PO.TB04.05 · 肿瘤生物学
在原位肌层浸润性膀胱癌模型中通过膀胱内灌注增强联合疗法的抗肿瘤疗效
Enhanced antitumor efficacy of combination therapy via intravesical perfusion in an orthotopic muscle-invasive bladder cancer model
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
膀胱癌是一种常见且侵袭性强的疾病，若未得到适当治疗会带来严重的健康风险。肌层浸润性原位动物模型能够紧密复制人类膀胱癌的病理生理学。原位肌层浸润性膀胱癌模型在技术上更具挑战性，但对转化研究至关重要。在这些模型中，基于IVIS的光学成像提供了一种无创、动态的方法来实时监测肿瘤进展。鉴于该疾病的异质性和对治疗的耐药性，联合治疗对于通过靶向多条致癌通路来增强疗效至关重要。在本研究中，我们通过将T24-Luc细胞直接注射到膀胱壁中，在无胸腺裸鼠中建立了肌层浸润性原位膀胱癌模型。通过一个小的腹部切口暴露膀胱以放置导管，导管用荷包缝合固定并隧道式引至颈部，连接到背带上。恢复后，T24-Luc细胞被准确递送至膀胱壁而无泄漏。使用IVIS光学成像每周两次监测肿瘤进展。大鼠按总光通量强度分组，然后通过膀胱插管给药，使用厄达替尼（Erdafitinib，5μg/mL）、多柔比星（Doxorubicin，400μg/mL）、吉西他滨（Gemcitabine，90μg/mL）作为单独用药以及与厄洛替尼（Erlotinib）联合用药，在7天内通过持续灌注递送。总光通量（光子/秒）、体重变化、临床体征、死亡率每周监测两次，最长至2周。研究结束时，切除膀胱，通过多个参数评估治疗疗效，包括离体生物发光成像、膀胱重量测量、拍照以及组织病理学和IHC分析。在当前的原位肌层浸润性膀胱癌（MIBC）模型中，单独使用厄达替尼、多柔比星或吉西他滨治疗导致中度肿瘤消退。而多柔比星和吉西他滨与厄达替尼的联合用药表现出最高的抗肿瘤疗效，表现为生物发光信号强度和膀胱重量的显著降低。组织病理学分析未显示肿瘤形成或侵入膀胱深层的迹象，且联合疗法相比单一治疗显著延长了生存期。总体而言，本研究结果表明，将传统化疗药物与靶向FGFR抑制剂相结合的联合疗法比单一疗法显著增强了抗肿瘤疗效。通过膀胱插管进行的持续膀胱内灌注实现了局部药物递送，有效地将全身毒性降至最低，同时最大化肿瘤暴露和治疗效果。
查看英文原文 English abstract
Bladder cancer is a prevalent and aggressive disease with serious health risks if not properly treated. Muscle-invasive orthotopic animal models closely replicate the pathophysiology of human bladder cancer. Orthotopic muscle-invasive bladder cancer model is more technically demanding but essential for translational research. In these models, IVIS-based optical imaging provides a non-invasive and dynamic method to monitor tumor progression in real time. Given the disease's heterogeneity and resistance to therapy, combination treatments are essential to enhance efficacy by targeting multiple oncogenic pathways. In this study, a muscle-invasive orthotopic bladder cancer model was developed in athymic nude rats by injecting T24-Luc cells directly into the bladder wall. A minor abdominal incision exposed the bladder for catheter placement, which was secured with a purse-string suture and tunnelled to the neck, connected to a harness. After recovery, T24-Luc cells were accurately delivered into the bladder wall without leakage. Tumor progression was monitored twice weekly using IVIS optical imaging. Rats were grouped by total flux intensity, then treated via bladder cannulation with Erdafitinib (5µg/mL), Doxorubicin (400µg/mL), Gemcitabine (90µg/mL) as standalone and combination with Erlotinib, delivered through continuous perfusion over a 7-day period. Total flux (photons/second), changes in body weight, clinicals signs, mortality were monitored twice weekly up to 2 weeks. At end of the study, bladder was excised for assessment of treatment efficacy through multiple parameters, including ex-vivo bioluminescence imaging, bladder weight measurement, photographed, and histopathological and IHC analysis. In the current orthotopic muscle-invasive bladder cancer (MIBC) model, treatment with standalone Erdafitinib, Doxorubicin, or Gemcitabine led to moderate tumor regression. Whereas combination of Doxorubicin and Gemcitabine with Erdafitinib demonstrated the highest anti-tumor efficacy, as evidenced by marked reductions in bioluminescence signal intensity, bladder weight. Histopathological analysis revealed no signs of tumor formation or invasion into deeper bladder layers, and the combination therapy significantly prolonged survival compared to individual treatments. Overall, the findings from this study indicate that combination therapy integrating conventional chemotherapeutic agents with targeted FGFR inhibitors significantly enhances anti-tumor efficacy than monotherapies. Continuous intravesical perfusion via bladder cannulation enables localized drug delivery, effectively minimizing systemic toxicity while maximizing tumor exposure and therapeutic impact
利益披露 Disclosure
B. Ramachandran, None..
S. Rajendiran, None..
G. Joshi, None..
K. Haladasappa, None.