This translational research program made important discoveries during the current funding cycle. Melanoma cells growing at low pH rely primarily on the monocarboxylic acid transporter (MCT) rather than the NHE1 to regulate intracellular pH, do not demonstrate a Crabtree effect, and upregulate stress proteins HSP27 and 70 that are responsible for enhanced cytoskeletal stability and hyperthermia resistance. In the presence of excess glucose and an inhibitor of respiration melanoma xenografts are acutely acidified by 0.5-0.7 pH unit and pO2 increases. Normal tissues are not affected. It was found that heat activates a checkpoint inhibiting DNA replication through a trans-acting factor, nucleolin, a key component of the nucleolus that regulates the activity of replication protein A (RPA). Nucleolin translocates from the nucleolus to facilitate the interaction with RPA. These findings support the global hypothesis of this program that growth at low pH provides a mechanism unique to tumors by which melanoma can be selectively sensitized by chemical means to pH-dependent therapeutic agents such as hyperthermia. The long-range goal is to sensitize melanoma to thermoradiotherapy by acute acidification from lactic acidosis produced safely by hyperglycemia combined with inhibitors of respiration or lactate transport. Through four interactive projects and two cores this program will: Develop methods to sensitize melanoma xenografts to thermoradiotherapy in vivo (Project 1); Develop NMR techniques to provide non-invasive analysis of pH, 23Nai, glucose metabolism, blood flow and oxygen consumption during acute acidification of heated and unheated melanoma xenografts (Project 2, Subcontract: Univ. of Pennsylvania); Define the relationship between downregulation of heat shock protein synthesis by acute acidification, apoptotic killing during and after hyperthermia, and clonal survival (Project 3); and Elucidate the molecular mechanisms underlying checkpoint activation in cells exposed to heat and acute acidification as a strategy to abrogate heat-induced checkpoint response (Project 4, Subcontract: Univ. of Essen). The measurement of pHe and pHi in vitro and the identification of new methods to inhibit proton transport in melanoma cells grown at low pH will be performed in Core A to benefit all projects. Core B provides biostatistical, electronic communication and data management support for all projects. Results will help direct a Phase I/II clinical trial to demonstrate the effects of acute acidification on melanoma response to hyperthermic limb perfusion, and to identify clinically applicable measures of acidification and bioenergetics to predict response to hyperthermic therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA056690-10
Application #
6776975
Study Section
Subcommittee G - Education (NCI)
Program Officer
Stone, Helen B
Project Start
1993-04-23
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
10
Fiscal Year
2004
Total Cost
$1,281,745
Indirect Cost
Name
Thomas Jefferson University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Coss, Ronald Allen; Storck, Christopher W; Wells, Tiffany C et al. (2014) Thermal sensitisation by lonidamine of human melanoma cells grown at low extracellular pH. Int J Hyperthermia 30:75-8
Li, Lin Z; Zhou, Rong; Leeper, Dennis B et al. (2011) ³¹P-MRS studies of melanoma xenografts with different metastatic potential. Adv Exp Med Biol 701:69-73
Xu, He N; Zhou, Rong; Nioka, Shoko et al. (2009) Histological basis of MR/optical imaging of human melanoma mouse xenografts spanning a range of metastatic potentials. Adv Exp Med Biol 645:247-53
Li, Lin Z; Zhou, Rong; Xu, He N et al. (2009) Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential. Proc Natl Acad Sci U S A 106:6608-13
Sonveaux, Pierre; Vegran, Frederique; Schroeder, Thies et al. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930-42
Li, Lin Z J; Zhou, Rong; Zhong, Tuoxiu et al. (2007) Predicting melanoma metastatic potential by optical and magnetic resonance imaging. Adv Exp Med Biol 599:67-78
Chi, Sulene L; Wahl, Miriam L; Mowery, Yvonne M et al. (2007) Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase. Cancer Res 67:4716-24
Fang, Jun; Quinones, Quintin J; Holman, Trevor L et al. (2006) The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol 70:2108-15
Adams, David J; Wahl, Miriam L; Flowers, James L et al. (2006) Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient. Cancer Chemother Pharmacol 57:145-54
Coss, Ronald A (2005) Inhibiting induction of heat shock proteins as a strategy to enhance cancer therapy. Int J Hyperthermia 21:695-701

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