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Item CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy(American Association for Cancer Research, 2014-04-01) Ding, Liya; Chen, Shuai; Liu, Ping; Pan, Yunqian; Zhong, Jian; Regan, Kevin M.; Wang, Liguo; Yu, Chunrong; Rizzardi, Tony; Cheng, Liang; Zhang, Jun; Schmechel, Stephen C.; Cheville, John C.; van Deursen, Jan; Tindall, Donald J.; Huang, Haojie; Department of Pathology & Laboratory Medicine, IU School of MedicineDespite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients.Item Fluorescence in situ Hybridization in Surgical Pathology: Principles and Applications(Wiley, 2017) Cheng, Liang; Zhang, Shaobo; Wang, Lisha; MacLennan, Gregory T.; Davidson, Darrell D.; Department of Pathology and Laboratory Medicine, IU School of MedicineIdentification of recurrent tumour-specific chromosomal translocations and novel fusion oncogenes has important diagnostic, therapeutic and prognostic implications. Over the past decade, fluorescence in situ hybridization (FISH) analysis of tumour samples has been one of the most rapidly growing areas in genomic medicine and surgical pathology practice. Unlike traditional cytogenetics, FISH affords a rapid analysis of formalin-fixed, paraffin-embedded cells within a routine pathology practice workflow. As more diagnostic and treatment decisions are based on results of FISH, demand for the technology will become more widespread. Common FISH-detected alterations are chromosome deletions, gains, translocations, amplifications and polysomy. These chromosome alterations may have diagnostic and therapeutic implications for many tumour types. Integrating genomic testing into cancer treatment decisions poses many technical challenges, but rapid progress is being made to overcome these challenges in precision medicine. FISH assessment of chromosomal changes relevant to differential diagnosis and cancer treatment decisions has become an important tool for the surgical pathologist. The aim of this review is to provide a theoretical and practical survey of FISH detected translocations with a focus on strategies for clinical application in surgical pathology practice.Item The Impact of Genomic Profiling for Novel Cancer Therapy–Recent Progress in Non-Small Cell Lung Cancer(Elsevier, 2016-01) Xie, Jingwu; Zhang, Xiaoli; Department of Pediatrics, IU School of MedicineThere is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as an example. We also discuss possible future implications of cancer genome analyses.Item Systematic literature review and meta-analysis of clinical outcomes and prognostic factors for melanoma brain metastases(Frontiers, 2022-12-07) Tan, Xiang-Lin; Le, Amy; Scherrer, Emilie; Tang, Huilin; Kiehl, Nick; Han, Jiali; Jiang, Ruixuan; Diede, Scott J.; Shui, Irene M.; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: More than 60% of all stage IV melanoma patients develop brain metastases, while melanoma brain metastases (MBM) is historically difficult to treat with poor prognosis. Objectives: To summarize clinical outcomes and prognostic factors in MBM patients. Methods: A systematic review with meta-analysis was conducted, and a literature search for relevant studies was performed on November 1, 2020. Weighted average of median overall survival (OS) was calculated by treatments. The random-effects model in conducting meta-analyses was applied. Results: A total of 41 observational studies and 12 clinical trials with our clinical outcomes of interest, and 31 observational studies addressing prognostic factors were selected. The most common treatments for MBM were immunotherapy (IO), MAP kinase inhibitor (MAPKi), stereotactic radiosurgery (SRS), SRS+MAPKi, and SRS+IO, with median OS from treatment start of 7.2, 8.6, 7.3, 7.3, and 14.1 months, respectively. Improved OS was observed for IO and SRS with the addition of IO and/or MAPKi, compared to no IO and SRS alone, respectively. Several prognostic factors were found to be significantly associated with OS in MBM. Conclusion: This study summarizes pertinent information regarding clinical outcomes and the association between patient characteristics and MBM prognosis.Item Targeted Inhibition of the HGF/c-Met Pathway by Merestinib Augments the Effects of Albumin-Bound Paclitaxel in Gastric Cancer(2022-07-28) Kaurich, Quinn; Huang, Jennifer; Awasthi, NiranjanBACKGROUND AND HYPOTHESIS: Combination chemotherapy regimens are commonly used to treat gastric adenocarcinoma (GAC), but the median survival time remains less than one year. Nab-paclitaxel has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. We hypothesize that merestinib, a small-molecule inhibitor targeting c-Met, Axl, and DDR1/2 pathways, will have significant antitumor effects and will enhance the response to nab-paclitaxel in GAC preclinical models. PROJECT METHODS: In vitro proliferation and protein expression were assessed using WST-1 and immunoblot assays. Subcutaneous xenografts of MKN-45 and SNU-1 cell lines were implanted in mice to study tumor growth inhibition. Immunohistochemistry was performed to examine intratumor proliferation and microvessel density. RESULTS: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three cell lines, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45 cell line, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1 cell line, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab¬-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. CONCLUSION: The data suggest that merestinib in combination with nab-paclitaxel carry a promising potential for improving clinical GAC therapy.Item Targeted therapy for pancreatic cancer: lessons learned and future opportunities(AME, 2021-06) Thomas, Alex G.; Awasthi, Niranjan; Medicine, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is associated with a very poor prognosis because of its aggressive character, late-stage diagnosis, and resistance against systemic treatments. The current standard of care treatment for advanced PDAC is a combination of nab-paclitaxel and gemcitabine. However, other therapeutic approaches are necessary to combat cases where PDAC develops significant resistance against conventional chemotherapy. So far, targeted therapies have not been highlighted significantly with regards to facilitating successful treatment in PDAC patients. This review focuses on different targeted therapies tested in PDAC preclinically and clinically, such as antiangiogenic therapy, DNA repair inhibitors, KRAS pathway inhibitors, and anti-stromal therapy, summarizing data obtained regarding their implementation in treating PDAC, both by themselves and in combination with other drugs. This review also highlights recent advances in PDAC targeted therapies that may provide avenues for improved survival and facilitate further investigation into other potential therapeutic approaches in the future, including direct KRAS inhibitors, novel anti-stromal therapies, multikinase inhibitors, nanoparticle targeted therapy, and immunotherapy. Given the multifactorial nature of PDAC and how this disease has immense complexity in its treatment response with the development of resistance mechanisms, greater consideration and evaluation of novel targeted therapies are necessary towards improving PDAC treatment efficacy and patient outcomes.