Targeting Deubiquitinases to Treat Drug-Resistant Colorectal Cancer

结直肠癌（CRC）是世界上发病率和死亡率最高的癌症之一（每年有130万新发病例和约61万例死亡）。因此，迫切需要开发新的治疗方法来治疗这种疾病，特别是在死亡率最高的后期阶段。此外，随着西方人口老龄化，这种疾病将变得更加普遍，给我们本已不堪重负的医疗保健系统带来沉重负担。这种新颖的学术与工业合作旨在改善预后不良的CRC患者的治疗结果。最初，使用CRC患者队列，将鉴定参与驱动目前无法治愈的疾病的称为“DUB”的酶。然后，该计划将使用Almac Discovery开发的最先进的计算方法和试剂来开发针对这些DUB的新药（“抑制剂”）。这些新药将使用先进的实验模型进行测试，这些模型可以准确模拟人类疾病。在借调到Almac Discovery期间，Longley将担任以CRC为重点的DUB药物开发项目的生物学负责人。虽然最终目标将是为目前死于疾病的患者提供新的治疗选择，但该项目也将使生物技术部门和学术界之间的互动（该计划的关键目标之一），因为Longley将在Almac Discovery度过60%的时间。作为一名资深学者，朗利将把多年的癌症生物学经验带到他的借调中。此外，通过保留40%的学术地位，这种交流也将反过来发挥作用，工业最佳实践，知识和试剂回流到QUB。Longley的学术实验室团队和Almac Discovery在昆士兰大学生命科学园区的共同办公将进一步加强这种交流。Longley的借调将有助于指导Almac Discovery DUB抑制剂组合的临床开发。这将大大降低Almac Discovery药物发现项目的流失率（该行业的一个主要问题），提高特定项目对第三方合作伙伴和投资者的吸引力。由于Longley在其他几种癌症（肺癌、前列腺癌、胰腺癌和白血病）的耐药性方面拥有丰富的经验，他还将能够为Almac Discovery在其他疾病领域的资产开发提供建议。因此，这一借调将为Almac Discovery增加重要价值，从而使英国经济的生物医学科学部门受益（该计划的另一个关键目标）。

Colorectal cancer (CRC) has one of the highest Worldwide incidences and mortality rates (annually \>1.3M new cases and ~610,000 deaths). Hence, there is a critical need to develop new therapeutic approaches to treat this disease, particularly in its later stages where the mortality rates are worst. Moreover, as Western populations age, this disease is going to become more prevalent placing a significant burden on our already overstretched healthcare systems.This novel academic-industrial collaboration aims to improve outcomes for patients with poor-prognosis CRC. Initially, using CRC patient cohorts, enzymes called "DUBs" that are involved in driving currently incurable disease will be identified. The plan is then to use state-of-the-art computational approaches and reagents developed by Almac Discovery to develop new drugs ("inhibitors") to target these DUBs. These new drugs will then be tested using advanced experimental models that accurately mimic the human disease.During his secondment to Almac Discovery, Longley will be the biology lead for a CRC-focussed DUB drug development programme. While the ultimate goal will be to provide new treatment options for patients currently dying from their disease, this project will also enable interactions between the Biotech Sector and Academia (one of the key goals of the scheme) as Longley will spend 60% of his time in Almac Discovery. As a senior academic, Longley will bring years of experience in cancer biology to his secondment. Moreover, by retaining a 40% academic position, this interchange will also work in reverse, with industrial best practice, knowledge and reagents flowing back into QUB. This exchange will be further enhanced by the co-location of Longley's academic lab group and Almac Discovery on the Life Sciences campus at QUB.Longley's secondment will help guide the clinical development of Almac Discovery's portfolio of DUB inhibitors. This will significantly reduce the attrition rates (a major problem in the sector) in Almac Discovery's drug discovery programmes, enhancing the attractiveness of specific programmes to 3rd party partners and investors. Since Longley has experience in drug resistance in several other cancers (lung cancer, prostate cancer, pancreatic cancer and leukaemia), he will also be able to advise Almac Discovery on the development of assets in other disease areas. Thus, this secondment will add significant value to Almac Discovery and thereby benefit the Biomedical Sciences sector of the UK economy (another key goal of the scheme).