Getting to the Source: Selective Drug Targeting of Cancer Stem Cells

Abstract

Cancers are among the most important and most difficult to treat diseases of the 21st century. Conventional therapies include surgery, immunotherapy, and radiotherapy, as well many forms of drug treatments such as tamoxifen and Gleevec. However, these forms of treatment often do not eradicate the cancer stem cells, only managing to decrease the size of the tumor, allowing the cancer to return. The cancer stem cell hypothesis stipulates that malignancy is maintained through self-renewal of cancer stem cells (CSCs), which generate rapidly dividing progeny that comprise the tumors, and that are largely untouched by conventional therapies. Evidence for the central role of CSCs in many tumors has provided a paradigm shift in the way cancer chemotherapy may be addressed. Recent discoveries regarding the nature of the stem cell niche, and the key signaling pathways involved in stem cell self-renewal and differentiation from regenerative medicine, have provided key information that facilitates selective targeting of CSCs by small-molecule drugs. The growing body of biochemical knowledge on the nature of CSCs, and differences between them and normal adult stem cells essential for maintaining organisms, has augmented the increasing number of small molecules shown to control normal and aberrant stem cells. Here, we review small-molecule approaches to the selective targeting of CSCs.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…In this study, cellular and molecular pharmacological data demonstrate that DLC-carborane compounds target cancer and primary GBM CSCs highly selectively and also that these agents exert a very significant pharmacological behavior while sparing normal cells. Based on the principle of the elimination of CSCs toward achieving patient long-term cure rates in the clinical setting [3,6,7], it is of significance that DLCcarborane compounds exert such remarkable effect on GBM CSC lines. The effect is most meaningfully demonstrated by the determined IC 50 values, which are markedly 18 lower than those calculated for normal cells (ca.…”

“…It has been suggested that as long as technological advancements empower the translational medicine capacity in enabling the pharmacological exploitation of cancer cell molecular and genomic knowledge, the advances to therapeutically overcome heterogeneity and to target the tumor cell microenvironment will occur at increasing rates [2][3][4][5][6][7][8][9][10]. A major milestone towards organelle-specific drug delivery was reached by the discovery of delocalized lipophilic cations (DLCs) [11].…”

Adrien Albert Award: How to Mine Chemistry Space for New Drugs and Biomedical Therapies

“…These methods have been used to design and optimise green pesticides [16][17][18][19][20] in collaboration with Du Pont and Schering Plough, have discovered new peptides and small molecules to control stem cells and cancers, [21][22][23][24][25][26][27] are accelerating the development of biomaterials for implantation and stem cell culture, [28][29][30][31][32][33] have provided new scientific insight into the potential adverse properties of nanomaterials, [34][35][36][37][38] have yielded clinical candidates for Australian SMEs and international companies, and were instrumental in the discovery of antibiotics [39,40] with a novel mode of action for the biotechnology spin off company, Betabiotics. Some of this research is discussed in more detail in the following sections.…”

“…[73,74] Design of small molecules to reprogram somatic and stem cells, and to selectively kill cancer stem cells. [21] Clearly science and technology have moved on very rapidly since Adrien Albert's day, but he would be very pleased to see his area of selective toxicity flourishing in the twenty-first century. …”

Robust Prediction of Personalized Cell Recognition from a Cancer Population by a Dual Targeting Nanoparticle Library

“…It is clear that, while markers such as folate receptors [ 1 ] and other proteins on cancer cells, [ 2 ] or aldehyde dehydrogenase receptors on cancer stem cells [ 3 ] can provide some selective targeting of therapeutics or diagnostics, a single protein marker will not be enough to achieve the selectivity required. A better understanding of the types surface marker populations in specifi c types of cells is necessary to generate the selectivity required to generate maximum effi cacy against cancers, and to avoid effects on healthy bystander cells that also express a subset of these markers.…”