I-Corps: Model-driven precision oncology for cancer therapy design

I-Corps项目更广泛的影响/商业潜力是创建临床决策支持软件，使肿瘤学家能够应用精准医学来提高癌症存活率，同时最大限度地降低化疗引起的周围神经病变的风险。化疗引起的周围神经病变是一种常见的癌症治疗副作用，它引起持续的感觉损伤并伴有疼痛，通常导致剂量限制甚至停止治疗。随着癌症存活率的提高，化疗引起的周围神经病变的患病率和经济影响预计会增加。迫切需要制定有效的预防战略。使用I-Corps项目开发的临床决策支持软件，肿瘤学家可以通过避免神经病变相关的有害剂量减少或停止治疗来提高5年的癌症存活率。肿瘤学家还可以通过降低化疗引起的周围神经病变的风险来改善患者的生活质量（例如，在增加活动水平的同时减少疼痛和残疾）。通过减轻化疗引起的周围神经病变，医疗费用也有望降低。I-Corps项目可以通过应用基于模型的精确肿瘤学来改善临床决策。癌症是与细胞周期控制丧失相关的疾病的总称，细胞周期控制是通过维持细胞增殖和细胞死亡之间的适当平衡来严格调节细胞数量的机制。这种细胞周期控制的丧失通常表现为细胞信号网络的故障。对于绝大多数癌症，迫切需要精确识别各种信号网络中的失效点，以提高靶向治疗的成功率。I-Corps项目利用基因调控网络模型确定关键药物靶点，以杀死几种侵袭性癌症系（如胰腺癌、乳腺癌、肺癌、骨肉瘤和转移性黑色素瘤）中的癌细胞。新的网络模型将被创建，包括癌症信号网络以及化学疗法诱导的周围神经病变的发展网络。在I-Corps项目中开发的基于模型的精确肿瘤学方法可以为癌症和神经病变设计治疗计划。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the creation of clinical decision support software that will enable oncologists to apply precision medicine to improve cancer survivor rates while minimizing the risk of chemotherapy-induced peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a common cancer treatment side effect that causes persistent sensory impairments accompanied by pain that often results in dose limitation or even treatment discontinuation. As cancer survivor rates improve, the prevalence and economic impact of chemotherapy-induced peripheral neuropathy is expected to increase. There is a critical need for effective preventative strategies to be developed. Using the clinical decision support software developed with this I-Corps project, oncologists may increase cancer survival rates at the 5-year mark by avoiding neuropathy-related detrimental dose reduction or treatment discontinuation. Oncologists may also improve their patient's quality of life (e.g., decrease pain and disability while increasing activity level) by reducing the risk of chemotherapy-induced peripheral neuropathy. By alleviating chemotherapy-induced peripheral neuropathy, medical costs are expected to be reduced as well.This I-Corps project may improve clinical decision making by applying model-based precision oncology. Cancer is an umbrella term for diseases that are associated with the loss of cell-cycle control, the mechanism that tightly regulates cell numbers by maintaining the right balance between cell proliferation and cell death. This loss of cell-cycle control usually manifests itself as a malfunction in the cellular signaling networks. For the vast majority of cancers, there is a critical need for the precise identification of the failure points in the various signaling networks, with the goal of targeting therapy with a better likelihood of success. This I-Corps project utilizes gene regulatory network models to identify key drug targets to kill cancer cells in several aggressive cancer lines (e.g., pancreatic, breast, lung, osteosarcoma and metastatic melanoma). New network models will be created that incorporate both cancer signaling networks as well as networks for the development of chemotherapy-induced peripheral neuropathy. Designing treatment plans to address both cancer and neuropathy benefits from the model-based precision oncology approach developed in this I-Corps project.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.