Page 257 - 2014 Printable Abstract Book
P. 257
combination RT and MK-2206 in an orthotopic mouse model of high-grade NB is currently under way.
(PS4-36) Gold nanoparticle-bound TNF markedly enhances radiation therapy in an in-vivo breast cancer
model. Nathan A. Koonce; Charles M. Quick; Judy Dent; Azemat Jamshidi-Parsian; Matthew E. Hardee;
and Robert J. Griffin, University of Arkansas for Medical Sciences, Little Rock, AR
Purpose: Previously, systemic toxicity associated with TNF-α-based therapeutic approaches reduced its
clinical utility, giving rise to the need for a selective mechanism of tumor delivery. CYT-6091 is a 33-nm
polyethylene glycol- TNF-α coated gold nanoparticle which has undergone Phase I trials successfully
(Cytimmune, Inc). Due to extensive publications on the synergistic anti-tumor effect noted when TNF is
combined with radiotherapy, we investigated CYT-6091 combined with radiotherapy in a preclinical tumor
model. Experimental design: In vivo effect on tumor growth was studied in a subcutaneous mouse
mammary carcinoma model, 4T1. Interstitial fluid pressure was measured after therapy. Tumor tissue was
harvest for histological analysis at various time points. Results: We found a >2-fold tumor growth delay
when CYT-6091 was combined with a single dose of 20Gy irradiation. Interestingly, treatment sequence
did not change the efficacy of CYT-6091 in potentiating radiation response, suggesting vascular
destabilization induced by TNF-α can potently affect radiotherapy regardless of sequence. In a
translational hypofractionated dose schedule (12Gy*3), irradiation delayed tumor growth to reach 4-fold
the starting volume by 2-fold (10 day v. 21 day); while the combined treatment group failed to reach 2-
fold the starting volume by day 21 of observation. We observed a significant reduction in tumor interstitial
pressure (p<0.05) 24h after systemic treatment with CYT-6091 or combined 12Gy and CYT-6091. Marked
vascular damage was noted histologically with release of red blood cells into tumor interstitium 24h-post
CYT-6091 alone and post-combined therapy. Additionally, tumor cell density was significantly reduced
(p<0.05) in the combined therapy compared to control and CYT-6091 at day 7 post therapy. Conclusions:
Overall, this multi-modality approach may provide a method to shrink large bulky tumors to a size
amenable for resection and also control inoperable malignancies.
1
1
(PS4-37) Latexin inactivation mitigates radiotherapy-induced myelosuppression. Yanan You ; Yi Liu ;
1
1
1
2
Daohong Zhou ; Gary Van Zant ; Ying Liang, University of Kentucky, Lexington, KY and University of
Arkansas for Medical Sciences, Little Rock, AR
2
Many cancer patients receiving chemotherapy and/or ionizing radiation (IR) develop infection and
hemorrhage that limits the success of cancer treatment and increases the morbidity and mortality. These
side effects are attributed to loss of leukocytes (leukopenia) and platelets (thrombocytopenia), ultimately
resulting from damage of bone marrow hematopoietic stem and progenitor cells (HSCs and HPCs). HPC
damage has been managed in clinic by the use of various hematopoietic growth factors. However, toxicity
to HSCs, a population producing all HPCs and mature blood cells, and its long-term adverse effect have
not been clearly defined, and no effective treatment has been developed to ameliorate HSC toxicity. We
previously identified latexin (Lxn) as a negative regulator of HSC number. To further delineate the specific
role of Lxn in hematopoiesis, we generated mice in which Lxn gene is constitutively deleted in the whole
body (Lxn-/-), and found that loss of Lxn in vivo significantly increases the number of all stages of
hematopoietic cells. Of particular note, the expanded HSCs in Lxn knockout mice maintain the capacity
for self-renewal and multilineage differentiation. In addition, deletion of Lxn protects bone marrow HSCs
255 | P a g e
(PS4-36) Gold nanoparticle-bound TNF markedly enhances radiation therapy in an in-vivo breast cancer
model. Nathan A. Koonce; Charles M. Quick; Judy Dent; Azemat Jamshidi-Parsian; Matthew E. Hardee;
and Robert J. Griffin, University of Arkansas for Medical Sciences, Little Rock, AR
Purpose: Previously, systemic toxicity associated with TNF-α-based therapeutic approaches reduced its
clinical utility, giving rise to the need for a selective mechanism of tumor delivery. CYT-6091 is a 33-nm
polyethylene glycol- TNF-α coated gold nanoparticle which has undergone Phase I trials successfully
(Cytimmune, Inc). Due to extensive publications on the synergistic anti-tumor effect noted when TNF is
combined with radiotherapy, we investigated CYT-6091 combined with radiotherapy in a preclinical tumor
model. Experimental design: In vivo effect on tumor growth was studied in a subcutaneous mouse
mammary carcinoma model, 4T1. Interstitial fluid pressure was measured after therapy. Tumor tissue was
harvest for histological analysis at various time points. Results: We found a >2-fold tumor growth delay
when CYT-6091 was combined with a single dose of 20Gy irradiation. Interestingly, treatment sequence
did not change the efficacy of CYT-6091 in potentiating radiation response, suggesting vascular
destabilization induced by TNF-α can potently affect radiotherapy regardless of sequence. In a
translational hypofractionated dose schedule (12Gy*3), irradiation delayed tumor growth to reach 4-fold
the starting volume by 2-fold (10 day v. 21 day); while the combined treatment group failed to reach 2-
fold the starting volume by day 21 of observation. We observed a significant reduction in tumor interstitial
pressure (p<0.05) 24h after systemic treatment with CYT-6091 or combined 12Gy and CYT-6091. Marked
vascular damage was noted histologically with release of red blood cells into tumor interstitium 24h-post
CYT-6091 alone and post-combined therapy. Additionally, tumor cell density was significantly reduced
(p<0.05) in the combined therapy compared to control and CYT-6091 at day 7 post therapy. Conclusions:
Overall, this multi-modality approach may provide a method to shrink large bulky tumors to a size
amenable for resection and also control inoperable malignancies.
1
1
(PS4-37) Latexin inactivation mitigates radiotherapy-induced myelosuppression. Yanan You ; Yi Liu ;
1
1
1
2
Daohong Zhou ; Gary Van Zant ; Ying Liang, University of Kentucky, Lexington, KY and University of
Arkansas for Medical Sciences, Little Rock, AR
2
Many cancer patients receiving chemotherapy and/or ionizing radiation (IR) develop infection and
hemorrhage that limits the success of cancer treatment and increases the morbidity and mortality. These
side effects are attributed to loss of leukocytes (leukopenia) and platelets (thrombocytopenia), ultimately
resulting from damage of bone marrow hematopoietic stem and progenitor cells (HSCs and HPCs). HPC
damage has been managed in clinic by the use of various hematopoietic growth factors. However, toxicity
to HSCs, a population producing all HPCs and mature blood cells, and its long-term adverse effect have
not been clearly defined, and no effective treatment has been developed to ameliorate HSC toxicity. We
previously identified latexin (Lxn) as a negative regulator of HSC number. To further delineate the specific
role of Lxn in hematopoiesis, we generated mice in which Lxn gene is constitutively deleted in the whole
body (Lxn-/-), and found that loss of Lxn in vivo significantly increases the number of all stages of
hematopoietic cells. Of particular note, the expanded HSCs in Lxn knockout mice maintain the capacity
for self-renewal and multilineage differentiation. In addition, deletion of Lxn protects bone marrow HSCs
255 | P a g e
