Page 79 - 2014 Printable Abstract Book
P. 79
only protect from immediate damaging effects from cell death but also the downstream longer term
squeal which can be debilitating, as well as the potential increased risk of subsequent radiotherapy
induced cancers. Such protection could also reduce the dose-limiting effect of radiotherapy, with the
potential for greater cure rates. Protection of normal tissue could also be particularly helpful for patients
with increased radio-sensitivity. We are using in vivo mouse prostate cancer models to perform pre-
clinical studies with design input from treating physicians with the aim that our pre-clinical studies could
be rapidly translated into the clinic. These studies are aimed at determining the optimal doses, dose-rates,
amount of tissue exposure and timing of administration of low doses for normal tissue protection while
ensuring that the efficacy of tumor radiotherapy is not compromised.
(S2004) Survivin-mediated response in radiotherapy. David J. Grdina, University of Chicago, Chicago, IL
Exposure of cells to a very low dose of ionizing radiation can induce an enhanced resistance or adaptive
response to a subsequent larger radiation dose as evidenced by an increase in cell survival. This expression
of an adaptive response has been attributed to the result of signaling processes induced by very low
radiation doses in the range of 0.5 to 100 mGy. The radiation-induced adaptive response is garnering
considerable attention now due in part to the burgeoning increase in the use of imaging technologies such
as computerized axial tomography (CAT) and portal imaging to monitor tumor response and positioning
during multi-dose standard radiation therapy protocols. An adaptive response can be induced in tumor
cells under these conditions by very low radiation doses typically resulting from CAT and other diagnostic
imaging methods in the range from 5 to 100 mGy when administered 15 min or more before each
therapeutic dose of 2 Gy. The adaptive response measured under this circumstance is associated with a
reduction in apoptosis frequencies, a 5 to 20% increase in cell survival, and a rapid 2 to 3 fold elevation in
survivin but not SOD2 protein levels. Very low dose radiation-induced elevation in survivin levels is
completely inhibited by transfection of cells with survivin siRNA. This was accompanied by an increase in
apoptosis and a loss of the expression of these survival related adaptive responses. Transfection with
SOD2 siRNA, in contrast, has no effect on the development and expression of this particular adaptive
response. A novel very low radiation dose-induced survivin-mediated adaptive response has been
identified that may adversely affect therapeutic outcomes associated with increased usage of imaging
procedures in radiation therapy. Experiments leading to the discovery of this adaptive response and its
clinical implications will be discussed. This work was supported by NIH/NCI grant R01 CA132998 and DOE
Low Dose Program/Project Grant DE-SC0001271.
S21 NOVEL APPROACHES TO RADIOSENSITIZATION
This session will provide an overview of new molecular targets for the development of radiation sensitizing
drugs. The first presentation will provide an overview of the use of kinomics to identify molecular targets
for radiosensitization. This work has identified signaling through PI3K and identified novel molecular
targets for drug development. The signal transduction pathway and efficacy of novel radiosensitizing
drugs will be discussed. The second session will describe genome sequencing of lung cancer to identify
novel molecular targets. Immune checkpoint blockade through antibodies to PD1 and CTLA4 can enhance
efficacy in lung cancer. A combined approach of immunotherapy together with radiotherapy enhances
efficacy in preclinical models. The third session investigates metabolomics in irradiated cervix cancer. This
77 | P a g e
squeal which can be debilitating, as well as the potential increased risk of subsequent radiotherapy
induced cancers. Such protection could also reduce the dose-limiting effect of radiotherapy, with the
potential for greater cure rates. Protection of normal tissue could also be particularly helpful for patients
with increased radio-sensitivity. We are using in vivo mouse prostate cancer models to perform pre-
clinical studies with design input from treating physicians with the aim that our pre-clinical studies could
be rapidly translated into the clinic. These studies are aimed at determining the optimal doses, dose-rates,
amount of tissue exposure and timing of administration of low doses for normal tissue protection while
ensuring that the efficacy of tumor radiotherapy is not compromised.
(S2004) Survivin-mediated response in radiotherapy. David J. Grdina, University of Chicago, Chicago, IL
Exposure of cells to a very low dose of ionizing radiation can induce an enhanced resistance or adaptive
response to a subsequent larger radiation dose as evidenced by an increase in cell survival. This expression
of an adaptive response has been attributed to the result of signaling processes induced by very low
radiation doses in the range of 0.5 to 100 mGy. The radiation-induced adaptive response is garnering
considerable attention now due in part to the burgeoning increase in the use of imaging technologies such
as computerized axial tomography (CAT) and portal imaging to monitor tumor response and positioning
during multi-dose standard radiation therapy protocols. An adaptive response can be induced in tumor
cells under these conditions by very low radiation doses typically resulting from CAT and other diagnostic
imaging methods in the range from 5 to 100 mGy when administered 15 min or more before each
therapeutic dose of 2 Gy. The adaptive response measured under this circumstance is associated with a
reduction in apoptosis frequencies, a 5 to 20% increase in cell survival, and a rapid 2 to 3 fold elevation in
survivin but not SOD2 protein levels. Very low dose radiation-induced elevation in survivin levels is
completely inhibited by transfection of cells with survivin siRNA. This was accompanied by an increase in
apoptosis and a loss of the expression of these survival related adaptive responses. Transfection with
SOD2 siRNA, in contrast, has no effect on the development and expression of this particular adaptive
response. A novel very low radiation dose-induced survivin-mediated adaptive response has been
identified that may adversely affect therapeutic outcomes associated with increased usage of imaging
procedures in radiation therapy. Experiments leading to the discovery of this adaptive response and its
clinical implications will be discussed. This work was supported by NIH/NCI grant R01 CA132998 and DOE
Low Dose Program/Project Grant DE-SC0001271.
S21 NOVEL APPROACHES TO RADIOSENSITIZATION
This session will provide an overview of new molecular targets for the development of radiation sensitizing
drugs. The first presentation will provide an overview of the use of kinomics to identify molecular targets
for radiosensitization. This work has identified signaling through PI3K and identified novel molecular
targets for drug development. The signal transduction pathway and efficacy of novel radiosensitizing
drugs will be discussed. The second session will describe genome sequencing of lung cancer to identify
novel molecular targets. Immune checkpoint blockade through antibodies to PD1 and CTLA4 can enhance
efficacy in lung cancer. A combined approach of immunotherapy together with radiotherapy enhances
efficacy in preclinical models. The third session investigates metabolomics in irradiated cervix cancer. This
77 | P a g e
