Page 57 - 2014 Printable Abstract Book
P. 57
(S1103) Overcoming radioresistance with nanoparticle-mediated microRNA delivery. Li Ma,
The University of Texas MD Anderson Cancer Center, Houston, TX
Tumor cells associated with therapy resistance (radioresistance and drug resistance) are likely to
give rise to local recurrence and distant metastatic relapse. Radiation therapy plays an important role in
breast cancer management, whereas intrinsic and therapy-induced radioresistance represents a major
obstacle. Combining chemotherapy with radiation improves outcomes but often increases toxicity. Recent
studies have revealed microRNA (miRNA)-mediated regulation of breast cancer metastasis and epithelial-
mesenchymal transition; however, whether specific miRNAs regulate breast cancer radioresistance and
can be exploited as radiosensitizing agents remains unclear. Using an unbiased profiling approach, we
found that the miR-205 miRNA promotes radiosensitivity and is downregulated in radioresistant
subpopulations of breast cancer cells derived from ionizing radiation, and that loss of miR-205 expression
is highly associated with poor distant relapse-free survival in breast cancer patients. Notably, therapeutic
delivery of miR-205 mimics via nanoliposomes sensitized the tumor to radiation in a xenograft model.
Mechanistically, radiation suppresses miR-205 expression through ataxia telangiectasia mutated (ATM)
and zinc finger E-box binding homeobox 1 (ZEB1). Moreover, miR-205 inhibits homologous
recombination-mediated DNA damage repair by targeting ZEB1 and the ubiquitin-conjugating enzyme
Ubc13. These findings identify miR-205 as a radiosensitizing miRNA and reveal a new therapeutic strategy
for radioresistant tumors.
(S1104) Development of a thermally sensative doxorubicin containing limousine-a bench to bedside
story. Mark W. Dewhirst, Duke University, Durham, NC
S12 RADIATION RESPONSE OF NORMAL TISSUE STEM CELLS
The potential of regenerative medicine has created considerable excitement in the biology and application
of normal tissue stem cells. We will highlight evidence demonstrating the importance of radiation
responses of normal tissue stem cells for (1) tumorigenesis and (2) other normal tissue injury sequelae.
(S1201) Persistent effects of radiation quality on intestinal stem cells: implications for colorectal
carcinogenesis. Shubhankar Suman; Santosh Kumar; Albert J. Fornace; Kamal Datta. Georgetown
University Medical Center, Washington, NW, DC
Adult stem cells, similar to somatic cells, are also subject to a similar array of insults and are
therefore presumed to accrue radiation damage. Unlike somatic cells, however, lesions arising in the stem
cell compartment are propagated both to daughter stem cells and to downstream lineages through the
processes of self-renewal and differentiation. The impact of damage accrued in individual stem cells can
thus have major ramifications for all levels of the developmental hierarchy leading to cancer initiation and
promotion in human as well as in animal models of human colorectal cancer (CRC) such as in APCMin/+.
Differentiation of intestinal stem cell (ISC) and ordered migration of differentiated cells along crypt-villus
axis is essential for maintenance of intestinal homeostasis and provides a model system to study stem cell
alterations after radiation. Furthermore, considering that tumors in animal models of CRC almost
55 | P a g e
The University of Texas MD Anderson Cancer Center, Houston, TX
Tumor cells associated with therapy resistance (radioresistance and drug resistance) are likely to
give rise to local recurrence and distant metastatic relapse. Radiation therapy plays an important role in
breast cancer management, whereas intrinsic and therapy-induced radioresistance represents a major
obstacle. Combining chemotherapy with radiation improves outcomes but often increases toxicity. Recent
studies have revealed microRNA (miRNA)-mediated regulation of breast cancer metastasis and epithelial-
mesenchymal transition; however, whether specific miRNAs regulate breast cancer radioresistance and
can be exploited as radiosensitizing agents remains unclear. Using an unbiased profiling approach, we
found that the miR-205 miRNA promotes radiosensitivity and is downregulated in radioresistant
subpopulations of breast cancer cells derived from ionizing radiation, and that loss of miR-205 expression
is highly associated with poor distant relapse-free survival in breast cancer patients. Notably, therapeutic
delivery of miR-205 mimics via nanoliposomes sensitized the tumor to radiation in a xenograft model.
Mechanistically, radiation suppresses miR-205 expression through ataxia telangiectasia mutated (ATM)
and zinc finger E-box binding homeobox 1 (ZEB1). Moreover, miR-205 inhibits homologous
recombination-mediated DNA damage repair by targeting ZEB1 and the ubiquitin-conjugating enzyme
Ubc13. These findings identify miR-205 as a radiosensitizing miRNA and reveal a new therapeutic strategy
for radioresistant tumors.
(S1104) Development of a thermally sensative doxorubicin containing limousine-a bench to bedside
story. Mark W. Dewhirst, Duke University, Durham, NC
S12 RADIATION RESPONSE OF NORMAL TISSUE STEM CELLS
The potential of regenerative medicine has created considerable excitement in the biology and application
of normal tissue stem cells. We will highlight evidence demonstrating the importance of radiation
responses of normal tissue stem cells for (1) tumorigenesis and (2) other normal tissue injury sequelae.
(S1201) Persistent effects of radiation quality on intestinal stem cells: implications for colorectal
carcinogenesis. Shubhankar Suman; Santosh Kumar; Albert J. Fornace; Kamal Datta. Georgetown
University Medical Center, Washington, NW, DC
Adult stem cells, similar to somatic cells, are also subject to a similar array of insults and are
therefore presumed to accrue radiation damage. Unlike somatic cells, however, lesions arising in the stem
cell compartment are propagated both to daughter stem cells and to downstream lineages through the
processes of self-renewal and differentiation. The impact of damage accrued in individual stem cells can
thus have major ramifications for all levels of the developmental hierarchy leading to cancer initiation and
promotion in human as well as in animal models of human colorectal cancer (CRC) such as in APCMin/+.
Differentiation of intestinal stem cell (ISC) and ordered migration of differentiated cells along crypt-villus
axis is essential for maintenance of intestinal homeostasis and provides a model system to study stem cell
alterations after radiation. Furthermore, considering that tumors in animal models of CRC almost
55 | P a g e
