Targeting cadherin-11 in pancreatic cancer

胰腺癌很快将成为癌症相关死亡的第二大原因， 8 - 11个月。对于70%的患者来说，全身化疗是唯一的选择，这主要是缓解 症状和/或稍微延长生存期，而不是治愈患者。PDAC的特点之一是 广泛的纤维化，占肿瘤的80%。癌症相关成纤维细胞（CAF）及其 细胞外基质的沉积影响肿瘤的进展、转移和治疗抗性。CAF发布 生长因子和细胞因子不仅影响胰腺癌细胞的生长，而且影响浸润 肿瘤微环境（TME）。然而，CAFs本身的耗尽也是可能的。 在这里，我们提出的基本原理，它是更好地调制串扰之间 CAF，免疫细胞浸润和癌细胞，以限制肿瘤生长，而不是完全耗尽CAF从 TME。在疾病进展过程中，PDAC患者的间质室显著增加， 粘附分子钙粘蛋白11（CDH 11）的表达，其在正常胰腺中不表达。CDH11 在与慢性炎症性疾病如类风湿性关节炎相关的活化成纤维细胞中也增加 关节炎、炎性肠病、肺纤维化、硬皮病和心脏纤维化。重要的是，Cdh 11-/- 动物受到了很好的保护，免受这些疾病的侵害。在2021年，我们公布了CDH 11的损失和一个小的 我们开发的分子CDH 11抑制剂（SD 133）（本申请的主题）也显著地 延长了携带胰腺癌的基因工程小鼠的生存期。与此同时， 纤维化、抗肿瘤免疫细胞浸润增加和细胞因子变化。SD 133是 对缺乏T和B细胞的小鼠无效，证实了适应性免疫系统在其机制中的作用 行动上描述SD 133这种免疫调节作用的完整专利已于2021年提交。在本STTR中 我们的目标是改进SD 133的治疗，并评估体内反应-单独或联合 化疗或免疫疗法，使用最先进的技术，可通过我们的学术 搭档我们的第一个目标是建立最佳的制剂，剂量，给药途径和治疗方案， CDH 11的第一个小分子抑制剂，SD 133。为了增加研究的翻译价值，我们 接下来将使用另外两种动物模型，一种PDAC的基因工程小鼠模型， 类似于人类疾病进展，并选择人类PDAC PDX模型和人源化小鼠。我们 CDH 11抑制调节细胞外基质组成，并免疫调节 胰腺TME通过增加抗肿瘤免疫细胞的浸润， 免疫抑制细胞是非常创新的。此外，我们假设CDH 11抑制促进了 对标准化疗或免疫治疗的敏感性，以获得额外的益处。完成这些 这些研究将促进我们将SD 133转化为PDAC患者临床试验的长期目标。

Pancreatic cancer is soon to be the second leading cause of cancer-related death with an overall median survival of 8 - 11 months. For 70% of patients, systemic chemotherapy is the only option and this mainly relieves the symptoms and/or slightly extends survival, rather than cures the patients. One of the hallmarks of PDAC is extensive fibrosis that comprises up to 80% of the tumor. Cancer-associated fibroblasts (CAFs) and their deposition of extracellular matrix influences tumor progression, metastasis and therapy resistance. CAFs release growth factors and cytokines that not only influence growth of pancreatic cancer cells, but also affect infiltration of immune cells into the tumor microenvironment (TME). However, depletion of CAFs themselves is just as likely to promote PDAC as inhibit it. Here, we propose the rationale that it is better to modulate crosstalk between CAFs, immune cell infiltrates and cancer cells to limit tumor growth, rather than entirely deplete CAFs from the TME. During disease progression, the stromal compartment of patients with PDAC markedly increases expression of the adhesion molecule cadherin 11 (CDH11), which is not expressed in normal pancreas. CDH11 is also increased in activated fibroblasts associated with chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, scleroderma and heart fibrosis. Importantly, Cdh11-/- animals are significantly protected from these diseases. In 2021 we published that CDH11 loss and a small molecule CDH11 inhibitor (SD133) we developed (the subject of the current application) also significantly extended survival in pancreatic cancer-bearing genetically engineered mice. This was accompanied by reduced fibrosis, increased infiltration of anti-tumor immune cells and changes in cytokines. Importantly, SD133 is ineffective in mice lacking T and B cells confirming a role for the adaptive immune system in its mechanism of action. A full patent describing this immunomodulatory role of SD133 was submitted in 2021. In this STTR proposal our objective is to refine therapy with SD133, and assess response in vivo – alone or in combination with chemotherapy or immunotherapy, using state-of-art technologies that are available through our Academic Partner. Our first aim is to establish optimal formulation, dose, administration route and treatment schedule of the first-in-class small molecule inhibitor of CDH11, SD133. To increase the translational value of the study, we will next use two additional animal models, a genetically engineered mouse model of PDAC that closely resembles human disease progression, and selected human PDAC PDX models and humanized mice. Our proposal that CDH11 inhibition modulates extracellular matrix composition, and immunomodulates the pancreatic TME by increasing infiltration of anti-tumor immune cells, and deterring infiltration by immunosuppressive cells is highly innovative. Additionally, we hypothesize that CDH11 inhibition promotes susceptibility to standard-of-care chemotherapy or immunotherapy, for added benefit. Completion of these studies will promote our long-term goal of translating SD133 into a clinical trial for PDAC patients.