Targeting Human Cancer Stem Cells with Monoclonal Antibodies

Abstract

Cancer stem cells (CSCs) constitute a distinct subpopulation of tumor cells that exhibit self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess various intrinsic mechanisms of resistance to conventional chemotherapeutics, novel tumor-targeted drugs and radiation therapy, permitting them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, EpCAM (CD326), CD123, CD133, GD2, Lgr5, insulin-like growth factor receptor I (IGF-IR), and members of the Notch and Wnt signaling pathways, have been identified and mainly used for the characterization of CSCs in experimental settings. Recently, monoclonal antibodies and antibody constructs such as Triomabs and BiTEs raised against these CSC proteins have shown efficacy against CSCs in human xenograft mice, and some of them have been demonstrated to induce tumor regression in clinical trials.Since current cancer therapies fail to eliminate CSCs, ultimately leading to cancer recurrence and progression, selective targeting of CSCs with mAbs and antibody constructs reviewed herein may represent a novel and promising therapeutic strategy to eradicate cancer.

Targeting the Wnt pathways for therapies

“…Trastuzumab monotherapy has only a 30% response rate and acquired resistance to trastuzumab occurs frequently. Trastuzumab has been shown to be effective only in the context of PI3K signaling and in the presence of PTEN, but CSCs display the aberrant former and the absence of latter [ 33 ]. Since current cancer therapies fail to eradicate CSCs, selective targeting of CSCs would be a promising therapeutic strategy.…”

Understanding the colon cancer stem cells and perspectives on treatment

“…Recently several compounds and drugs have been discovered selectively against CSC [ 77 ]. Some of these are microbe-derived and plant-derived biomolecules [ 78 , 79 ], small molecule inhibitors that target key components of the intrinsic signaling pathways of CSCs, some classical drugs, such as metformin, tranilast, and thioridazine [ 77 ], monoclonal antibodies (mAbs) and antibody constructs that are directed against CSC-specific cell surface molecules, such as the CD44, CD47, EpCAM, CD123, GD2, Lgr5, IGF-IR, Dll4 and FZD receptors [ 15 , 80 ], or antibody derivatives. Technologies such as antibody PEGylation [ 81 ] polysialylation [ 82 ] and albumin can be used to engineer a longer blood half-life for use against target signaling pathways and/or molecules that selective operate in CSCs, some of which are also capable of killing subpopulations of cancer cells that do not display CSC properties.…”

“…Other authors have reported the use of antibody constructs that target CSCs, which are more effective when combined with conventional cytostatic drugs [ 77 , 88 ]. Combinations or cocktails of antibodies against bulk tumor targets and CSC targets can sometimes destroy the whole tumor as well as the resilient CSC population, preventing relapse [ 95 ].…”

Triple Negative Breast Cancer

“…Triple-negative basal-like breast cancer cells resemble many features of breast CSCs, including expression of CD44 high, CD24 low and ALDH-1. The triple negative basal like subtype of breast cancer is characterized by a high content of breast CSCs, aggressive proliferation, high metastatic capability and poor overall survival of patients (Naujokat, 2012). Unlike rapidly dividing cancer cells within the tumor mass, CSCs have a slower cycle under the effect of various factors such as microenvironment in which they reside and therefore following conventional cancer therapies that kill rapidly dividing cells, CSCs can survive (Cetin and Topcul, 2012).…”