Page 251 - 2014 Printable Abstract Book
P. 251
delivery approaches, long-term follow-up studies and the insight on the mechanistic flow-through are
warranted and are currently underway in our laboratory.
(PS4-27) In vitro evaluation of histone deacetylase (HDAC) inhibitors as radiosensitizers for charged
particle radiotherapy. Paula Bennett; Alicia Johnson; Katherine Sanidad; Lucia Kolodiuk; James Jardine;
Deborah Keszenman; Paul F. Wilson, Brookhaven National Laboratory, Upton, NY
The broad goal of this project is to assess impacts of epigenetic modifications on in vitro cellular
responses to photon and charged particle irradiation in terms of DNA repair capacity and cellular
radiosensitivity and their potential translation to higher risks of carcinogenesis and other IR-associated
disease endpoints. We have previously shown that inter-individual genetic variation in DNA damage
response (DDR) pathway capacities, e.g., post-translational modifications (PTMs) of DDR chromatin
proteins, directly impacts cellular radiosensitivity of primary cells derived from the general population,
particularly after low dose and low dose rate exposures. We investigated whether clinical histone
deacetylase (HDAC) inhibitors SAHA (vorinostat), M344 and PTACH impact DNA damage induction /
processing, cell killing, and cell transformation (acquisition of anchorage-independent growth in soft agar)
following gamma ray and light ion irradiation in human normal and tumor cell lines. Treatment of NFF28
normal fibroblast, U2OS osteosarcoma, A549 lung carcinoma, and U87-MG glioma cells with 5-10 µM
HDAC inhibitor concentrations 18 h prior to cesium-137 gamma ray irradiation results in significantly
delayed/impaired clustered DNA damage and double-strand break (DSB) repair processing and ≥2-fold
radiosensitization by clonogenic survival assays. To test the utility of adjuvant HDAC inhibitors as
radiosensitizers to increase therapeutic gain during hadron radiotherapy, we irradiated cells with 200 MeV
proton, 290 MeV/n carbon and 350 MeV/n oxygen ions at the NASA Space Radiation Laboratory (NSRL)
to assess the same cellular endpoints. Unlike uniform gamma ray radiosensitization, effects of the HDAC
inhibitors were unexpectedly cell type and ion species-dependent, with the carbon and oxygen ion
irradiations showing significantly enhanced fibroblast cell survival and transformation. The results of these
in vitro studies cast initial doubt on the efficacy of this radiosensitization strategy for hadron radiotherapy,
and we will be seeking confirmation of these results in an immunodeficient tumor xenograft model. This
work was performed under the auspices of the U.S. Department of Energy by Brookhaven National
Laboratory under contract DE-AC02-98CH10886 and supported by BNL LDRD grant 12-012.
(PS4-28) Hedgehog inhibitor LDE225 increases efficacy of 177Lu-octreotate therapy on GOT1 tumors in
2
3
2
1
1
4
nude mice. Johan Spetz ; Britta Langen ; Toshima Z. Parris ; Bo Wängberg ; Ola Nilsson ; Khalil Helou ;
1
and Eva Forssell-Aronsson, Department of Radiation Physics, Sahlgrenska Cancer Center, Gothenburg,
1
2
Sweden ; Department of Oncology, Sahlgrenska Cancer Center, Gothenburg, Sweden ; Department of
Surgery, Sahlgrenska Cancer Center, Gothenburg, Sweden ; and Department of Pathology, Sahlgrenska
3
4
Cancer Center, Gothenburg, Sweden
Background: 177Lu-octreotate is commonly used for treatment of somatostatin receptor (SSTR)
expressing neuroendocrine (NE) tumors. Although it is a highly successful treatment in animal models (e.g.
the human midgut carcinoid cell line GOT1 transplanted to nude mice), clinical studies have still only
demonstrated low cure rates. In order to optimize treatment, combination therapy has been proposed
and some studies have shown synergistic effects (radiosensitizing). Hedgehog inhibitors have previously
249 | P a g e
warranted and are currently underway in our laboratory.
(PS4-27) In vitro evaluation of histone deacetylase (HDAC) inhibitors as radiosensitizers for charged
particle radiotherapy. Paula Bennett; Alicia Johnson; Katherine Sanidad; Lucia Kolodiuk; James Jardine;
Deborah Keszenman; Paul F. Wilson, Brookhaven National Laboratory, Upton, NY
The broad goal of this project is to assess impacts of epigenetic modifications on in vitro cellular
responses to photon and charged particle irradiation in terms of DNA repair capacity and cellular
radiosensitivity and their potential translation to higher risks of carcinogenesis and other IR-associated
disease endpoints. We have previously shown that inter-individual genetic variation in DNA damage
response (DDR) pathway capacities, e.g., post-translational modifications (PTMs) of DDR chromatin
proteins, directly impacts cellular radiosensitivity of primary cells derived from the general population,
particularly after low dose and low dose rate exposures. We investigated whether clinical histone
deacetylase (HDAC) inhibitors SAHA (vorinostat), M344 and PTACH impact DNA damage induction /
processing, cell killing, and cell transformation (acquisition of anchorage-independent growth in soft agar)
following gamma ray and light ion irradiation in human normal and tumor cell lines. Treatment of NFF28
normal fibroblast, U2OS osteosarcoma, A549 lung carcinoma, and U87-MG glioma cells with 5-10 µM
HDAC inhibitor concentrations 18 h prior to cesium-137 gamma ray irradiation results in significantly
delayed/impaired clustered DNA damage and double-strand break (DSB) repair processing and ≥2-fold
radiosensitization by clonogenic survival assays. To test the utility of adjuvant HDAC inhibitors as
radiosensitizers to increase therapeutic gain during hadron radiotherapy, we irradiated cells with 200 MeV
proton, 290 MeV/n carbon and 350 MeV/n oxygen ions at the NASA Space Radiation Laboratory (NSRL)
to assess the same cellular endpoints. Unlike uniform gamma ray radiosensitization, effects of the HDAC
inhibitors were unexpectedly cell type and ion species-dependent, with the carbon and oxygen ion
irradiations showing significantly enhanced fibroblast cell survival and transformation. The results of these
in vitro studies cast initial doubt on the efficacy of this radiosensitization strategy for hadron radiotherapy,
and we will be seeking confirmation of these results in an immunodeficient tumor xenograft model. This
work was performed under the auspices of the U.S. Department of Energy by Brookhaven National
Laboratory under contract DE-AC02-98CH10886 and supported by BNL LDRD grant 12-012.
(PS4-28) Hedgehog inhibitor LDE225 increases efficacy of 177Lu-octreotate therapy on GOT1 tumors in
2
3
2
1
1
4
nude mice. Johan Spetz ; Britta Langen ; Toshima Z. Parris ; Bo Wängberg ; Ola Nilsson ; Khalil Helou ;
1
and Eva Forssell-Aronsson, Department of Radiation Physics, Sahlgrenska Cancer Center, Gothenburg,
1
2
Sweden ; Department of Oncology, Sahlgrenska Cancer Center, Gothenburg, Sweden ; Department of
Surgery, Sahlgrenska Cancer Center, Gothenburg, Sweden ; and Department of Pathology, Sahlgrenska
3
4
Cancer Center, Gothenburg, Sweden
Background: 177Lu-octreotate is commonly used for treatment of somatostatin receptor (SSTR)
expressing neuroendocrine (NE) tumors. Although it is a highly successful treatment in animal models (e.g.
the human midgut carcinoid cell line GOT1 transplanted to nude mice), clinical studies have still only
demonstrated low cure rates. In order to optimize treatment, combination therapy has been proposed
and some studies have shown synergistic effects (radiosensitizing). Hedgehog inhibitors have previously
249 | P a g e
