Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

Abstract

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.

Keywords: M-CRAC; anakoinosis; drug repurposing; drug resistance; metastases; metronomic chemotherapy; pioglitazone; transcriptional modulation; tumor cell repopulation; tumor heterogeneity; tumor tissue editing.

Figure 1

Tumor tissue editing for rescuing relapsed or refractory tumor disease separates M-CRAC as targetable phenomenon: suggested mechanisms of action.

Figure 2

Disease traits of M-CRAC trigger spontaneous cancer progression. The therapeutic tumor tissue editing tool may control, resolve, or bypass M-CRAC via access to shared triggers for tumor promotion present in histologically different tumor types.

Figure 3

Differential tumor tissue editing approaches for overcoming M-CRAC.

Figure 4

A novel therapy model: tumor tissue editing for M-CRAC control derived from knowledge-generating patient care with tumor tissue editing techniques. Arnol et al. drafted a communication-derived tumor model [40,48].