Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers

SIMPLE SUMMARY: Effective cancer treatment hinges upon overcoming therapeutic resistance mechanisms that allow for the continued proliferation of cancer cell subpopulations. Exposure to pharmacotherapy invariably leads to resistance as tumor cells with selected advantageous features evade destruction and alter the tumor composition. Cancer stem cells (CSCs) with features of plasticity that allow for regeneration and differentiation are particularly responsible for this phenomenon. Advances in tumor biology and molecular signaling have highlighted their role in neoplastic initiation, invasion, and maintenance. Novel strategies to direct therapy against these tumor cell subpopulations have the potential to dramatically alter tumor response and change the course of cancer care. ABSTRACT: Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation—represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/β-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance.