Exploiting tumor stroma interactions for cancer therapy

描述（由申请人提供）：胰腺腺癌是一种毁灭性的疾病，其治疗是当今未满足医疗需求的主要领域。胰腺癌的三个公认特征是KRAS在疾病早期突变，广泛的纤维炎症（结缔组织增生）导致血流量减少和药物传递不良，以及高水平的肿瘤缺氧。我们已经确定了一种连接这些特征的新机制，该机制由KRAS突变启动，并通过自我延续的缺氧循环、HIF-1a增加、刺猬信号、结缔组织形成和更多的缺氧来维持和放大。我们的初步研究表明，胰腺癌细胞与肿瘤间质在这一过程中存在一个关键的相互作用，癌细胞缺氧导致HIF-1a的增加和hedgehog配体的产生，然后基质成纤维细胞响应纤维组织成分的hedgehog配体形成，从而进一步增加癌细胞的缺氧应激。为了支持这一机制，我们发现肿瘤HIF-1a和间质sonic hedgehog配体的升高是胰腺癌患者生存率降低的标志。在这些研究中，我们将探讨胰腺癌细胞与其间质之间相互作用导致结缔组织形成、肿瘤生长和转移的机制。具体来说，我们将研究缺氧在抑制胰腺癌细胞自分泌hedgehog信号、促进基质hedgehog信号和间接刺激癌细胞生长中的作用。我们还将研究间质对缺氧的反应在限制目前用于局部晚期胰腺癌治疗的放疗效果中的作用。根据获得的信息，我们将确定更有效治疗胰腺癌的新靶点和方法。我们还将利用我们已经确定的调节胰腺癌细胞对缺氧的HIF-1a反应的新途径，开发新的小分子抑制剂，可以打破肿瘤细胞缺氧/间质粘连形成周期，从而找到新的更有效的治疗胰腺癌的方法。这些研究的创新之处在于提供了一种新的机制来解释胰腺癌中高水平的缺氧和结缔组织增生导致患者生存率降低。它提供了一个新的范式，挑战了所有胰腺癌都是KRAS癌基因成瘾疾病的观点。相反，我们认为，虽然由KRAS突变引发，但对于一些胰腺癌的进展是通过缺氧、hedgehog信号和结缔组织形成的循环自我维持的。最后，我们已经确定并验证了小分子药物开发的新靶点，这将使我们能够打破胰腺癌中缺氧和结缔组织增生的循环。

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is a devastating disease whose treatment represents a major area of unmet medical need today. Three well recognized characteristics of pancreatic cancer are KRAS mutation early in the disease, extensive fibroinflammation (desmoplasia) leading to decreased blood flow and poor drug delivery, and high levels of tumor hypoxia. We have identified a novel mechanism linking these characteristics that is initiated by KRAS mutation, and maintained and amplified through a self perpetuating cycle of hypoxia, increased HIF-1a, hedgehog signaling, desmoplasia and more hypoxia. Our preliminary studies show a critical interaction between pancreatic cancer cells and the tumor stroma in this process whereby hypoxia of the cancer cells leads to increased HIF-1a and the production of hedgehog ligand, and then formation by stroma fibroblasts in response to hedgehog ligand of fibrous tissue components, thus further increasing the hypoxic stress on the cancer cell. In support of this mechanism we show that elevated tumor HIF-1a and stroma sonic hedgehog ligand are markers of decreased patient survival in pancreatic cancer. In or studies we will investigate the mechanism(s) of the interaction between the pancreatic cancer cell and its stroma leading to desmoplasia, tumor growth and metastasis. Specifically will investigating the role of hypoxia in inhibiting pancreatic cancer cell autocrine hedgehog signaling, and in promoting stroma hedgehog signaling and indirect stimulation of cancer cell growth. We will also investigate the role of the stroma response to hypoxia in limiting the effectiveness of radiation as is currently used for therapy of locally advanced pancreatic cancer. With the information derived we will identify new targets and approaches for more effectively treating pancreatic cancer. We will also exploit a new pathway we have identified that regulates the HIF-1a response of the pancreatic cancer cell to hypoxia to develop novel small molecule inhibitors that can break the tumor cell hypoxia/stroma desmoplasia cycle leading to new and more effective ways of treating pancreatic cancer. The studies are innovative in providing a novel mechanism that explains the high levels of hypoxia and desmoplasia seen in pancreatic cancer leading to decreased patient survival. It provides a new paradigm challenging the view that all pancreatic cancer is a disease of KRAS oncogene addiction. Rather, we propose that while initiated by a mutation of KRAS, for some pancreatic cancers progression is thereafter self sustaining through the cycle of hypoxia, hedgehog signaling and desmoplasia. Finally, we have identified and validated a novel target for small molecule drug development that will allow us to break the cycle of hypoxia and desmoplasia in pancreatic cancer.