Targeting therapy-persistent residual disease

Abstract

Disease relapse driven by acquired drug resistance limits the effectiveness of most systemic anti-cancer agents. Targeting persistent cancer cells in residual disease before relapse has emerged as a potential strategy for enhancing the efficacy and the durability of current therapies. However, barriers remain to implementing persister-directed approaches in the clinic. This Perspective discusses current preclinical and clinical complexities and outlines key steps toward the development of clinical strategies that target therapy-persistent residual disease.

Figure 1.. Non-genetic sources of therapy-persistent residual disease.

A: Inadequate elimination of cancer cells by standard-of-care therapies results in residual disease and subsequent tumor recurrence. B: A subpopulation of cancer cells, termed “persisters,” can initially survive drug treatment without harboring genetic resistance mutations, thereby serving as a reservoir for the development of diverse acquired resistance mechanisms. C: The evolution of persister cells culminating in drug resistance is complex and context dependent. A myriad of extracellular and intracellular signals promotes their emergence; once established, these cells exhibit molecular heterogeneity; and diverse mutational processes underpin their evolutionary trajectory.

Figure 2.. Framework for clinical evaluation of persister-directed therapies (PTx).

A: A PTx (orange) can be combined upfront with standard-of-care therapy (SoC; black) to prevent therapy-persistent residual disease (RD). The selection of patients would be guided by prognostic and/or predictive markers present prior to initiation of therapy. B: Upon achieving a stable residual disease state with an initial period of SoC therapy, a PTx can be introduced in combination with the SoC. Patients could be selected based on the burden of residual disease. C: The initial phase of SoC therapy allows for monitoring of predictive biomarkers induced in persister cells. These biomarkers would guide selection of specific PTx matched to the biology of the residual tumor. Right: Early indicators of response, such as clearance of ctDNA or decrease in tumor volumetric measurements from RD “baseline”, could increase efficiency in evaluating the efficacy of a PTx.