Nyce Jonathan
Clinical Research, ACGT Biotechnology, Collegeville, PA 19426, USA.
Cancer Drug Resist. 2019 Dec 19;2(4):1207-1214. doi: 10.20517/cdr.2019.89. eCollection 2019.
We recently reported our detection of an anthropoid primate-specific, adrenal androgen-dependent, "kill switch" tumor suppression mechanism that is triggered by the inactivation of the p53 tumor suppressor. This mechanism reached its highest expression only in humans as a result of the human-specific harnessing of fire, which resulted in an extraordinary increase in exposure to polycyclic aromatic hydrocarbons. This "kill switch" becomes inoperative in modern humans once they exceed the primitive human lifespan of 25-30 years, because lifespan has more than tripled in modern times, but the secretion curve for dehydroepiandrosterone sulfate remains fixed at the level required for the primitive human lifespan. Components of this "kill switch" are consequently usurped by human tumors, and these are already targets for inhibition in cancer chemotherapy. Here, we suggest a different strategy: using the usurped components of the kill switch to activate prodrugs, rather than as targets for inhibition. This strategy is in its infancy, but has the potential to enable more tumor-specific cytotoxicity, which the inhibition strategy generally cannot achieve. Detection of the usurpation of kill switch elements in liquid biopsy analyses enables the collection of information relevant to this new class of tumor biomarkers without the necessity of invasive tissue biopsy.
我们最近报告了我们对一种灵长类动物特有的、肾上腺雄激素依赖性的“死亡开关”肿瘤抑制机制的检测，该机制由p53肿瘤抑制因子的失活触发。由于人类对火的特殊利用，这种机制仅在人类中达到最高表达，这导致多环芳烃暴露显著增加。一旦现代人类超过原始人类25至30岁的寿命，这个“死亡开关”就会失效，因为现代人类的寿命已经增长了两倍多，但硫酸脱氢表雄酮的分泌曲线仍固定在原始人类寿命所需的水平。因此，这个“死亡开关”的组成部分被人类肿瘤篡夺，而这些已经是癌症化疗中抑制的靶点。在这里，我们提出一种不同的策略：利用死亡开关被篡夺的组成部分来激活前药，而不是作为抑制的靶点。这种策略尚处于起步阶段，但有可能实现更高的肿瘤特异性细胞毒性，这是抑制策略通常无法实现的。在液体活检分析中检测死亡开关元件的篡夺情况，无需进行侵入性组织活检就能收集与这类新的肿瘤生物标志物相关的信息。
