A novel strategy to overcome drug resistance in cancer

摘要 癌症治疗成功的主要障碍是抗药性的快速发展。虽然有针对性 治疗通常延长致敏突变患者亚群的总存活率，它们的效果是 是短暂的。最初对这些药物有反应的患者通常在几个月内产生抗药性。 肿瘤的单细胞测序显示了显著的遗传异质性；没有 使突变敏化，存活治疗，并重新滋生肿瘤。同时，代偿性表观遗传 而基因变化减轻了对靶向途径的依赖，也导致了耐药性。的确有 因此，对能够提供更强有力的癌症控制的新的治疗策略的迫切需求尚未得到满足。一个 即使单个组件发生故障，健壮的系统仍能继续运行。在毒品的背景下 开发一种强有力的疗法将产生平行的、多余的抗癌效果，每一种效果都是 足以抑制肿瘤生长。实现这种冗余的一种方法是接受多效性 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 通过并行瞄准多个信令节点。例如，内源性鞘脂显示出强大的肿瘤活性。 通过在信号通路中产生多方面和不完全特征化的变化来抑制活性 这会导致正常细胞的增殖停滞和癌细胞的死亡。SH-BC-893(893)，合成 鞘磷脂具有更好的药物特性，保留了这些天然化合物的抗肿瘤活性。在一个 严格的基因工程小鼠侵袭性前列腺癌模型，893减少了本土 肿瘤增长82%。在一个相关的皮下同种异体移植模型中，893在&gt；50%的 老鼠。893对患者来源的前列腺癌有机化合物也有效，这些有机化合物对标准的 护理疗法。反对多效药的主要论点是，毒性将是不可接受的 相对于更具体的药物而言，它被放大了。然而，天然鞘磷脂在正常细胞中诱导静止，如 对压力做出的适应性、动态平衡反应的一部分。事实上，893不会造成器官毒性，也不会破坏 即使在治疗3个月后，骨髓或肠腺中的正常细胞仍有增殖 抗肿瘤剂量。正常细胞对893的耐药性更强，但893‘S的药代动力学特性也可能 为其安全边际做出贡献。我们的初步数据显示，893从事多种高价值肿瘤学 靶标结果增加了893不太容易产生耐药性的可能性，并可以克服 对FDA批准的疗法产生抵抗力。这一提议将检验这一具有挑衅性的假设。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来产生重大的积极影响 这一策略将对晚期致命前列腺癌患者有效。

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.