MICA: Radiobiology for effective alpha particle and Auger electron molecular radionuclide therapy in neuroendocrine cancer

每两分钟，英国就有一人被诊断出患有癌症。这里的重点是神经内分泌癌，它开始于释放神经内分泌细胞，可以发生在身体的任何地方，包括肺，阑尾，小肠，直肠和胰腺。虽然罕见，但它们很难治疗;因此需要新的选择来治疗原始肿瘤和已经扩散到全身的癌细胞。这将通过我们创造新的可注射的放射性药物来解决，这些药物专门针对身体任何地方的癌细胞。这里研究的放射性化合物使用镓-67和铊-201连接到DOTATATE上，DOTATATE将放射性传递到神经内分泌癌细胞。镓-67和铊-201都释放短距离高能俄歇电子。这些仅照射它们所附着的细胞，并且容易获得。该项目还将使用铅-212，因为它也会在短距离内发射高能量辐射（α粒子）。这是杀死单个癌细胞所必需的。但铅-212也同时释放β粒子，这在治疗肿瘤球时是有用的。与其他α粒子发射体不同，铅-212可以在临床上以可行的、可持续的治疗所需的数量获得。我们正在与一家生产放射性铅标记肽（203 Pb-和212 Pb-VMT-alpha-NET）的公司合作，用于神经内分泌肿瘤的成像和治疗。然后，我们将在实验室中以层和球体生长的神经内分泌癌细胞中进行研究，以更好地模拟肿瘤，以及神经内分泌癌的动物模型。这些研究将使我们能够了解辐射剂量与肿瘤细胞和健康肾细胞损伤之间的关系。这一成果与计算机模拟一起，将为未来的临床试验提供信息，说明在不损害肾脏等健康组织的情况下，放射性化合物有效杀死肿瘤所需的和规定的注射量。最后，将进行研究，以确定放射性化合物在杀死经过化疗预处理的癌细胞方面的有效性。希望我们能证明，将化学疗法与放射性化合物结合起来，可以提高整体的肿瘤杀伤能力，并找出实现这一点的方法。通过这项工作，我们不仅可以提高对高能短距离放射性形式的放射生物学理解，例如67 Ga-和201 Tl-DOTATATE和212 Pb-VMT-α-NET，但是通常在癌症模型中是俄歇电子和α粒子发射体。我们的研究还将指导进一步研究具有治疗潜力的其他形式的放射性。

Every two minutes, someone in the UK is diagnosed with cancer. The focus here is on neuroendocrine cancer, which begins in hormone-releasing neuroendocrine cells and can occur anywhere in the body including the lungs, appendix, small intestine, rectum and pancreas. Although rare, they are very hard to treat; there is therefore a need for novel options to treat both the original tumour and cancer cells that have spread throughout the body. This will be addressed by us creating new injectable, radioactive drugs that specifically home to cancer cells anywhere in the body. The radioactive compounds investigated here use gallium-67 and thallium-201 attached to DOTATATE, which delivers the radioactivity to neuroendocrine cancer cells. Gallium-67 and thallium-201 both release short-distance, high energy Auger electrons. These only irradiate cells to which they are attached and are available with ease. The project will also use lead-212, as it too emits radiation at a high energy across a short distance (alpha particles). This is needed to kill singular cancer cells. But lead-212 also simultaneously releases beta particles that are useful when treating tumour spheres. Unlike other alpha particle-emitters, lead-212 can crucially be obtained at quantities needed for a feasible, sustainable therapy in the clinic. We are working with a company that has produced radioactive lead-labeled peptides (203Pb- and 212Pb-VMT-alpha-NET) for imaging and therapy of neuroendocrine tumours. We will then carry out studies in neuroendocrine cancer cells grown in the lab in layers and as spheres, to better mimic a tumour, as well as in animal models of neuroendocrine cancer. These studies will allow us to understand the relationship between radiation dose delivered and damage to tumour cells as well as healthy kidney cells. This, alongside computer modelling, will inform future clinical trials in terms of required and prescribed injected amounts of radioactive compounds for effective tumour killing at levels that do not damage healthy tissues such as the kidneys.Finally, studies will be carried out to ascertain how effective the radioactive compounds are in killing cancer cells that have been pretreated with chemotherapies. Hopefully, we will show that combining chemotherapies with the radioactive compounds increases the overall tumour killing ability and work out how this is achieved.Through this work, we will have advanced the radiobiological understanding not only of forms of radioactivity that are high in energy and short in distance, such as 67Ga- and 201Tl-DOTATATE and 212Pb-VMT-alpha-NET but of Auger electron and alpha particle-emitters in cancer models in general. Our research will also guide further work with other forms of radioactivity that have therapeutic potential.