Page 186 - 2014 Printable Abstract Book
P. 186
mg/kg/day did not significantly impact survival or improve pulmonary dysfunction following WTLI.
Conclusions: Treatment with AEOL 10150 significantly improves survival and lung function when given at
a dose of 25 mg/kg/day for a total of 28 days starting 24 hours post WTLI in CBA/J mice. Future studies
will determine the optimal duration and therapeutic window for drug delivery.
(PS2-85) Potential radioprotective and anti-tumor effects of an SOD mimetic, GC4419, in a stereotactic
ablative radiotherapy mouse model. David A. Bloom, MD, PhD; Deepti Ramnarain, PhD; Taek-Keun Nam,
MD; Debabrata Saha, PhD; and Michael D. Story, PhD, UT Southwestern, Dallas, TX
Stereotactic Ablative Body Radiotherapy (SABR) has revolutionized the management of early
stage non-small cell lung cancer (NSCLC). However, it has been associated with increased toxicity in
centrally located lesions, necessitating the use of lower dose per fraction regimens. Compounds with the
ability to prevent or decrease fibrosis may allow for more efficacious treatment of centrally located early
stage NSCLCs. GC4419, (Galera Therapeutics, St. Louis, MO) is a novel small molecule superoxide
dismutase (SOD) mimetic that can prevent radiation-induced oral mucositis in hamsters and which is in
Phase I clinical trials for mucocitis in head and neck cancer. Our early preliminary data also suggested
protection as well as mitigation from radiation-induced lung fibrosis. We are now following up with more
extensive studies of lung fibrosis. A focal area (3.5 mm) of the left lung of sixty C57B6 mice was irradiated
with 60, 70 or 80 Gy in a single fraction using image guidance. The mice were injected with GC4419 or
vehicle control 30 minutes prior to radiation. The ability of GC4419 to prevent or reduce radiation induced
pulmonary fibrosis at 12 weeks after irradiation will be quantified using the Ashcroft Score as well as by
image analysis of picrosirius red staining. Other endpoints such as macrophage invasion, 8-oxo-dG, a5B6
integrin levels, TGFB staining and other markers of oxidative stress will be quantified. In addition to the
radioprotective effects of GC4419, we have now shown modification of the radioresponse of a number of
NSCLC lung cancer cell lines. In addition, GC4419 appears to enhance the cytotoxicity of cisplatin, and
radiation in combination with cisplatin. The anti-tumor effect of GC4419 is now undergoing analysis in
subcutaneous tumors generated from H1299 cells injected into the flank of immune-compromised mice.
Tumor growth delay after radiation (18 Gy), cisplatin and the combination will be determined with and
without GC4419.
(PS2-86) Combination therapy with Bolder Biotechnology (BBT) pegylated (peg) hematopoietic growth
factors (HGF) peg-G-CSF, peg-GM-CSF, and peg-IL-11 increases 30 day survival compared to single peg-
1
HGF in a mouse model of the hematopoietic acute radiation syndrome (H-ARS). Sasidhar Vemula, Ph.D ;
1
1
1
1
1
Artur Plett, PhD ; Hui Lin Chua, PhD ; Rajendran Sellamuthu, PhD ; Alexa Fett, BS ; Carol Sampson, M.S. ;
1
1
2
2
Hailin Feng, M.S. ; Nathan Garrison, A.S. ; Christine M. Fam, BS ; George N. Cox, PhD ; and Christie M.
1
Orschell, Ph.D, Indiana University School of Medicine, Indianapolis, IN and Bolder Biotechnology, Inc,
1
2
Boulder, CO
We recently reported significantly increased 30d survival in mice treated 24hr post-total body
irradiation (TBI) with a single dose of any of three pegylated hematopoietic growth factors (peg-HGF) from
Bolder Biotechnology [huG-CSF BBT-015 (peg-G), muGM-CSF BBT-007 (peg-GM), and huIL-11 BBT-059
(peg-IL11), Health Phys. 106:7, 2014]. The current study aimed to determine if combinations of these peg-
HGF further enhances survival at higher doses of radiation compared to single peg HGF. To this end, 12w/o
184 | P a g e
Conclusions: Treatment with AEOL 10150 significantly improves survival and lung function when given at
a dose of 25 mg/kg/day for a total of 28 days starting 24 hours post WTLI in CBA/J mice. Future studies
will determine the optimal duration and therapeutic window for drug delivery.
(PS2-85) Potential radioprotective and anti-tumor effects of an SOD mimetic, GC4419, in a stereotactic
ablative radiotherapy mouse model. David A. Bloom, MD, PhD; Deepti Ramnarain, PhD; Taek-Keun Nam,
MD; Debabrata Saha, PhD; and Michael D. Story, PhD, UT Southwestern, Dallas, TX
Stereotactic Ablative Body Radiotherapy (SABR) has revolutionized the management of early
stage non-small cell lung cancer (NSCLC). However, it has been associated with increased toxicity in
centrally located lesions, necessitating the use of lower dose per fraction regimens. Compounds with the
ability to prevent or decrease fibrosis may allow for more efficacious treatment of centrally located early
stage NSCLCs. GC4419, (Galera Therapeutics, St. Louis, MO) is a novel small molecule superoxide
dismutase (SOD) mimetic that can prevent radiation-induced oral mucositis in hamsters and which is in
Phase I clinical trials for mucocitis in head and neck cancer. Our early preliminary data also suggested
protection as well as mitigation from radiation-induced lung fibrosis. We are now following up with more
extensive studies of lung fibrosis. A focal area (3.5 mm) of the left lung of sixty C57B6 mice was irradiated
with 60, 70 or 80 Gy in a single fraction using image guidance. The mice were injected with GC4419 or
vehicle control 30 minutes prior to radiation. The ability of GC4419 to prevent or reduce radiation induced
pulmonary fibrosis at 12 weeks after irradiation will be quantified using the Ashcroft Score as well as by
image analysis of picrosirius red staining. Other endpoints such as macrophage invasion, 8-oxo-dG, a5B6
integrin levels, TGFB staining and other markers of oxidative stress will be quantified. In addition to the
radioprotective effects of GC4419, we have now shown modification of the radioresponse of a number of
NSCLC lung cancer cell lines. In addition, GC4419 appears to enhance the cytotoxicity of cisplatin, and
radiation in combination with cisplatin. The anti-tumor effect of GC4419 is now undergoing analysis in
subcutaneous tumors generated from H1299 cells injected into the flank of immune-compromised mice.
Tumor growth delay after radiation (18 Gy), cisplatin and the combination will be determined with and
without GC4419.
(PS2-86) Combination therapy with Bolder Biotechnology (BBT) pegylated (peg) hematopoietic growth
factors (HGF) peg-G-CSF, peg-GM-CSF, and peg-IL-11 increases 30 day survival compared to single peg-
1
HGF in a mouse model of the hematopoietic acute radiation syndrome (H-ARS). Sasidhar Vemula, Ph.D ;
1
1
1
1
1
Artur Plett, PhD ; Hui Lin Chua, PhD ; Rajendran Sellamuthu, PhD ; Alexa Fett, BS ; Carol Sampson, M.S. ;
1
1
2
2
Hailin Feng, M.S. ; Nathan Garrison, A.S. ; Christine M. Fam, BS ; George N. Cox, PhD ; and Christie M.
1
Orschell, Ph.D, Indiana University School of Medicine, Indianapolis, IN and Bolder Biotechnology, Inc,
1
2
Boulder, CO
We recently reported significantly increased 30d survival in mice treated 24hr post-total body
irradiation (TBI) with a single dose of any of three pegylated hematopoietic growth factors (peg-HGF) from
Bolder Biotechnology [huG-CSF BBT-015 (peg-G), muGM-CSF BBT-007 (peg-GM), and huIL-11 BBT-059
(peg-IL11), Health Phys. 106:7, 2014]. The current study aimed to determine if combinations of these peg-
HGF further enhances survival at higher doses of radiation compared to single peg HGF. To this end, 12w/o
184 | P a g e
