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Cancer Stem Cell inhibitors (CSCiTM) Cancer
Stem Cells (CSC), represent a small population of cells within a tumor, which
drives growth and metastasis, and have characteristic phenotypic properties of
stem cells. Evidence for the presence of CSC has been found for a number of
tumor sites, including brain, breast, colon and leukemia (1). CSC are
self-renewing, able to give rise to a xenograft tumor from a single cell, and
able to recapitulate all cell types in the resultant tumor (2). Interaction of
CSC with their microenvironment (niche), including their response to signals
from specific cell types, has been suggested as a support mechanism for cancer
development (3). While chemotherapy and radiation therapy are able to eradicate
most of the tumor cells, especially the fast dividing cells, these treatments
frequently fail in eradicating the CSC, resulting in recurrence. Clinical
eradication of the CSC, considered a requirement for obtaining a cure, has
turned out to be challenging to date. CSCs are few in number, estimated at
between 0.1%-5% depending on the tumor type and stage of development, and appear
to be largely quiescent (4). Furthermore, CSC are enriched for the ATP binding
cassette (ABC) drug resistant genes, resulting in resistance to most current
therapies (5). We
have recently developed a microenvironement niche based drug screening assay for
CSC isolated from Acute Myeloid Leukemia (AML) patients. This artificial in-vitro modeled biomaterial
hydrogel microenvironment niche assay is specific to CSC self-renewal. The assay
system uses typical high throughput drug screening assay format. Combinatorial
cocktails of growth factors, ECM, crude extracts, and other native niche
components are presented to CSC kinetically (slow, fast, and
inducible) within their
native microenvironment composed of optimal 3-D modern synthetic biomaterials.
Drug screening is performed within this optimal assay background to accurately
quantify self-renewal of CSC. Work in progress will further develop CSC assays
for cancers of different origins including solid tumors (i.e. neuronal and breast cancers) and CSC assay formats to monitor
drug toxicity and efficacy, in-vivo. Screening
of a focused library of compounds has so far generated a resourceful list of
candidate compound structures with specific activities targeting self-renewal signal
transduction pathways. This project’s exploratory R&D is focused on
structure assisted drug design, structure activity relationship (SAR), medicinal
chemistry, target validation and preclinical studies with the goal of initiating
clinical studies of highly efficacious anti-CSC therapeutic agents that eradicate CSC
either individually or in combination with current anticancer
drugs in the clinic. DNAmicroarray,
Inc. is currently seeking corporate partnerships/ strategic alliances for CSC drug repositioning
projects. For further information please send us an email to TAP@dnamicroarray.com
.
References 1) Jordan CT. et al (2006) N
Engl J Med 355:1253-61. 2) Hill et al (2007) Natl Cancer Inst. 99(19):1435-40. 3) Li L., and Neaves WB, (2006) Cancer Res. 1;66(9):4553-7. 4) Jordan CT , and Guzman ML, (2004) Oncogene 23: 7178–718. 5)
Hdnagy A, et al (2006) Exp Cell Res. 15;312(19):3701-10. |
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