Page 81 - 2014 Printable Abstract Book
P. 81
inferior survival outcomes and increased rates of distant metastasis after concurrent chemoradiation
therapy, suggesting a clinically relevant connection between alterations of PI3K/AKT signaling and tumor
radio-resistance. Taken together, these results suggest that inhibition of PI3K/AKT may reverse the
Warburg effect that is associated with the radio-resistant tumor phenotype in cervical cancer.
(S2103) Cancer therapy targeting autophagy. Bo Lu, PhD, Vanderbilt University, Nashville, TN
This presentation will review the changing landscape of lung cancer treatment. Genomic sequencing of
lung cancer is increasingly utilized in clinical practice to identify appropriate targeted therapeutics that
effectively inhibit the driver mutation of individual lung cancer. Genome-directed cancer therapy is
becoming the standard care for stage IV lung cancer and is being tested in clinical trials for managing
locally advanced lung cancer (RTOG1306). Another exciting development for lung cancer treatment came
from the promising results of using immunocheckpoint inhibitors (PD1/PDL1 inhibitors) in patients with
lung cancer. Activation of host immune defense against lung cancer can lead to long-term cure of lung
cancer of all genotypes. These agents may be effectively combined with local radiotherapy for triggering
therapeutic abscopal systemic effect/response. Laboratory investigations relating to these therapeutic
strategies will be discussed. Ultimately ongoing molecular advances will help to prolong the survival of
lung cancer patients.
(S2104) Lipid second messenger signaling in irradiated lung cancer and glioblastoma. Dennis E. Hallahan
and Dinesh Thotala, PhD, Washington University School of Medicine, St. Louis, MO
Poor prognosis cancers such as glioblastoma and non-small cell lung cancer are treated with radiotherapy
but continue to demonstrate resistance resulting in local progression of disease. Both of these poor
prognosis cancers have overexpression of an extracellular enzyme, autotaxin. This enzyme converts LPC
to LPA. LPA in turn binds to receptors in both cancer and endothelium to enhance cell viability. We studied
the efficacy of interruption of this signaling pathway during radiotherapy in mouse models of glioblastoma
and lung cancer. Phospholipase A2 activation by radiation results in the production of the lipid second
messenger LPC. LPC is then converted by autotaxin to form LPA. We studied levels of LPC and LPA and
found increased production following irradiation of these tumor models. LPA receptor activation leads to
signaling through cell viability pathway involving AKT. We found that inhibition of PLA2 reduces LPC
production and enhances efficacy in tumor models in mice. The Pfizer compound, Giripladiv, is a specific
inhibitor of PLA2 used to treat arthritis. This compound enhanced tumor control in irradiated mouse
models of glioblastoma and lung cancer. The specific inhibitor of autotaxin, PF-8380, attenuated
production of LPA. Moreover, LPA receptors were not activated in the presence of the inhibitor. This
attenuated signaling through AKT and enhanced cytotoxicity from ionizing radiation. The autotaxin
specific inhibitor PF-8380 was administered to mice during radiotherapy and enhanced tumor growth
delay. In conclusion, these molecular targets for the development of radiosensitization show preclinical
efficacy in compounds that have been tested in humans.
79 | P a g e
therapy, suggesting a clinically relevant connection between alterations of PI3K/AKT signaling and tumor
radio-resistance. Taken together, these results suggest that inhibition of PI3K/AKT may reverse the
Warburg effect that is associated with the radio-resistant tumor phenotype in cervical cancer.
(S2103) Cancer therapy targeting autophagy. Bo Lu, PhD, Vanderbilt University, Nashville, TN
This presentation will review the changing landscape of lung cancer treatment. Genomic sequencing of
lung cancer is increasingly utilized in clinical practice to identify appropriate targeted therapeutics that
effectively inhibit the driver mutation of individual lung cancer. Genome-directed cancer therapy is
becoming the standard care for stage IV lung cancer and is being tested in clinical trials for managing
locally advanced lung cancer (RTOG1306). Another exciting development for lung cancer treatment came
from the promising results of using immunocheckpoint inhibitors (PD1/PDL1 inhibitors) in patients with
lung cancer. Activation of host immune defense against lung cancer can lead to long-term cure of lung
cancer of all genotypes. These agents may be effectively combined with local radiotherapy for triggering
therapeutic abscopal systemic effect/response. Laboratory investigations relating to these therapeutic
strategies will be discussed. Ultimately ongoing molecular advances will help to prolong the survival of
lung cancer patients.
(S2104) Lipid second messenger signaling in irradiated lung cancer and glioblastoma. Dennis E. Hallahan
and Dinesh Thotala, PhD, Washington University School of Medicine, St. Louis, MO
Poor prognosis cancers such as glioblastoma and non-small cell lung cancer are treated with radiotherapy
but continue to demonstrate resistance resulting in local progression of disease. Both of these poor
prognosis cancers have overexpression of an extracellular enzyme, autotaxin. This enzyme converts LPC
to LPA. LPA in turn binds to receptors in both cancer and endothelium to enhance cell viability. We studied
the efficacy of interruption of this signaling pathway during radiotherapy in mouse models of glioblastoma
and lung cancer. Phospholipase A2 activation by radiation results in the production of the lipid second
messenger LPC. LPC is then converted by autotaxin to form LPA. We studied levels of LPC and LPA and
found increased production following irradiation of these tumor models. LPA receptor activation leads to
signaling through cell viability pathway involving AKT. We found that inhibition of PLA2 reduces LPC
production and enhances efficacy in tumor models in mice. The Pfizer compound, Giripladiv, is a specific
inhibitor of PLA2 used to treat arthritis. This compound enhanced tumor control in irradiated mouse
models of glioblastoma and lung cancer. The specific inhibitor of autotaxin, PF-8380, attenuated
production of LPA. Moreover, LPA receptors were not activated in the presence of the inhibitor. This
attenuated signaling through AKT and enhanced cytotoxicity from ionizing radiation. The autotaxin
specific inhibitor PF-8380 was administered to mice during radiotherapy and enhanced tumor growth
delay. In conclusion, these molecular targets for the development of radiosensitization show preclinical
efficacy in compounds that have been tested in humans.
79 | P a g e
