Emerging strategies for treating metastasis

Abstract

The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.

Figure 1.. 5-Year survival rates of patients diagnosed with select cancer types over the time period from 2000–2017.

Patients were stratified into three groups according to the extent of invasion or metastasis upon the original diagnosis. The year in the x-axis indicates the year of diagnosis and the first year of the 5-year monitoring period with data last reported in 2017. Data adapted from the NIH-NCI SEER database.

Figure 2.. Metastatic ability, therapeutic resistance and plasticity are intrinsically linked by genetic, epigenetic and metabolic pathways that offer promising therapeutic nodes for drug development.

Epigenetic modifications created by DNA methyltransferases (DNMT1–4), histone methyltransferases (EZH2), and histone deacetylases (HDAC) repress tumor suppressors while promoting dedifferentiation to enhance both plasticity and therapeutic resistance. Metastatic ability and therapeutic resistance are linked by metabolic adaptations that enhance the reductive capacity of tumor cells via NAD(P)H generating pathways, such as lipid catabolism and antioxidant pathways. Cellular plasticity, epithelial-mesenchymal transition (EMT), stemness and metastasis are commonly driven by aberrant activities of key developmental pathways (TGF-β, Wnt, Notch and SHH). Therapeutic strategies to target shared mechanisms between these three hallmark characteristics of metastatic cancers may yield durable remissions either as monotherapies or when combined with classic cytotoxic therapies.

Figure 3.. Development of metastasis competency requires additional malignant properties beyond primary tumorigenesis.

Distinct primary tumor types evolve in a stepwise fashion with each additional mutation in a tumor suppressor or oncogene leading to incremental increases in competitive advantage. Key oncogene and suppressor mutations driving common cancers are often distinct from other cancer types and relatively few mutations are required for tumor formation (estimated at 2–8 driver mutations). In comparison, mutations in common oncogenes are not sufficient for metastatic competence, which instead requires the acquisition of multiple cellular programs that must align in order for the cells to withstand the stresses imposed by the metastatic process. Distinct tumor types therefore convergently evolve to acquire these pro-metastatic programs, which in turn offer the opportunity for biomarker-driven tumor type-agnostic therapies in metastatic cancer patients. CIN: Chromosomal instability UPR: Unfolded protein response.

Figure 4.. Targeting the immune microenvironment of metastatic cancers.

Metastatic lesions enforce immune suppression through the stimulation of key immunoregulatory cell types, including tumor-associated macrophages (TAM), regulatory dendritic cells (DC), regulatory T cells (T_reg) and other myeloid-derived suppressive cell populations, that prevent effector T cells (T_eff) from recognizing and destroying tumor cells. PD-1/PD-L1 inhibitors have already shown strong efficacy in alleviating T_reg-imposed immune suppression at the metastatic site of immunologically-active tumors and additional immune checkpoint blocking therapies are in development (TIGIT, LAG3, VISTA). For immunologically-cold tumors, depletion of immunosuppressive cells through antibody treatment (CSF1R, MARCO, CD25) or inhibition of various differentiation/growth pathways (retinoid and cytokine) may enforce durable remissions of metastatic disease.