Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12

随着下一代测序技术在过去几年中的广泛整合， 全面的基因组研究表明，前列腺癌可以分为不同的分子 亚型鉴定这些亚型和发病机制的分子驱动因素是一个机会， 设计合理的精确肿瘤治疗方法。为此，我们最近确定并 特征在于以CDK 12的双等位基因失活为代表的前列腺癌的新分子亚型，并显示 它在转移性去势抵抗性前列腺癌（mCRPC）的病例中富集。CDK 12突变型前列腺 癌症表现出与其他前列腺癌亚型不同的基因组不稳定性模式，包括同源的 重组和错配修复缺陷，与局灶性串联重复（FTD）相关 表型。重要的是，CDK 12-FTDs导致基因融合增加导致新抗原负荷升高， 这反映在肿瘤微环境中的主动免疫应答和增加的T细胞运输。 因此，我们队列中mCRPC患者的初步结果表明， 对免疫检查点阻断的反应可能性。因此，我们假设CDK 12的失活 导致mCRPC的免疫原性类别，其可能受益于免疫导向疗法。这一假设 将通过以下具体目标进行探索： 目的1：确定CDK 12丢失与前列腺癌生物学的功能相关性，并鉴定合成致死性CDK 12。 目标的该目标的实验将集中在体外方法，生物信息学分析和CRISPR筛选上 研究CDK 12丢失如何影响前列腺癌的发病机制，并推动前列腺癌的出现。 免疫基因组表型 目的2：确定Cdk 12消融对体内前列腺肿瘤生长和免疫应答的影响。我们将 建立几种Cdk 12-null小鼠前列腺模型，以直接评估Cdk 12在前列腺中的作用。 肿瘤发生和对免疫检查点阻断的应答。 目的3：在免疫检查点阻断的第一次临床试验中确定应答的分子决定因素， CDK 12突变型mCPRC患者。使用来自我们的纳武单抗和伊匹单抗II期试验（IMPACT）的样本 在CDK 12突变型患者中，我们将分析免疫应答的变化，并确定肿瘤内源性 反应的生物标志物。 总之，这些目标的完成将确定CDK 12在前列腺肿瘤发生中的作用，并评估精确度。 最近发现的前列腺癌亚型的肿瘤学方法。

With the wide-spread integration of next-generation sequencing technology over the past several years, comprehensive genomic studies have shown that prostate cancers can be classified into different molecular subtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity to design rational precision oncology approaches for treatment. To this end, we have recently identified and characterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shown that it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostate cancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes, including homologous recombination and mismatch repair-deficient, that is associated with a focal tandem duplication (FTD) phenotype. Importantly, CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions, and this is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment. Accordingly, preliminary results from mCRPC patients in our cohort suggest that they may have a higher likelihood of response to immune checkpoint blockade. We, therefore, hypothesize that inactivation of CDK12 results in an immunogenic class of mCRPC that may benefit from immune-directed therapies. This hypothesis will be explored through the following Specific Aims: Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethal targets. Experiments in this Aim will focus on in vitro methods, bioinformatics analyses, and a CRISPR screen to examine how CDK12 loss impacts prostate cancer pathogenesis and drives the emergence of an immunogenomic phenotype. Aim 2: Determine the impact of Cdk12 ablation on prostate tumor growth and immune response in vivo. We will generate several Cdk12-null mouse prostate models to directly evaluate the role of Cdk12 in prostate tumorigenesis and response to immune checkpoint blockade. Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade for CDK12-mutant mCPRC patients. Using samples from our Phase II trial (IMPACT) of nivolumab and ipilimumab in CDK12-mutant patients, we will analyze changes in the immune response and determine tumor-intrinsic biomarkers of response. Together, completion of these Aims will define the role of CDK12 in prostate tumorigenesis and assess precision oncology approaches for this recently identified subtype of prostate cancer.