Pathway Specific Imaging in VHL Deficient Renal Cancer

描述(申请人提供)：在美国，每年新增54,000例肾细胞癌(RCC)病例，每年约有13,000名患者死于这种疾病。最近，抗血管生成治疗取得了一定的进展，而化疗对这种类型的肿瘤没有影响。因此，很明显，迫切需要新的替代方案。在这里，我们建议研究一种新的肾癌治疗方法，该方法也可能产生一种快速评估治疗反应的技术，从而帮助选择合适的疗程。发酵糖酵解在许多实体肿瘤中是常见的，但在由Von-Hippel Lindau(VHL)缺陷肿瘤突变引起的一组肾癌中起关键作用，VHL缺陷肿瘤发生在大多数肾癌中(因为它导致缺氧诱导因子(HIF)稳定)。我们建议研究寻求逆转华宝效应的肾癌治疗方法。这可以通过激活丙酮酸脱氢酶(PDH)中线粒体的重新激活来实现，PDH有助于丙酮酸进入三羧酸循环(TCA)。PDH酶可以被小分子抑制剂二氯乙酸酯(DCA)激活，二氯乙酸酯(DCA)可以阻断丙酮酸脱氢酶激酶(PDK)，后者反过来负面调节PDH。因此，影响丙酮酸代谢命运的分子途径可能会反过来影响肿瘤的存活率。这一提议的关键特征是将丙酮酸的命运重新定向到Krebs循环中，从而使肿瘤细胞优先受到伤害。然而，到目前为止，还没有体内方法学来确定DCA或其他重定向丙酮酸命运的方法实际上是否在体内实现了他们的目标。超极化磁共振成像是一种新兴的技术，可以提供这样的生物相关性。在这里，我们建议使用超极化丙酮酸作为一种工具来评估肾癌肿瘤对旨在逆转Warburg效应的治疗的反应。我们的主要工作假设是，在肾细胞癌的原位小鼠模型中，DCA的管理将导致乳酸的形成减少，并且这种“药效学”测量将与该模型中肿瘤负担的减少相关。使用不同剂量和时间表的DCA给药，我们将收集使用超极化碳-13标记丙酮酸的非侵入性成像数据。因此，我们的具体目标如下：目标1：将非侵入性成像数据与不同剂量的DCA相关联(“初步研究”)。目的：探讨慢性DCA治疗后丙酮酸代谢的影像指标与肿瘤负荷、肿瘤细胞增殖和凋亡指数以及PDH磷酸化状态的相关性(纵向研究)。这些研究的重要性在于，它们将使影响丙酮酸命运的药物有效地转化到临床上，这可能为癌症治疗提供一种全新的方法。 公共卫生相关性：发酵糖酵解(丙酮酸转化为乳酸)在许多实体肿瘤中很常见，但在Von-Hippel Lindau(VHL)突变引起的肾癌中起着关键作用。研究表明，在VHL缺乏的透明细胞肾癌中，缺氧诱导因子(HIF-1)介导葡萄糖摄取增加，乳酸产生增加，呼吸减少。在这个提案中，我们聚集了一个由放射科医生、物理学家、病理学家和癌症科学家组成的团队，使用一种被称为超极化核磁共振的最先进技术来帮助实现这一目标。特别是，我们提供的临床前数据表明，这种方法确实是可行的，我们已经有了一个经过验证的临床前肾癌动物模型。我们建议测试二氯乙酸酯(DCA)的体内给药是否导致该动物模型中丙酮酸形成乳酸的减少，以及这种通量测量是否与肿瘤负担的减少相关。这些研究的重要性在于，它将使影响丙酮酸盐命运的药物有效地转化到临床上，丙酮酸盐是一种全新的癌症治疗方法。

DESCRIPTION (provided by applicant): 54,000 new cases of renal cell cancer (RCC) are diagnosed each year in the US and approximately 13,000 patients succumb to the disease annually. Recently, anti-angiogenic therapy has produced modest gains, whereas chemotherapy has had no impact in this tumor type. It is therefore clear that novel alternatives are sorely needed. Here we propose to study a novel therapeutic approach to renal cancer that may also yield a technique to rapidly assess treatment response and hence aid in the selection of an appropriate course of treatment. Fermentative glycolysis is common to many solid tumors but has a key role in a subset of renal cancers resulting from mutations in Von-Hippel Lindau (VHL) deficient tumors which occurs in the majority of RCC (as it leads to hypoxia inducible factor (HIF) stabilization). We propose to study renal cancer therapies that seek to reverse the Warburg effect. This can be accomplished through reactivation of the mitochondria in activating PDH (pyruvate dehydrogenase), which facilitates pyruvate entry into tricarboxylic acid cycle (TCA). The enzyme PDH can be activated by a small molecule inhibitor, dichloroacetate (DCA) that blocks pyruvate dehydrogenase kinase (PDK), which in turn negatively regulates PDH. Hence molecular pathways influencing pyruvate's metabolic fate may, in turn, impact tumor survival. The key feature of this proposal is to redirect the fate of pyruvate into the Krebs cycle, so that tumor cells will be preferentially harmed. To date, however, there has been no in vivo methodology to determine whether DCA or other methods of redirecting the fate of pyruvate are in fact accomplishing their goal in vivo. Hyperpolarized magnetic resonance imaging is an emerging technology that may provide such a biocorrelate. Here we propose to use hyperpolarized pyruvate as a tool for assessing the response RCC tumors to therapies that aim to reverse the Warburg effect. Our major working hypothesis is that administration of DCA will result in decreased lactate formation in an orthotopic mouse model of renal cell carcinoma, and that this "pharmacodynamic" measurement will correlate with decreased tumor burden in this model. Using a variety of doses and schedules for DCA administration, we will collect non-invasive imaging data using hyperpolarized carbon-13 labeled pyruvate. Hence our specific aims are as follows; Aim 1: To correlate non-invasive imaging data with various DCA doses ("the pilot study"). Aim 2: To correlate these imaging measurements of pyruvate metabolism after chronic DCA treatment with tumor burden, tumor proliferation and apoptotic indices, and PDH phosphorylation status in this model ("the longitudinal study"). The importance of these studies is that they will allow for efficient translation into the clinic of drugs that affect the fate of pyruvate, which may provide a whole new approach to cancer therapeutics. PUBLIC HEALTH RELEVANCE: Fermentative glycolysis (conversion of pyruvate to lactate) is common to many solid tumors but has a key role in renal cancers resulting from mutations in Von-Hippel Lindau (VHL). Studies have demonstrated that in VHL-deficient clear cell renal carcinoma, hypoxia inducible factor (HIF-1) mediates increased glucose uptake, increased lactate production, and decreased respiration. In this proposal we bring together a team of radiologists, physicists, pathologists, and cancer scientists to help accomplish this goal using a state of the art technology known as hyperpolarizing MRI. In particular, we present pre-clinical data showing that this approach is indeed feasible and that we have a validated preclinical renal cancer animal model available to us. We propose to test whether the in vivo administration of dichloroacetate (DCA) results in decreased formation of lactate from pyruvate in this animal model and whether this flux measurement correlates with decreased tumor burden. The importance of these studies is that it will allow for efficient translation into the clinic of drugs that affect the fate of pyruvate, a whole new approach to cancer therapeutics.