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Browsing by Author "Wang, Song"
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Item A Critical Role of CDKN3 in Bcr-Abl-Mediated Tumorigenesis(PLoS, 2014-10) Chen, Qinghuang; Chen, Ke; Guo, Guijie; Li, Fang; Chen, Chao; Wang, Song; Nalepa, Grzegorz; Huang, Shile; Chen, Ji-Long; Department of Medical and Molecular Genetics, IU School of MedicineCDKN3 (cyclin-dependent kinase inhibitor 3), a dual specificity protein phosphatase, dephosphorylates cyclin-dependent kinases (CDKs) and thus functions as a key negative regulator of cell cycle progression. Deregulation or mutations of CDNK3 have been implicated in various cancers. However, the role of CDKN3 in Bcr-Abl-mediated chronic myelogenous leukemia (CML) remains unknown. Here we found that CDKN3 acts as a tumor suppressor in Bcr-Abl-mediated leukemogenesis. Overexpression of CDKN3 sensitized the K562 leukemic cells to imanitib-induced apoptosis and dramatically inhibited K562 xenografted tumor growth in nude mouse model. Ectopic expression of CDKN3 significantly reduced the efficiency of Bcr-Abl-mediated transformation of FDCP1 cells to growth factor independence. In contrast, depletion of CDKN3 expression conferred resistance to imatinib-induced apoptosis in the leukemic cells and accelerated the growth of xenograph leukemia in mice. In addition, we found that CDKN3 mutant (CDKN3-C140S) devoid of the phosphatase activity failed to affect the K562 leukemic cell survival and xenografted tumor growth, suggesting that the phosphatase of CDKN3 was required for its tumor suppressor function. Furthermore, we observed that overexpression of CDKN3 reduced the leukemic cell survival by dephosphorylating CDK2, thereby inhibiting CDK2-dependent XIAP expression. Moreover, overexpression of CDKN3 delayed G1/S transition in K562 leukemic cells. Our results highlight the importance of CDKN3 in Bcr-Abl-mediated leukemogenesis, and provide new insights into diagnostics and therapeutics of the leukemia.Item Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial(American Association for Cancer Research, 2022) Boni, Valentina; Fidler, Mary J.; Arkenau, Hendrik-Tobias; Spira, Alexander; Meric-Bernstam, Funda; Uboha, Nataliya; Sanborn, Rachel E.; Sweis, Randy F.; LoRusso, Patricia; Nagasaka, Misako; Garcia-Corbacho, Javier; Jalal, Shadi; Harding, James J.; Kim, Stella K.; Miedema, Iris H. C.; Vugts, Danielle J.; Huisman, Marc C.; Zwezerijnen, Gerben J. C.; van Dongen, Guus A. M. S.; van der Houven van Oordt, C. Willemien Menke; Wang, Song; Dang, Tam; Zein, Ivan A.; Vasiljeva, Olga; Lyman, Susan K.; Paton, Virginia; Hannah, Alison; Liu, Joyce F.; Medicine, School of MedicinePurpose: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. Patients and methods: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). Results: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. Conclusions: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.Item The Sapheos Project: Transparency in Multi-image Collation, Analysis, and Representation(University of South Carolina Research Foundation, 2011) Waggoner, Jarrell; Salvi, Dhaval; Zhou, Jun; Wang, Song; Guiliano, JenniferOur proposal for a Level II Start-Up grant for the Sapheos project seeks to develop innovative software to analyze, represent, and collate images in the humanities. While there are an array of text based digital projects underway that offer increasingly powerful tools for marking up, analyzing, and visualizing textual data in the humanities, image-based analysis has not received similar attention. From the project's inception, our aim has been to develop extensible open-source software that researchers across the humanities can use to link image to text in a discrete, granular fashion. Working with the NEH-funded Spenser Project, a multi-institutional Scholarly Editions project, we're developing two significant image-based software tools: (a) digital collation software that builds on and extends the work of optical methods, using transparency to "stack" and collate multiple copies, and (b) software for automatically sectioning and identifying (x,y) coordinate pairs for images.