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

在英国，每两分钟就有一人被诊断出患有癌症。这里的重点是神经内分泌癌，它始于释放激素的神经内分泌细胞，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。我们将创造新的可注射的放射性药物来解决这个问题，这些药物专门针对身体任何部位的癌细胞。这里研究的放射性化合物使用附着在DOTATATE上的镓-67和铊-201，它将放射性传递给神经内分泌癌细胞。镓-67和铊-201都能释放短距离高能俄歇电子。这些只照射它们附着的细胞，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出高能量的辐射（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，这种粒子在治疗肿瘤球时很有用。与其他α粒子发射器不同，铅-212可以在临床上获得可行的、可持续的治疗所需的数量。我们正在与一家生产放射性铅标记肽（203Pb-和212Pb-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状和球形的形式培养神经内分泌癌细胞，以更好地模拟肿瘤，以及在神经内分泌癌的动物模型中进行研究。这些研究将使我们了解辐射剂量与对肿瘤细胞和健康肾细胞的损害之间的关系。这与计算机建模一起，将为未来的临床试验提供信息，以确定所需和规定的注射放射性化合物的量，从而在不损害肾脏等健康组织的情况下有效杀死肿瘤。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效果如何。希望我们能证明化疗与放射性化合物的结合提高了肿瘤的整体杀伤能力，并找出实现这一目标的方法。通过这项工作，我们不仅将提高对高能短距离放射性形式的认识，如67Ga-和201Tl-DOTATATE和212Pb-VMT-alpha-NET，而且还将提高对癌症模型中俄杰电子和α粒子发射器的认识。我们的研究也将指导其他具有治疗潜力的放射性形式的进一步工作。

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.