Exploiting tumor stroma interactions for cancer therapy

描述（由申请人提供）：胰腺癌是一种毁灭性疾病，其治疗代表了当今未满足的医疗需求的主要领域。胰腺癌的三个公认的特征是疾病早期的KRAS突变，导致血流量减少和药物递送不良的广泛纤维炎症（结缔组织增生），以及高水平的肿瘤缺氧。我们已经确定了一种新的机制，将这些特征联系起来，该机制由KRAS突变启动，并通过缺氧、增加的HIF-1a、hedgehog信号传导、结缔组织增生和更多缺氧的自我延续循环来维持和放大。我们的初步研究表明，在这个过程中，胰腺癌细胞和肿瘤间质之间存在关键的相互作用，癌细胞的缺氧导致HIF-1 a和hedgehog配体的产生增加，然后基质成纤维细胞响应hedgehog配体形成纤维组织成分，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和间质音刺猬配体升高是胰腺癌患者生存率降低的标志物。在或研究中，我们将研究胰腺癌细胞与其基质之间的相互作用导致结缔组织增生、肿瘤生长和转移的机制。特别是将研究缺氧在抑制胰腺癌细胞自分泌hedgehog信号，促进间质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治疗局部晚期胰腺癌的放射有效性方面的作用。通过这些信息，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反应的新途径来开发新的小分子抑制剂，这些抑制剂可以打破肿瘤细胞缺氧/基质结缔组织增生周期，从而导致治疗胰腺癌的新的和更有效的方法。这些研究是创新性的，提供了一种新的机制，解释了胰腺癌中观察到的高水平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例，挑战所有胰腺癌都是KRAS癌基因成瘾的观点。相反，我们提出，虽然由KRAS突变启动，但对于某些胰腺癌，其进展此后通过缺氧、刺猬信号传导和结缔组织增生的循环自我维持。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。 公共卫生相关性：胰腺癌是一种毁灭性的疾病，很少有患者在诊断后存活超过一年。胰腺癌的特征是大量的纤维组织限制了血液流动，导致肿瘤缺氧并抑制癌症药物到达肿瘤的能力。我们现在表明，缺氧导致纤维组织的增加，从而更多的缺氧，通过与患者生存率降低相关的途径。了解这一途径将为癌症药物提供新的靶点，这些药物可以与其他药物或放射联合使用，以更有效地治疗胰腺癌。

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with very few patients surviving more than a year from diagnosis. Characteristics of pancreatic cancer are very large amounts of fibrous tissue which restricts blood flow, causing tumor hypoxia and inhibiting the ability of cancer drugs to reach the tumor. We now show that hypoxia leads to an increase in fibrous tissue and thus more hypoxia, by a pathway that is associated with decreased patient survival. Understanding this pathway will lead to new targets for cancer drugs that can be used in combination with other drugs or radiation to more effectively treat pancreatic cancer.