Phage Display Peptide Probes for Imaging Early Response to Cancer Therapy

描述（由申请人提供）：本SBIR提案的最终目标是开发新的分子成像标记物，用于监测肿瘤对抗血管生成治疗方案的早期反应和疗效。抗血管生成疗法在癌症治疗方面取得了令人兴奋的进展。靶向血管系统已被证明对几种类型的恶性肿瘤患者有益。数百种具有抗血管生成活性的分子已在临床前模型中被报道，其中许多已进入肿瘤临床试验。据预测，阿瓦斯汀将成为2014年销量最高的药物，预计销售额为89亿美元。虽然许多患者受益于抗血管生成治疗，但通常是通过实现疾病的稳定性，由于对治疗缺乏反应，只有一半的患者受益于阿瓦斯汀治疗。此外，在产品开发过程中，还没有基于阿瓦斯汀反应特异性生物标志物的技术来监测抗血管生成疗法。因此，开发疾病反应和复发的无创生物标志物是帮助患者管理的关键目标。快速评估癌症对治疗方案的反应可以在治疗过程的早期确定疗效。早期评估癌症对治疗方案的反应可以帮助调整有效的治疗方案，终止无效的治疗，最大限度地减少不必要的毒性和费用。最近，我们应用噬菌体展示策略并鉴定出可以选择性结合抗血管生成治疗反应的肿瘤的肽。我们从噬菌体展示文库中鉴定出一种12聚肽，它可以特异性地结合抗血管生成药物阿瓦斯丁反应性肿瘤，而不是非反应性或未经治疗的肿瘤。这种肽被称为阿瓦斯汀反应肽（AVRP）。在这项I期SBIR提案中，我们将扩展这些努力，进一步探索和开发临床相关的AVRP特异性探针，用于PET成像监测肿瘤早期反应和抗肿瘤血管生成治疗的疗效。我们将评估AVRP肽在各种肿瘤类型和治疗方案中定量测量肿瘤对阿瓦斯汀治疗反应的能力。我们还将通过鉴定AVRP的靶蛋白来研究AVRP的作用机制。此外，我们将测试一些其他疗法，以确定是否适当标记的AVRP肽可以作为一个普遍的探针来成像癌症治疗效果。我们将在完成SBIR项目后将该产品商业化。本提案的创新之处在于探索一种新的策略，开发有效的靶向成像探针，用于监测肿瘤对抗血管生成治疗的早期反应和疗效。这项提案的成功将为加速和降低药物开发成本、对患者群体进行分层、评估治疗效果以及最大限度地缩短癌症患者无效方案的治疗时间提供令人兴奋的前景。

DESCRIPTION (provided by applicant): The ultimate goal of this SBIR proposal is to develop novel molecular imaging markers for monitoring tumor early response and efficacy to anti-angiogenic treatment regimens. Anti-angiogenic therapy represents an exciting advance in the management of cancer. Targeting of the vasculature has been shown to benefit patients with several types of malignancies. Hundreds of molecules with anti-angiogenic activity in preclinical models have been reported, and many of them have entered clinical testing in oncology. It is predicted that Avastin will be the top one drug in 2014 with a projected $8.9 billion in sales. Although many patients benefit from anti-angiogenic therapies, it is often by achieving stability of their disease and only half of patients are benefit from Avastin therapy due to lack of response to the treatment. Furthermore, there is no Avastin-response specific biomarker-based technologies to monitor anti-angiogenic therapies in the product development pipeline. Thus, development of noninvasive biomarkers of disease response and relapse is a crucial objective to aid in the management of patients. Rapid assessment of cancer response to a therapeutic regimen can determine efficacy early in the course of treatment. Early evaluation of cancer response to a therapeutic regimen can help adjust the efficacious treatment scheme, terminate ineffective treatments, minimizing unnecessary toxicity and expenditure. Recently, we applied phage display strategy and identified peptides that can selectively bind to tumors that respond to anti-angiogenic therapies. We identified a 12-mer peptide from phage display library that binds specifically to anti-angiogenic drug Avastin responsive tumors but not non-responsive or untreated tumors. This peptide was termed as Avastin- responsive peptide (AVRP). In this Phase I SBIR proposal, we will extend these efforts and further explore and develop clinically relevant AVRP specific probes for PET imaging monitoring tumor early response and efficacy to anti-tumor angiogenesis treatments. We will evaluate the ability of AVRP peptide to quantitatively measure tumor response to Avastin treatment in various tumor types and treatment regimens. We will also study the mechanism of AVRP action by identifying the target protein(s) of AVRP. Furthermore we will test a number of other therapies to determine whether suitably labeled AVRP peptide can be used as a universal probe to image cancer treatment efficacy in general. We will commercialize the product after we accomplish the SBIR project. The innovation in this proposal is to explore a novel strategy for developing efficient targeted imaging probes for monitoring tumor early response and efficacy to anti-angiogenic treatment. The success of this proposal will provide exciting promise to accelerate and reduce the cost of drug development, stratify patient populations, assess the treatment efficacy, and minimize the duration of treatment with ineffective regimens in cancer patients. PUBLIC HEALTH RELEVANCE: We will develop the clinically translatable novel molecular imaging probes for monitoring tumor early response and efficacy to anti-angiogenic treatment regimens. Rapid assessment of cancer response to a therapeutic regimen can determine efficacy early in the course of treatment. We anticipate that the new tracers will provide early evaluation of cancer response to a therapeutic regimen that can help accelerate the drug development, adjust the efficacious treatment scheme, reduce the healthcare cost, eventually leading to personalized cancer therapy, treatment monitoring, and dose optimization.