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

使用溴化二氢睾酮类似物对晚期去势抵抗性前列腺癌进行俄歇电子放射治疗

• 批准号: 9023992
• 负责人: BRADLEY J BEATTIE
• 金额: $ 19.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023992
• 关键词: Affinity; Androgen Receptor; Androgens; Animal Model; Antiandrogen Therapy; Beneficence; Binding; Blood; Castration; Cell Death; Cell Nucleus; Cells; Chemicals; Clinical Research; Complex; DNA; DNA Binding; Data; Diagnostic Neoplasm Staging; Disease; Electrons; Enzymes; Exhibits; Gene Amplification; Gene Targeting; Goals; Growth; Guns; Hormone Receptor; Hormone use; Hormones; Image; Implant; In Vitro; Isotopes; Malignant neoplasm of prostate; Mediating; Metabolism; Methods; Modeling; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Patient Selection; Patients; Plasma; Positron; Positron-Emission Tomography; Prostatic Neoplasms; Radiation; Radiation therapy; Radioactive Elements; Rattus; Receptor Inhibition; Resistance; Resistance development; Signal Transduction; Site; Specificity; Staging; Stanolone; System; Testosterone; Therapeutic; Toxic effect; Travel; Tumor stage; Work; analog; base; cancer cell; cancer imaging; castration resistant prostate cancer; cell growth; cell killing; density; deprivation; design; follow-up; hormone response element; imaging agent; ionization; killings; liver metabolism; men; nanometer; next generation; oncology; overexpression; prostate cancer cell; public health relevance; receptor; receptor binding; receptor expression; resistance mechanism; response; standard of care; stem; targeted agent; theranostics; therapy design; therapy resistant; tumor; uptake; Affinity; Androgen Receptor; Androgens; Animal Model; Antiandrogen Therapy; Beneficence; Binding; Blood; Castration; Cell Death; Cell Nucleus; Cells; Chemicals; Clinical Research; Complex; DNA; DNA Binding; Data; Diagnostic Neoplasm Staging; Disease; Electrons; Enzymes; Exhibits; Gene Amplification; Gene Targeting; Goals; Growth; Guns; Hormone Receptor; Hormone use; Hormones; Image; Implant; In Vitro; Isotopes; Malignant neoplasm of prostate; Mediating; Metabolism; Methods; Modeling; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Patient Selection; Patients; Plasma; Positron; Positron-Emission Tomography; Prostatic Neoplasms; Radiation; Radiation therapy; Radioactive Elements; Rattus; Receptor Inhibition; Resistance; Resistance development; Signal Transduction; Site; Specificity; Staging; Stanolone; System; Testosterone; Therapeutic; Toxic effect; Travel; Tumor stage; Work; analog; base; cancer cell; cancer imaging; castration resistant prostate cancer; cell growth; cell killing; density; deprivation; design; follow-up; hormone response element; imaging agent; ionization; killings; liver metabolism; men; nanometer; next generation; oncology; overexpression; prostate cancer cell; public health relevance; receptor; receptor binding; receptor expression; resistance mechanism; response; standard of care; stem; targeted agent; theranostics; therapy design; therapy resistant; tumor; uptake

 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.

 描述（由适用提供）：前列腺癌的生长和进展主要是由骑马（例如睾丸激素）驱动的，它们自然存在于血液中。旨在降低血液中的马烯水平，手术和化学cast割方法已成为前列腺癌的标准，已有70多年的历史了。尽管cast割最初是非常有效的，大大降低了肿瘤的大小，但不可避免地会发展耐castration castration的抗castration前列腺癌。在此阶段，肿瘤继续生长并传播目的地降低了马龙水平。通常，前列腺癌变为cast割的机制是过度产生与骑马结合的受体靶标，从而继续产生生长信号。一旦前列腺癌变得耐castration抗性，第二层的治疗方法是试图通过抑制这些受体来延迟生长。这种方法有可能提供延长的生存，但不能治愈。在此提案中，我们计划开发一种用于castratiation castration抗性前列腺癌的新型疗法，该治疗将这种耐药机制变成一种治疗优势。前列腺癌细胞的产生越多，产生其马酮受体，对我们建议的治疗的杀戮作用应该越敏感。具体来说，我们做到了 通过产生发射非常特殊类型的辐射类型的分子。该分子类似于肿瘤使用的一匹马，因为它与过度产生的接收器结合，然后到达与DNA结合的细胞核us。我们将放射性元件纳入分子是特殊的，与其他形式的辐射不同，该辐射HS具有极为有限的致死性范围。当它对DNA等关键分子而言时，它有点像枪，非常致命，但是当细胞中的其他地方或血液中的其他地方时，它几乎是无害的。由于这些分子与DNA不合时间，因此通常将这种类型的辐射注射到患者中而无效。该建议的主要目的是开发该治疗分子，以选择性地结合前列腺癌细胞中的DNA。作为该提案的次要目标，我们计划产生与治疗分子相同作用的分子，但使用非治疗性同位素，可用于制作肿瘤的三维图像。这些图像可用于选择最有可能通过这种疗法成功治疗的患者。