Discovery of a Novel, Integrated Combination Peptide Therapeutic Targeting Angiog

描述（由申请人提供）：鉴于疾病涉及的分子网络的复杂性，中断单个过程通常会产生不充分的治疗反应。虽然这一事实得到广泛承认，但如何克服这一问题尚不清楚。联合小分子靶向多通路的前景（联合治疗）对患者来说很复杂（和医生）受到不期望的副作用特征和复杂的给药方案的影响，并且对于行业来说受到昂贵的治疗发现、开发和批准途径的影响。多靶点治疗的益处在癌症中变得特别明显，随着多受体酪氨酸激酶抑制剂如索坦（PDGFR和VEGFR）和nexavar（BRAF和VEGFR）的最近批准以及临床开发中的泛激酶抑制剂的过多（齐默尔曼，2007）。这种趋势并不令人惊讶，因为癌细胞具有利用替代信号传导途径获得生长优势和细胞存活的能力，这一过程甚至可以通过使用选择性靶向药物来促进。然而，单一化合物、多靶向方法充满了挑战;许多靶点需要独特的化学物质才能有效靶向，一种药物对每个靶点的最佳效力难以实现，并且非选择性是常见的。由于上述所有原因，用高度特异性抑制剂靶向多个途径的新策略代表了一种有吸引力的治疗替代方案，并为正在进行的发现工作提供了强有力的理由。在CytomX，我们打算展示一种用于发现和组装位点特异性多靶点肽治疗剂的新方法，而不是所谓的脏的小分子方法。如果成功，这种第一代整合肽治疗剂将适用于许多靶点和临床问题。在我们的实验室中，存在着发现高亲和力、高特异性肽和蛋白酶的动力学最佳肽底物的独特专业知识。这些能力中的每一种都成功地靶向了潜在的高价值治疗靶点。在这项研究中，我们将结合联合收割机这些技术，都基于细菌展示文库的迭代筛选，开发和测试第一个针对癌症的定点多靶向肽治疗剂。生物学研究的一个共同目标是发现更好、更安全的药物。目前正在采取许多方法来解决这一问题，从专门的药物递送纳米系统到多靶向小分子，再到直接靶向人类基因组。 公共卫生相关性：我们计划运用我们在肽发现方面的专门知识来解决这个世界性的问题，并开发一种药物，这种药物在疾病部位比在正常组织中更有活性，并且针对疾病过程中的一个以上参与者。我们的目标是使这种方法足够普遍，可用于许多不同的疾病状态，但我们的研究重点是目前在血管生成领域。

DESCRIPTION (provided by applicant): Given the complexity of molecular networks involved in disease, the interruption of a single process often yields an insufficient therapeutic response. Although this fact is widely recognized, it is not clear how to overcome the problem. The prospect of targeting multiple pathways with a combination of small molecules (co-therapy) is complicated for the patient (and physician) by undesired side effect profiles and complicated dosing regimens and for the industry by a costly therapeutic discovery, development and approval path. The benefits of multi-target therapeutics are becoming particularly evident in cancer, with the recent approval of multi-receptor tyrosine kinase inhibitors such as sutent (PDGFR and VEGFR) and nexavar (BRAF and VEGFR) and with the plethora of pan-kinase inhibitors in clinical development (Zimmerman, 2007). This trend is not surprising, given that cancer cells possess the ability to utilize alternative signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Yet, the single compound, multi-targeting approach is laden with challenges; many targets require unique chemical matter for effective targeting, optimal potency at each target is elusive with one agent and nonselectivity is common. For all of the reasons stated above, novel strategies that target multiple pathways with highly specific inhibitors represent an attractive therapeutic alternative and provide a strong rationale for ongoing discovery efforts. At CytomX, instead of the so-called }dirty}, small molecule approach, we intend to demonstrate a new method for the discovery and assembly of site-specific multi-target peptide therapeutics. If successful, this first-generation integrated peptide therapeutic will be applicable to many targets and clinical problems. Within our laboratory resides unique expertise for the discovery of high affinity, high specificity peptides and kinetically-optimal peptide substrates for proteases. Each of these capabilities alone has been successful in the targeting of potential high value therapeutic targets. In this research, we will combine these technologies, both based on the iterative screening of bacterial display libraries, to develop and test the first site-directed, multi-targeted peptide therapeutic for cancer. A common goal in biological research is the discovery of better and safer medicines. Many approaches are being taken to solve this problem, ranging from specialized drug delivery nano-systems, to multi-targeted small molecules to direct targeting of the human genome. PUBLIC HEALTH RELEVANCE: we plan to apply our expertise in peptide discovery to address this world-wide issue and to develop a type of drug which is more active at the site of disease than it is in normal tissues and which targets more than one player in the disease process. Our goal is to make this approach general enough to be used for many different disease states but our research emphasis is currently in the field of angiogenesis.