Differentiation and Elimination of Chemo-surviving Colon Tumors

化疗后存活的结肠肿瘤的分化和消除

• 批准号: 8803345
• 负责人: ADHIP P. N. MAJUMDAR
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803345
• 关键词: Alkaline Phosphatase; Apoptosis; Biological Availability; CD44 gene; Cancer Model; Cell Differentiation process; Cell model; Cells; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complementary DNA; Curcumin; Data; Development; Diet; Differentiation Therapy; Down-Regulation; Drug resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Excision; Exhibits; Failure; Fluorouracil; Growth; Health; Human; In Vitro; Large Intestine Carcinoma; Lead; Malignant Neoplasms; Medicine; MicroRNAs; Modeling; Mus; Natural regeneration; Neoplasm Metastasis; Oncogenes; Operative Surgical Procedures; Parents; Patients; Play; Population; Property; Recurrence; Recurrent disease; Refractory; Regimen; Reporting; Resistance; Role; SCID Mice; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toxic effect; Transfection; Treatment Efficacy; Tumor Burden; Tumor Promotion; Undifferentiated; Vertebral column; Xenograft Model; Xenograft procedure; analog; beta catenin; cancer cell; cancer stem cell; chemotherapy; clinical remission; conventional therapy; cytokeratin 20; improved; in vivo; killings; neoplastic cell; novel; oxaliplatin; pre-clinical; preclinical study; prevent; response; self-renewal; stem; stemness; tumor

DESCRIPTION (provided by applicant): Despite the use of aggressive surgical resection and chemotherapy, nearly 50% of patients with colorectal carcinoma, the 3rd deadliest cancer in the US, will develop recurrent disease, highlighting the need for improved therapies. The failure to produce long-term clinical remission in CRC patients could reflect the inability to target cancer stem or stem-like cells (CSCs/CSLCs; that express cancer stem cell markers) efficiently since these cells are known to be resistant to conventional therapies. Differentiation therapy, which results in loss of self-renewal and induction of terminal differentiation or apoptosis in CSLCs, may be a valid option for the treatment of recurrent colorectal cancer. We have shown that miR-21, an emerging oncogene which induces stemness by activating Wnt/¿-catenin and EGFR signaling in colon cancer cells stimulates tumor promotion, invasion and metastasis. miR-21 is also greatly elevated in 5-FU + Oxaliplatin (FUOX) resistant colon cancer cells; downregulation of miR-21 leads to differentiation of these cells, as evidenced by increased CK-20 expression and alkaline phosphatase activity. Moreover, this downregulation renders the FUOX-resistant colon cancer cells susceptible not only to FUOX but also to 3, 4-difluorobenzo-curcumin or difluorinated curcumin (CDF) and the combination of CDF and FUOX. CDF is a novel analog of the dietary ingredient curcumin with much greater bioavailability and growth inhibitory properties than the parent compound. Additionally, we have observed that in response to CDF or the combination CDF and FUOX, miR-21-downregulated FUOX-resistant colon cancer cells exhibit decreased expression of EGFR and CD44 and increased apoptosis. CDF alone and the combination of CDF and FUOX were much more effective than FUOX alone. We propose to extend this differentiation therapy in a preclinical setting. Therefore, we will use SCID mice xenograft and orthotopic models of colon cancer to test the hypothesis that down regulation of miR-21 by antagomir-21 (antisense miR-21) in chemotherapy surviving colon tumors will lead to differentiation of chemotherapy-resistant tumor cells known to be enriched in CSCs/CSLCs. We further hypothesize that while subsequent treatment with FUOX will only be partially effective in obliterating the refractory colon tumors, treatment with either CDF or the combination of CDF and FUOX will be highly effective in causing a complete or near complete regression of the tumor by killing differentiating chemo-resistant colon CSCs/CSLCs through inhibition of Wnt/¿-catenin and EGFR signaling. Finally, we will demonstrate that miR-21 regulates ¿-Wnt/catenin and EGFR signaling pathways in colon cancer chemo-resistant cells in vitro.

描述（由申请人提供）： 尽管采用了积极的手术切除和化疗，但仍有近 50% 的结直肠癌（美国第三大致命癌症）患者会出现复发性疾病，这突出表明需要改进治疗方法。结直肠癌无法实现长期临床缓解。患者可能反映无法有效地靶向癌症干细胞或干细胞样细胞（CSC/CSLC；表达癌症干细胞标记物），因为已知这些细胞对传统疗法具有抵抗力，从而导致细胞丧失。 CSLC 的自我更新和诱导终末分化或凋亡可能是治疗复发性结直肠癌的有效选择，我们已经证明 miR-21 是一种新兴的癌基因，可通过激活 Wnt/¿ -结肠癌细胞中的连环蛋白和 EGFR 信号传导刺激肿瘤促进、侵袭和转移，miR-21 在 5-FU + 奥沙利铂 (FUOX) 耐药的结肠癌细胞中也大大升高；miR-21 的下调导致这些细胞的分化。此外，这种下调使 FUOX 耐药性结肠癌细胞不仅对 FUOX 敏感，而且对 FUOX 敏感。 3, 4-二氟苯并姜黄素或二氟姜黄素 (CDF) 以及 CDF 和 FUOX 的组合是膳食成分姜黄素的新型类似物，具有比母体化合物更高的生物利用度和生长抑制特性。响应 CDF 或 CDF 与 FUOX 的组合，miR-21 下调的 FUOX 耐药结肠癌细胞表现出 EGFR 和 CD44 表达降低单独的 CDF 以及 CDF 和 FUOX 的组合比单独的 FUOX 更有效。因此，我们将使用 SCID 小鼠异种移植模型和原位结肠癌模型来测试。假设在化疗存活的结肠肿瘤中 antagomir-21（反义 miR-21）下调 miR-21 将导致化疗耐药肿瘤细胞分化，已知这些细胞富含我们进一步发现，虽然后续使用 FUOX 治疗只能部分有效消除难治性结肠肿瘤，但使用 CDF 或 CDF 与 FUOX 联合治疗将非常有效地导致结肠肿瘤完全或接近完全消退。通过抑制 Wnt/¿ 杀死分化的化疗耐药性结肠 CSC/CSLC，从而抑制肿瘤-连环蛋白和 EGFR 信号转导最后，我们将证明 miR-21 调节 ¿ -体外结肠癌化疗耐药细胞中的Wnt/连环蛋白和EGFR信号通路。