Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer.
Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer.
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DOI：
10.17140/poj-3-e010
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Saif, Muhammad W
中科院分区：
文献类型：
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作者：
Hakim, Nausheen;Patel, Rajvi;Saif, Muhammad W
胰腺癌（PC）的生存率仍然很低。目前的标准治疗方案提供了短暂的临床获益，但最终产生耐药性，导致不良结局。PC是一种相对耐药的肿瘤，其原因之一是结缔组织增生阻碍了药物递送。在此基础上，开发了基质修饰剂，如聚乙二醇透明质酸酶α（PEGPH 20），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，PEHPH 20的进一步开发也停止了。这种失败意味着单独靶向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，低肿瘤突变负荷，上皮间质转化可能在发挥作用。同样重要的是要考虑到，虽然肿瘤基质可能是阻碍药物递送的物理屏障，但它也可能在抑制肿瘤生长和进展方面具有保护作用。进一步的分子生物学研究，以更好地表征微环境和癌细胞之间的复杂相互作用是必要的。
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.