Harrer Dennis Christoph, Lüke Florian, Pukrop Tobias, Ghibelli Lina, Reichle Albrecht, Heudobler Daniel
Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Regensburg, Germany.
Cancers (Basel). 2023 Dec 29;16(1):180. doi: 10.3390/cancers16010180.
The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment.
治疗后转移扩散、癌症再增殖和获得性肿瘤细胞耐药性（M-CRAC）的概念解释了肿瘤进展的原因，这是由于治疗后基因损伤和随后的组织修复机制导致的肿瘤细胞异质性。旨在专门解决M-CRAC的治疗策略涉及组织编辑方法，如低剂量节拍化疗以及使用转录调节剂（无论是否联合靶向治疗）。值得注意的是，肿瘤组织编辑有潜力治疗那些对通常基于给予最大耐受剂量细胞毒性药物的传统化疗难治或复发（r/r）的患者。纳入r/r恶性肿瘤患者（如非小细胞肺癌、霍奇金淋巴瘤、朗格汉斯细胞组织细胞增多症和急性髓细胞白血病）的临床试验表明，组织编辑方法可能产生切实的临床益处。与传统化疗或最新的精准医学不同，组织编辑采用多管齐下的方法，针对各种肿瘤实体中M-CRAC的重要驱动因素，从而同时促进肿瘤细胞分化、免疫调节和炎症控制。在本综述中，我们强调M-CRAC概念是对传统癌症治疗耐药的一个主要因素，并讨论组织编辑作为一种潜在的治疗方法。
