Hypothermia Is a Potential New Therapy for a Subset of Tumors with Mutant p53.
Hypothermia Is a Potential New Therapy for a Subset of Tumors with Mutant p53.
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DOI：
10.1158/0008-5472.can-21-1025
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发表时间：
2021-07-15
期刊：
影响因子：
11.2
通讯作者：
Feng Z
中科院分区：
文献类型：
--
作者：
Hu W;Feng Z
肿瘤抑制基因p53在大约50%的人类肿瘤中发生突变。许多肿瘤相关的突变型P53蛋白错误折叠成一种常见的变性构象，并在人类肿瘤中积累到高水平。在这类肿瘤中，这些突变型的P53提供了促进肿瘤进展的“功能”。因此，靶向突变型P53已成为肿瘤治疗的一种有吸引力的方法。Lu等人的研究。支持某些形式的突变型p53在构象上对温度敏感的前提；这些形式的p53在生理温度下的构象是突变的，但在较低的温度(32-34°C)下可以重新折叠成正常的或‘野生型’构象。值得注意的是，这些温度敏感型突变占携带突变p53的所有人类肿瘤的7.5%，因此估计这一比例的患者相当重要。这项研究的结果表明，采用治疗性低温来降低携带这些温度敏感型突变型p53(ts突变型p53)的小鼠的核心温度，会导致ts突变型p53在肿瘤中形成野生型构象，从而抑制肿瘤生长。此外，该小组发现，将低温与化疗相结合可以使这种肿瘤持久缓解，对正常组织没有明显的毒性。
The tumor suppressor p53 gene is mutated in approximately 50% of all human tumors. Many tumor-associated mutant p53 proteins misfold into a common, denatured conformation, and accumulate to high levels in human tumors. In such tumors these mutant forms of p53 provide a “gain of function” to promote tumor progression. Therefore, targeting mutant p53 has become an attractive approach for cancer therapy. The study from Lu et al. supports the premise that certain forms of mutant p53 are temperature-sensitive in conformation; these forms of p53 are mutant in conformation at physiological temperature, but can refold into a normal, or ‘wild-type’ conformation at lower temperature (32–34°C). Notably, these temperature-sensitive mutants account for up to 7.5% of all human tumors that carry mutant p53, so this fraction of patients is estimated to be quite significant. Results from this study show that employing therapeutic hypothermia to reduce the core temperature of mice bearing tumors with these temperature-sensitive mutant forms of p53 (ts mutant p53) causes ts mutant p53 to become wild-type conformation in tumors, inhibiting tumor growth. Moreover, this group found that combining hypothermia with chemotherapy leads to durable remission of such tumors, with no obvious toxicity to normal tissues.