Tumors depend on neovascularization, and inhibiting angiogenesis is emerging as a major tumor treatment modality. A number of inhibitors are in clinical trials, powerful endogenous inhibitors have been discovered, and the search for additional inhibitors is proceeding worldwide. To help rationalize experiments and optimize future clinical trials, it is important to quantify angiogenic inhibitor effectiveness. However, rather than directly targeting tumor cells, many important anti-angiogenic agents target endothelial cells, perturbing the tumor indirectly. The concomitant time delay in tumor response, together with the fact that the treatments involve repeated dose fractions, means that to quantify inhibitor effectiveness, some mathematical model of tumor growth, implicit or explicit, is needed. This application proposes that effectiveness of angiogenic inhibitors be quantified in terms of carrying capacity, a very widely used model quantity specifying the maximum sustainable tumor size within the current limitations of the host environment. Mathematical models involving dynamic carrying capacity, increasing as the tumor induces angiogenesis or decreasing due to angiogenic inhibitors, will be used, analyzing ongoing murine experiments and pending experiments on spontaneous canine tumors in the laboratory of J. Folkman. Preliminary studies have given a numerical inhibitor effectiveness index, based on fractional decrease of carrying capacity, for TNP-470, angiostatin, and endostatin in the murine model. The project will obtain this index for additional sites, inhibitors, doses, and combinations. It will test the results for robustness and make the following significant and novel applications: (1) Ordering inhibitors numerically according to effectiveness; (2) investigating inhibitor dose-response curves for linearity; and (3) using a numerical, super-additivity criterion for synergism to analyze quantitatively whether the standard chemotherapeutic paradigm, that combinations of different agents are usually preferable to single agents, applies to angiogenic inhibitors. As a check on the mathematical modeling, and to deepen quantitative understanding of carrying capacity, digitized automated imaging of time-dependent intratumor microvessel density after inhibitor exposure will be performed on tumor sections supplied by the Folkman laboratory, testing for positive correlations with calculated carrying capacity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078496-02
Application #
2896576
Study Section
Special Emphasis Panel (ZRG2-PTHB (02))
Program Officer
Mohla, Suresh
Project Start
1998-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Shuryak, Igor; Hahnfeldt, Philip; Hlatky, Lynn et al. (2009) A new view of radiation-induced cancer: integrating short- and long-term processes. Part I: approach. Radiat Environ Biophys 48:263-74
Shuryak, Igor; Hahnfeldt, Philip; Hlatky, Lynn et al. (2009) A new view of radiation-induced cancer: integrating short- and long-term processes. Part II: second cancer risk estimation. Radiat Environ Biophys 48:275-86
Feinendegen, Ludwig; Hahnfeldt, Philip; Schadt, Eric E et al. (2008) Systems biology and its potential role in radiobiology. Radiat Environ Biophys 47:5-23
Sachs, Rainer K; Shuryak, Igor; Brenner, David et al. (2007) Second cancers after fractionated radiotherapy: stochastic population dynamics effects. J Theor Biol 249:518-31
Almog, Nava; Henke, Vanessa; Flores, Ludmila et al. (2006) Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J 20:947-9
Sachs, Rainer K; Chan, Michael; Hlatky, Lynn et al. (2005) Modeling intercellular interactions during carcinogenesis. Radiat Res 164:324-31
Abdollahi, Amir; Hahnfeldt, Philip; Maercker, Christian et al. (2004) Endostatin's antiangiogenic signaling network. Mol Cell 13:649-63
Sachs, R K; Levy, D; Hahnfeldt, P et al. (2004) Quantitative analysis of radiation-induced chromosome aberrations. Cytogenet Genome Res 104:142-8
Arsuaga, J; Greulich-Bode, K M; Vazquez, M et al. (2004) Chromosome spatial clustering inferred from radiogenic aberrations. Int J Radiat Biol 80:507-15
Hahnfeldt, Philip; Folkman, Judah; Hlatky, Lynn (2003) Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 220:545-54

Showing the most recent 10 out of 13 publications