Page 116 - 2014 Printable Abstract Book
P. 116
replication and pontentiation of TLR. The interaction of BCA2 and Rad18 increased upon UVC irradiation
whereas BCA2 knockdown revoked UVC-induced Rad18 up-regulation, leading to reduction of BCA2-
Rad18 interaction. These results unravel a new look of BCA2 in guarding cells from UV-induced DNA
damage and lethality. Acknowledgements: Supports from the Mitchell Cancer Institute and Alabama
State Research Grant.
(PS1-24) Inhibiting base excision repair (BER) sensitizes pancreatic cancer cells to the radiosensitizer ß-
1
1
1
1
1
lapachone. Gaurab Chakrabarti ; Xiuquan Luo, PhD ; Zachary Moore ; Xiumei Huang ; Evan Stevens ;
1
2
Stanton Gerson, PhD ; and David A. Boothman, PhD, University of Texas Southwestern Medical Center,
2
Dallas, TX and Case Western University, Cleavland, OH
1
Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020,
where 5-year survival is <6%. Therapeutic response for this disease is highly variable and there is a
desperate need for agents to specifically and efficaciously treat pancreatic cancer patients. We recently
discovered that not only were NAD(P)H:quinone oxidoreductase 1 (NQO1) levels elevated 5- to 40-fold in
nearly 90% of pancreatic tumors vs associated normal tissue, but that catalase levels were inversely
expressed comparatively; i.e., catalase was elevated in normal vs tumor tissue. NQO1 bioactivatable
drugs, such as the potent radiosensitizer β-lapachone (ß-lap), generate hydrogen peroxide (H2O2) as a
mechanism to induce oxidative DNA damage that leads to PARP1 hyperactivation, which rapidly depletes
NAD+/ATP pools, thereby selectively killing tumors via programmed necrosis. Given that PARP1 can bind
apurinic/apyrimidinic (AP) sites, we hypothesize that modulating base excision repair (BER) with the small
molecule AP site-modifying drug, methoxyamine (MeOX), or by genetically altering key BER factors, in
combination with β-lap will lead to synergistic killing of NQO1+ pancreatic or nonsmall cell lung cancer
cells (NSCLC). We have found that the tumor specificity and efficacy of BER inhibition using MeOX can be
greatly increased when used in combination with ß-lap. Similar results were noted in XRCC1 knockdown
cells, supporting an essential role for BER in ß-lap induced lethality. In contrast, knocking down human
OGG1 glycosylase levels dramatically spared the lethality of ß-lap treated NSCLC or PDAC cells. Thus,
preventing BER sensing pathways, and subsequent AP site formation, dramatically suppresses lethality of
ß-lap. Combination treatment resulted in increased DNA lesion formation, dramatic losses in NAD+/ATP
levels, with little recovery and a dramatic suppression of glycolysis. Mechanistically, our data suggest that
PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell killing
with ß-lap. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (ß-lap as Arq761,
Arqule), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing
cancers are being rapidly developed. NIH/NCI grant CA102972.
(PS1-25) Fractionated low doses of High LET ions and protons induce altered DNA repair, increased
1
neuro-inflammation, altered synaptic activity and cognitive deficits. Michael Peluso ; Mulampurath A.
1
Sureshkumar ; Jasbeer Dhawan ; Lynn Hlatky ; Mamta D. Naidu, Center of Cancer Systems Biology, GRI,
1
3
2
2
1
at Tufts School of Med, Boston, MA ; Center for Radiological Research, New York, NY ; and Stony Brook
University, Stony Brook, NY
3
NASA’s program emphasizes understanding the mechanisms of radiation-induced DNA damage.
As radiation research on the central nervous system (CNS) has predominantly focused on neurons, with
114 | P a g e
whereas BCA2 knockdown revoked UVC-induced Rad18 up-regulation, leading to reduction of BCA2-
Rad18 interaction. These results unravel a new look of BCA2 in guarding cells from UV-induced DNA
damage and lethality. Acknowledgements: Supports from the Mitchell Cancer Institute and Alabama
State Research Grant.
(PS1-24) Inhibiting base excision repair (BER) sensitizes pancreatic cancer cells to the radiosensitizer ß-
1
1
1
1
1
lapachone. Gaurab Chakrabarti ; Xiuquan Luo, PhD ; Zachary Moore ; Xiumei Huang ; Evan Stevens ;
1
2
Stanton Gerson, PhD ; and David A. Boothman, PhD, University of Texas Southwestern Medical Center,
2
Dallas, TX and Case Western University, Cleavland, OH
1
Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020,
where 5-year survival is <6%. Therapeutic response for this disease is highly variable and there is a
desperate need for agents to specifically and efficaciously treat pancreatic cancer patients. We recently
discovered that not only were NAD(P)H:quinone oxidoreductase 1 (NQO1) levels elevated 5- to 40-fold in
nearly 90% of pancreatic tumors vs associated normal tissue, but that catalase levels were inversely
expressed comparatively; i.e., catalase was elevated in normal vs tumor tissue. NQO1 bioactivatable
drugs, such as the potent radiosensitizer β-lapachone (ß-lap), generate hydrogen peroxide (H2O2) as a
mechanism to induce oxidative DNA damage that leads to PARP1 hyperactivation, which rapidly depletes
NAD+/ATP pools, thereby selectively killing tumors via programmed necrosis. Given that PARP1 can bind
apurinic/apyrimidinic (AP) sites, we hypothesize that modulating base excision repair (BER) with the small
molecule AP site-modifying drug, methoxyamine (MeOX), or by genetically altering key BER factors, in
combination with β-lap will lead to synergistic killing of NQO1+ pancreatic or nonsmall cell lung cancer
cells (NSCLC). We have found that the tumor specificity and efficacy of BER inhibition using MeOX can be
greatly increased when used in combination with ß-lap. Similar results were noted in XRCC1 knockdown
cells, supporting an essential role for BER in ß-lap induced lethality. In contrast, knocking down human
OGG1 glycosylase levels dramatically spared the lethality of ß-lap treated NSCLC or PDAC cells. Thus,
preventing BER sensing pathways, and subsequent AP site formation, dramatically suppresses lethality of
ß-lap. Combination treatment resulted in increased DNA lesion formation, dramatic losses in NAD+/ATP
levels, with little recovery and a dramatic suppression of glycolysis. Mechanistically, our data suggest that
PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell killing
with ß-lap. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (ß-lap as Arq761,
Arqule), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing
cancers are being rapidly developed. NIH/NCI grant CA102972.
(PS1-25) Fractionated low doses of High LET ions and protons induce altered DNA repair, increased
1
neuro-inflammation, altered synaptic activity and cognitive deficits. Michael Peluso ; Mulampurath A.
1
Sureshkumar ; Jasbeer Dhawan ; Lynn Hlatky ; Mamta D. Naidu, Center of Cancer Systems Biology, GRI,
1
3
2
2
1
at Tufts School of Med, Boston, MA ; Center for Radiological Research, New York, NY ; and Stony Brook
University, Stony Brook, NY
3
NASA’s program emphasizes understanding the mechanisms of radiation-induced DNA damage.
As radiation research on the central nervous system (CNS) has predominantly focused on neurons, with
114 | P a g e
