A novel strategy to overcome drug resistance in cancer

摘要 癌症治疗成功的主要障碍是耐药性的迅速发展。虽然目标 治疗通常延长具有致敏突变的患者亚组的总生存期，它们的效果是 短命的最初对这些药物有反应的患者通常会在几个月内产生耐药性。 肿瘤的单细胞测序已经揭示了显著的遗传异质性; 致敏突变在治疗中存活并重新填充肿瘤。与此同时， 而基因变化减轻了对靶向途径的依赖，也有助于耐药性。有 因此，对于能够提供更稳健的癌症控制的新治疗策略的关键的未满足的需求。一 即使单个组件发生故障，强大的系统也能继续运行。症与药物 发展，一个强大的治疗将产生平行的，多余的抗癌作用，其中每一个是 足以抑制肿瘤生长。实现这种冗余的一种方法是拥抱多效性 天然化合物的作用。内源性信号分子产生协调和复杂的反应 通过并行地瞄准多个信令节点。例如，内源性鞘脂表现出有效的肿瘤抑制作用。 通过产生多方面的和不完全特征的信号通路的变化抑制活性 引发正常细胞增殖停滞和癌细胞死亡。SH-BC-893（893），合成 具有改进的药物性质的鞘脂保留了这些天然化合物的抗肿瘤活性。中 严格的，基因工程小鼠模型的侵袭性前列腺癌，893减少原位 肿瘤生长82%。在相关的皮下同种移植物模型中，893在>50%的小鼠中产生肿瘤消退。 小鼠893还有效对抗对标准抗肿瘤药物具有抗性的患者来源的前列腺肿瘤类器官。 护理治疗。反对多效性药物的主要论点是毒性将是不可接受的 相对于更具体的药物，然而，天然鞘脂在正常细胞中诱导静止， 是对压力的适应性自我平衡反应的一部分事实上，893不会引起器官毒性或破坏 甚至在用所述药物治疗3个月后，骨髓或肠隐窝中的正常细胞的增殖 抗肿瘤剂量。正常细胞对893更有抵抗力，但893的药代动力学特性也可能 有助于其安全边际。我们的初步数据显示，893从事多种，高价值的肿瘤学 目标结果提高了893对耐药性不敏感的可能性， 对FDA批准的疗法的抵抗力。这一提议将检验这一挑衅性的假设。预期结果 将通过改变该领域的思维并提供一种新的治疗方法， 这一策略对晚期致命性前列腺癌患者有效。

ABSTRACT The major obstacle to successful cancer therapy is the rapid development of drug resistance. While targeted therapies often extend overall survival in the subset of patients with sensitizing mutations, their effects are short-lived. Patients who initially respond to these drugs generally develop resistance within a few months. Single-cell sequencing of tumors has revealed significant genetic heterogeneity; tumor cells without the sensitizing mutation survive therapy and re-populate the tumor. At the same time, compensatory epigenetic and genetic changes relieve dependence on the targeted pathway, also contributing to resistance. There is thus a critical unmet need for new therapeutic strategies capable of providing more robust cancer control. A robust system continues to function even when an individual component fails. In the context of drug development, a robust therapy would produce parallel, redundant anti-cancer effects, each of which is sufficient to inhibit tumor growth. One approach to achieving such redundancy is to embrace the pleiotropic actions of natural compounds. Endogenous signaling molecules produce coordinated and complex responses by targeting multiple signaling nodes in parallel. For example, endogenous sphingolipids exhibit potent tumor suppressor activity by producing multifaceted and incompletely characterized changes in signaling pathways that trigger proliferative arrest in normal cells and death in cancer cells. SH-BC-893 (893), a synthetic sphingolipid with improved drug properties, retains the anti-neoplastic activity of these natural compounds. In a rigorous, genetically-engineered mouse model for aggressive prostate cancer, 893 reduces autochthonous tumor growth by 82%. In a related subcutaneous isograft model, 893 produces tumor regressions in >50% of mice. 893 is also effective against patient-derived prostate tumor organoids that are resistant to standard-of- care therapies. The major argument against pleiotropic agents has been that toxicity will be unacceptably amplified relative to more specific drugs. However, natural sphingolipids induce quiescence in normal cells as part of an adaptive, homeostatic response to stress. Indeed, 893 does not cause organ toxicity or disrupt the proliferation of normal cells in the bone marrow or intestinal crypts even after 3 months of treatment with the anti-neoplastic dose. Normal cells are more resistant to 893, but 893’s pharmacokinetic properties also likely contribute to its safety margin. Our preliminary data showing that 893 engages multiple, high-value oncology targets results raise the possibility that 893 will be less susceptible to drug resistance and could overcome resistance to FDA-approved therapies. This proposal will test this provocative hypothesis. The expected results would have a significant positive impact by changing thinking in the field and providing a novel therapeutic strategy that would be effective in patients with late-stage, lethal prostate cancers.