography (PET) scan was used to detect and measure tumor volume and standard uptake value (SUV). Hematoxylin and eosin (H&E) staining was performed to establish neoplasm and immunohistochemistry (IHC) was performed to determine histological similarities with human FFPE biopsies. The MSI/microsatellite stable (MSS) status was determined. Finally, the tumors were extensively characterized at the molecular level to establish similarities with human CRC tumors. The model KPC: APC animals are conditional mutants that developed colonic tumors upon induction with tamoxifen in a dose-dependent manner. The tumors were confirmed to be malignant within four weeks of induction by H&E staining and higher radioactive [18F] fluoro-2-deoxyglucose (FDG) uptake (SUV) in micro-PET scan. Furthermore, the tumors histologically and molecularly resembled human colorectal carcinoma. Post tumor generation, the KPC: APC animals died of cachexia and rectal bleeding. Implications: This model is an excellent preclinical platform to molecularly characterize the KRAS mutated colorectal tumors and discern appropriate therapeutic strategies to improve disease management and overall survival.
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PMID:Development and Characterization of a Genetic Mouse Model of KRAS Mutated Colorectal Cancer. 3176 49

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and chemotherapy is still an important treatment. It is urgent to develop new medicines because of the limitation and side effects of chemotherapy. 2'-Hydroxyflavanone (2HF) is a citrus-bioflavonoid that is considered to have anti-cancer efficacy. Compared to human pancreatic ductal epithelial cells hTERT-HPNE, more significant growth-inhibitory effects were seen in PDAC cells BxPC-3 and MIA PaCa-2. We showed that apoptosis was induced and that the cell cycle was arrested when cells were treated with 2HF. The expression of the molecular proteins cleaved PARP, cleaved Caspase3, Bax, Bcl-2, CyclinD1, and p27 changed correspondingly. Also, we observed anti-metastatic effects and changes in MMP9, E-cadherin, N-cadherin and Vimentin when cells were treated with a low dose of 2HF. Suppression of STAT3 and EGFR phosphorylation was also identified as a result of treatment with a combination of 2HF and EGFR inhibitors. The in vivo antitumor effects in KPC mice were consistent with those observed in vitro. 2HF has impactful anti-cancer efficacy and sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3.
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PMID:2'-Hydroxyflavanone inhibits the progression of pancreatic cancer cells and sensitizes the chemosensitivity of EGFR inhibitors via repressing STAT3 signaling. 3181 6

Aberrant activation of ERK signaling is a hallmark of lung cancer. Although constitutively activating mutations of EGFR and KRAS contribute to the hyperactivation of ERK1/2, other mechanisms remain elusive. In this study, the zinc finger protein ZNF251 was found to be upregulated in clinical lung cancer samples, and it promoted the growth of lung cancer cells and the growth of primary lung KPC cells from mouse models (Ad-Cre, KrasG12D , and P53f/f ). In studying the molecular mechanism, ZNF251 was found to inhibit the expression of dual-specificity phosphatase 6, a negative regulator of ERK activation, by directly binding to its promoter region. Taken together, our data indicate the tumor-promoting effects of ZNF251 in lung cancer and suggest that ZNF251 is a therapeutic target.
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PMID:ZNF251 promotes the progression of lung cancer by activating ERK signaling. 3258 9