Joseph S. Dosch

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BACKGROUND & AIMS Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. METHODS We studied growth of primary human(More)
Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for(More)
Although cancer has been described in early medical texts from antiquity, it remains the second leading cause of death in the United States. Technological improvements in screening modalities have increased detection of smaller tumors, yet current therapies for most types of cancer often fail. Cancer death is usually attributable to the development of(More)
Patients with many types of malignancy commonly harbor quiescent disseminated tumor cells in bone marrow. These cells frequently resist chemotherapy and may persist for years before proliferating as recurrent metastases. To test for compounds that eliminate quiescent cancer cells, we established a new 384-well 3D spheroid model in which small numbers of(More)
PURPOSE The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. EXPERIMENTAL DESIGN Initial testing was carried out(More)
While several aberrant signaling pathways have been attributed to the formation and progression of pancreatic cancer, there is mounting evidence for the increased role of the Hedgehog (Hh) pathway in multiple aspects of pancreatic tumor development. The Hh pathway is a signaling cascade that plays an important role in cell patterning of multiple tissues and(More)
Transforming growth factor-β (TGF-β) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-β, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human kinome and a live-cell reporter(More)
Survival rates associated with pancreatic cancer remain dismal despite advancements in detection and experimental treatment strategies. Genetically engineered mouse models of pancreatic tumorigenesis have gained considerable attention based on their ability to recapitulate key clinical features of human disease including chemotherapeutic resistance and(More)
http:tke.scien D ow nladed from Transforming growth factor–b (TGF-b) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-b, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human(More)
Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy that Co-Targets MEK and CDK4/6 Elizabeth K. Ziemke, Joseph S. Dosch, Joel D. Maust, Amrith Shettigar , Ananda Sen, Theodore H. Welling, Karin M. Hardiman, Judith S. Sebolt-Leopold Translational Oncology Program, Department of Radiology, Department of Pharmacology, Department of Family(More)