Page 80 - 2014 Printable Abstract Book
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presentation will provide an overview of targeting tumor glucose metabolism during radiotherapy.
Description of efficacy utilizing novel radiosensitizing paradigms will be described. The fourth session is a
description of novel lipid second messengers that are produced in poor prognosis cancers during
radiotherapy. The lipid second messenger LPC is converted to LPA which enhances cell viability. Inhibition
of the enzymes required for production of LPC and LPA enhance the efficacy of radiotherapy in preclinical
models of lung cancer and glioblastoma.
(S2101) Using kinomics to identify targets for radiation enhancement. Christopher D. Willey, MD, PHD,
University of Alabama at Birmingham, Birmingham, AL
Kinases represent one of the most important groups of targets for drug development in cancer due to the
fact that they are principle players in signal transduction cascades in biology. However, investigating
kinases has been challenging as they are typically not regulated at the genomic or transcriptomic level but
are usually regulated post-translationally. Kinases are often transiently activated, particularly in response
to therapies such as radiation, which further complicate their investigation. As such, global kinase
evaluation (“kinomic profiling”) is being developed to better study biological systems. Indeed, kinomic
profiling represents an important functional proteomic strategy that we have applied to radiation
signaling and response. We have used the PamStation®12, a high content peptide substrate microarray
platform to investigate radiation-induced signaling and radiation response correlation. This approach
directly measures kinase activity within protein lysates that allows for hypothesis generation, particularly
related to radiation signaling. Bioinformatics are critical to interpreting this data and examples of
strategies are shown.
(S2102) Targeting tumor glucose metabolism in cervical cancer. Julie Schwarz, MD, PhD, Washington
University School of Medicine, St. Louis, MO
A fundamental observation in oncology is that tumor cells metabolize glucose primarily through glycolysis,
rather than glycolysis followed by oxidative phosphorylation, to generate ATP and other metabolites
needed for cell division. This aberrant tumor physiology is exhibited by cervical tumors that metabolize
18
glucose through aerobic glycolysis, i.e., the “Warburg effect”, and this can be imaged by F-fluoro-deoxy-
glucose positron emission tomography (FDG-PET). Our group has shown that human cervical tumors with
increased FDG uptake on pre-treatment FDG-PET imaging have inferior survival outcomes after standard-
of-care chemoradiation (pelvic irradiation with the concurrent administration of cisplatin chemotherapy).
This suggests that cisplatin alone is insufficient as a radio-sensitizer for patients with metabolically active
tumors. We have shown that human tumors with residual or abnormal FDG uptake on post-therapy FDG-
PET imaging have alterations in expression of genes and proteins from the PI3K/AKT pathway. Our results
demonstrate that phospho-AKT (pAKT) is a biomarker that is associated with decreased patient
progression-free survival outcomes after definitive chemoradiation. Most recently, we have shown that
increased pAKT, which indicates AKT enzymatic activation, induces mTOR to promote and to sustain
increased glucose uptake and glycolysis in cervical tumor cell lines. When cervical cancer cells are treated
with PI3K/AKT inhibitors, we observe decreased aerobic glycolysis and increased activity of the pentose
phosphate shunt, suggesting that PI3K/AKT activation may serve as a metabolic switch in cervical cancer.
Activating PIK3CA mutations have been identified in patients with cervical cancer, and these patients have
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Description of efficacy utilizing novel radiosensitizing paradigms will be described. The fourth session is a
description of novel lipid second messengers that are produced in poor prognosis cancers during
radiotherapy. The lipid second messenger LPC is converted to LPA which enhances cell viability. Inhibition
of the enzymes required for production of LPC and LPA enhance the efficacy of radiotherapy in preclinical
models of lung cancer and glioblastoma.
(S2101) Using kinomics to identify targets for radiation enhancement. Christopher D. Willey, MD, PHD,
University of Alabama at Birmingham, Birmingham, AL
Kinases represent one of the most important groups of targets for drug development in cancer due to the
fact that they are principle players in signal transduction cascades in biology. However, investigating
kinases has been challenging as they are typically not regulated at the genomic or transcriptomic level but
are usually regulated post-translationally. Kinases are often transiently activated, particularly in response
to therapies such as radiation, which further complicate their investigation. As such, global kinase
evaluation (“kinomic profiling”) is being developed to better study biological systems. Indeed, kinomic
profiling represents an important functional proteomic strategy that we have applied to radiation
signaling and response. We have used the PamStation®12, a high content peptide substrate microarray
platform to investigate radiation-induced signaling and radiation response correlation. This approach
directly measures kinase activity within protein lysates that allows for hypothesis generation, particularly
related to radiation signaling. Bioinformatics are critical to interpreting this data and examples of
strategies are shown.
(S2102) Targeting tumor glucose metabolism in cervical cancer. Julie Schwarz, MD, PhD, Washington
University School of Medicine, St. Louis, MO
A fundamental observation in oncology is that tumor cells metabolize glucose primarily through glycolysis,
rather than glycolysis followed by oxidative phosphorylation, to generate ATP and other metabolites
needed for cell division. This aberrant tumor physiology is exhibited by cervical tumors that metabolize
18
glucose through aerobic glycolysis, i.e., the “Warburg effect”, and this can be imaged by F-fluoro-deoxy-
glucose positron emission tomography (FDG-PET). Our group has shown that human cervical tumors with
increased FDG uptake on pre-treatment FDG-PET imaging have inferior survival outcomes after standard-
of-care chemoradiation (pelvic irradiation with the concurrent administration of cisplatin chemotherapy).
This suggests that cisplatin alone is insufficient as a radio-sensitizer for patients with metabolically active
tumors. We have shown that human tumors with residual or abnormal FDG uptake on post-therapy FDG-
PET imaging have alterations in expression of genes and proteins from the PI3K/AKT pathway. Our results
demonstrate that phospho-AKT (pAKT) is a biomarker that is associated with decreased patient
progression-free survival outcomes after definitive chemoradiation. Most recently, we have shown that
increased pAKT, which indicates AKT enzymatic activation, induces mTOR to promote and to sustain
increased glucose uptake and glycolysis in cervical tumor cell lines. When cervical cancer cells are treated
with PI3K/AKT inhibitors, we observe decreased aerobic glycolysis and increased activity of the pentose
phosphate shunt, suggesting that PI3K/AKT activation may serve as a metabolic switch in cervical cancer.
Activating PIK3CA mutations have been identified in patients with cervical cancer, and these patients have
78 | P a g e
