HALO 301失败的原因及其对胰腺癌治疗的意义

Pancreas (Fairfax, Va.) Pub Date : 2019-01-01 Epub Date: 2019-12-20 DOI:10.17140/POJ-3-e010
Nausheen Hakim, Rajvi Patel, Craig Devoe, Muhammad W Saif
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引用次数: 62

摘要

胰腺癌(PC)的生存率仍然很低。目前的标准护理治疗方案提供短暂的临床益处,但最终会产生化疗耐药性,导致不良结果。PC是一种相对耐药的肿瘤,其中一种解释是由于结缔组织增生阻碍了药物的传递。基于此,间质修饰剂如聚乙二醇透明质酸酶α (PEGPH20)被开发并在I-III期研究中进行了研究。尽管I-II期研究在高透明质酸(HA)表达肿瘤患者中显示出有希望的结果,但III期HALO 301研究未能错过其主要终点,PEHPH20的进一步开发被停止。这一失败表明仅针对结缔组织增生是不够的,其他内在因素,如缺乏重要的新抗原、低肿瘤突变负担和上皮细胞向间质细胞的转化可能在起作用。同样重要的是要考虑到,尽管肿瘤基质可能是阻碍药物传递的物理屏障,但它也可能具有抑制肿瘤生长和进展的保护作用。分子生物学的进一步研究,以更好地表征微环境和癌细胞之间复杂的相互作用是必要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer.

Survival rates for pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant tumor and one of the explanations for this is attributed to desmoplasia that impedes drug delivery. Based on this, stromal modifying agent such as Pegvorhyaluronidase alfa (PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high hyaluronic acid (HA) expressing tumors, the phase III HALO 301 study failed to miss it's primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the tumor stroma may be a physical barrier hampering drug delivery, it may also have protective effects in restraining tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.

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