Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leiomyomas are the most common gynecologic tumors in women, but very little is known about their molecular pathology. We used single-stranded conformational polymorphism/heteroduplex analysis to analyze 42 unselected uterine leiomyomas for somatic mutations in all coding exons of the gene encoding CCAAT displacement protein (CDP), as well as exons 5-8 of TP53 and codons 1-36 and 38-80 of KRAS. No somatic mutations were identified in either TP53 or KRAS, indicating that disregulation of these genes is not required for leiomyomas development. Aberrant band shifts were identified in CDP, but these were all germline nonpathogenic variants that have been reported previously. There is good functional and genetic evidence indicating that CDP is a leiomyoma suppressor, but our data suggested that somatic mutations in this gene were rare in unselected uterine leiomyomas. It is possible that CDP belongs to a class of tumor suppressor in which loss of only one copy of the gene, either by genetic or epigenetic mechanisms, is sufficient to allow tumor growth.
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PMID:Mutation analysis of CDP, TP53, and KRAS in uterine leiomyomas. 1276 5

Disruptions of the p53, retinoblastoma (Rb), and RAS signaling pathways and activation of human telomerase reverse transcriptase (hTERT) are common in human ovarian cancer; however, their precise role in ovarian cancer development is not clear. We thus introduced the catalytic subunit of hTERT, the SV40 early genomic region, and the oncogenic alleles of human HRAS or KRAS into human ovarian surface epithelial cells and examined the phenotype and gene expression profile of those cells. Disruption of p53 and Rb pathway by SV40 early genomic region and hTERT immortalized but did not transform the cells. Introduction of HRAS(V12) or KRAS(V12) into the immortalized cells, however, allowed them to form s.c. tumors after injection into immunocompromised mice. Peritoneal injection of the transformed cells produced undifferentiated carcinoma or malignant mixed Mullerian tumor and developed ascites; the tumor cells are focally positive for CA125 and mesothelin. Gene expression profile analysis of transformed cells revealed elevated expression of several cytokines, including interleukin (IL)-1beta, IL-6, and IL-8, that are up-regulated by the nuclear factor-kappaB pathway, which is known to contribute to the tumor growth of naturally ovarian cancer cells. Incubation with antibodies to IL-1beta or IL-8 led to apoptosis in the ras-transformed cells and ovarian cancer cells but not in immortalized cells that had not been transformed. Thus, the transformed human ovarian surface epithelial cells recapitulated many features of natural ovarian cancer including a subtype of ovarian cancer histology, formation of ascites, CA125 expression, and nuclear factor-kappaB-mediated cytokine activation. These cells provide a novel model system to study human ovarian cancer.
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PMID:A genetically defined model for human ovarian cancer. 1499 24

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
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PMID:BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. 1546 6

Activation of mitogen-activated protein kinase (MAPK) occurs in response to various growth stimulating signals and as a result of activating mutations of the upstream regulators, KRAS and BRAF, which can be found in many types of human cancer. To investigate the roles of MAPK activation in tumors harboring KRAS or BRAF mutations, we inactivated MAPK in ovarian tumor cells using CI-1040, a compound that selectively inhibits MAPK kinase, an upstream regulator of MAPK and thus prevents MAPK activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated tumor cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. Long serial analysis of gene expression identified several differentially expressed genes in CI-1040-treated MPSC1 cells harboring an activating mutation in BRAF (V599L). The most striking changes were down-regulation of cyclin D1, COBRA1, and transglutaminase-2 and up-regulation of tumor necrosis factor-related apoptosis-induced ligand, thrombospondin-1, optineurin, and palladin. These patterns of gene expression were validated in other CI-1040-treated tumor cells based on quantitative PCR. Constitutive expression of cyclin D1 partially reversed the growth inhibitory effect of CI-1040 in MPSC1 cells. Our findings indicate that an activated MAPK pathway is critical in tumor growth and survival of ovarian tumors with KRAS or BRAF mutations and suggest that the CI-1040 induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian tumors.
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PMID:Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. 1575 99

Activating mutations in the human KRAS proto-oncogene are acquired during the earliest stages of colorectal cancer development. If mutant KRAS is to be used as a target for therapy in colorectal cancer, tumor growth should depend on its continued presence. Here, we report that stable knockdown of Kras(D12) in murine C26 colorectal cancer cells by RNA interference resulted in loss of transformed properties in vitro. The incidence of subcutaneous tumor formation was reduced by 60% and the lag time was increased sevenfold. Kras(D12)-knockdown tumors grew noninvasively and did not cause morbidity. Remarkably, some of the Kras(D12)-knockdown tumors regressed spontaneously, which rendered these mice resistant to parental C26 tumor growth. In immune-deficient hosts, the incidence of tumor formation by Kras(D12)-knockdown cells was 100%. None of these tumors regressed spontaneously. We conclude that the reduced incidence of tumor formation by Kras(D12)-knockdown cells is due to tumor cell clearance by the host immune system, but not to an intrinsic inability of these cells to grow out as tumors. Interestingly, Kras(D12) knockdown resulted in increased production of interleukin 18 (Il-18), an immune-stimulatory cytokine that has been implicated in limiting colorectal tumor formation. Thus, mutant Kras(D12) suppresses Il-18 production in colorectal tumor cells, which may contribute to evasion of the local immune system during tumor development.
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PMID:Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy. 1609 32

Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.
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PMID:Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. 1614 72

Oncogenic activation of the BRAF serine/threonine kinase has been associated with initiation and maintenance of melanoma tumors. As such, development of pharmacologic agents to target RAF proteins or their effector kinases is an area of intense investigation. Here we report the biological properties of GDC-0879, a highly selective, potent, and orally bioavailable RAF small-molecule inhibitor. We used extracellular signal-regulated kinase (ERK)-1/2 and mitogen-activated protein kinase/ERK kinase (MEK)-1/2 phosphorylation as biomarkers to explore the relationship between tumor outcome and pharmacodynamic inhibition of the RAF-MEK-ERK pathway. In GDC-0879-treated mice, both cell line- and patient-derived BRAF(V600E) tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Despite the involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression was observed for some KRAS-mutant tumors following GDC-0879 administration. Moreover, striking differences were noted for RAF and MEK inhibition across a panel of 130 tumor cell lines. Whereas GDC-0879-mediated efficacy was associated strictly with BRAF(V600E) status, MEK inhibition also attenuated proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of BRAF(V600E) melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity. These data suggest that GDC-0879-induced signaling changes are dependent on the point of oncogenic activation within the RAS network. Taken together, these studies increase our understanding of the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition and have implications for therapeutic intervention in the clinic.
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PMID:Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. 1927 60

The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BRAF and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEN, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.
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PMID:PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. 1940 49

Tumor metastasis is a leading cause of cancer-related death. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Here, we show that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs. Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression.
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PMID:Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. 2023 93

The introduction of new cytotoxic agents and new targeted therapies has significantly broadened the therapeutic options for and the outcomes of patients with metastatic colorectal cancer (CRC). The introduction of the anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, has clearly contributed to this development. The concept of KRAS as a marker for resistance to anti-EGFR antibodies has been validated. However, new challenges have emerged: the complete understanding of the crucial and central role of KRAS in processes of tumor growth and the development of new treatment strategies for KRAS mutant tumors. KRAS seems to be so crucial that a further classification and description in KRAS wild-type and mutant may be warranted. Testing for KRAS mutations marks, therefore, a paradigm shift in the management of metastatic CRC. This testing also highlights the unmet need for new treatment options in KRAS mutant metastatic CRC. In this review we will focus on possible new treatment options for these patients.
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PMID:New strategies for treatment of KRAS mutant metastatic colorectal cancer. 2046 Apr 90


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