Auger Electron Radiotherapy of Late-Stage, Castration-Resistant Prostate Cancer using a Brominated Dihydrotestosterone Analogue

 描述（由申请人提供）：前列腺癌的生长和进展在很大程度上是由血液中天然存在的激素（例如，睾酮）驱动的。为了降低血液中的激素水平，手术和化学去势方法已经成为前列腺癌的标准治疗方法超过70年。尽管去势最初非常有效，显著减小了肿瘤大小，但去势抵抗性前列腺癌不可避免地发展。在这个阶段，尽管激素水平降低，肿瘤仍继续生长和扩散。通常，前列腺癌变得去势抵抗的机制是过度产生激素结合的受体靶点，从而继续产生生长信号。一旦前列腺癌变得去势抵抗，第二层治疗是试图通过抑制这些受体来延迟生长。这种方法可能延长生存期，但不能治愈。在这项提案中，我们计划开发一种新型的去势抵抗性前列腺癌治疗方法，将这种抵抗机制转化为治疗优势。前列腺癌细胞越多地产生其激素受体，它就应该对我们提出的疗法的杀伤作用越敏感。确切地说， 这是通过产生一种能发射一种非常特殊的辐射的分子来实现的。这种分子类似于肿瘤使用的激素之一，因为它与过度产生的受体结合，然后移动到细胞核，在那里与DNA结合。我们掺入分子中的放射性元素的特殊之处在于，与其他形式的辐射不同，这种辐射具有极其有限的杀伤力。它有点像一把猎枪，当它靠近像DNA这样的关键分子时非常致命，但当它在细胞或血液中的其他地方时几乎无害。这种类型的辐射通常被注射到患者体内而不会产生有害影响，因为这些分子不会与DNA结合。该提案的主要目标是开发这种治疗分子，以选择性地和致命地仅结合前列腺癌细胞内的DNA。作为该提案的次要目标，我们计划生产一种与治疗分子作用相同的分子，但使用可用于制作肿瘤三维图像的非治疗同位素。这些图像可用于选择最有可能通过该疗法成功治疗的患者。

 DESCRIPTION (provided by applicant): Prostate cancer's growth and progression is largely driven by hormones (for example, testosterone) that are naturally present in the blood. Aiming to reduce the hormone levels in the blood, surgical and chemical castration methods have been a standard of care for prostate cancer for over 70 years. Although castration is initially very effective, dramatically reducing tumor size, castration resistant prostate cancer inevitably develops. At this stage, the tumor continues to grow and spread despite reduced hormone levels. Often the mechanism by which prostate cancer becomes castration resistant is to over produce the receptor targets to which the hormones bind, thereby continuing to generate a growth signal. Once prostate cancer becomes castration resistant, the second tier of treatment is to try to delay growth by inhibiting these receptors. Such an approach potentially affords lengthened survival, but is not curative. In this proposal, we plan to develop a new type of therapy for castration resistant prostate cancer that turns this mechanism of resistance into a therapeutic advantage. The more a prostate cancer cell over produces its hormone receptors, the more sensitive it should be to the killing effects of our proposed therapy. Specifically, we do this by producing a molecule that emits a very special type of radiation. This molecule is similar to one of the hormones used by the tumor in that it binds to the over produced receptor and then travels to the cell nucleus where it binds to the DNA. The radioactive element that we incorporate into the molecule is special in that, unlike other forms of radiation, this radiation hs an extremely limited range of lethality. It is somewhat like a shot-gun, very lethal when it is cloe to critical molecules like DNA, but virtually harmless when it is elsewhere in the cell or in the blood. Radiation of this type is routinely injected into patients without harmful effect because these molecules do not bind to DNA. The main objective of this proposal is to develop this therapeutic molecule to bind selectively and lethally only to the DNA within prostate cancer cells. As a secondary objective in this proposal, we plan to produce a molecule that acts identically to the therapeutic molecule but uses a non-therapeutic isotope that can be used to make three-dimensional images of the tumor. These images can be used to select the patients that are most likely to be successfully treated by this therapy.