Philip Hahnfeldt, PhD. Senior Investigator Center of Cancer Systems Biology Caritas St.Elizabeth's Medical Center Tufts University School of Medicine 736 Cambridge Street, CBR-115 Boston, MA 02135   Tel: 617.789.2998 Mail: philip.hahnfeldt [at] tufts.edu

Dr. Philip Hahnfeldt, PhD, is Senior Investigator at the Center of Cancer Systems Biology and Associate Professor of Medicine, Tufts University School of Medicine. He joined the CCSB at its founding from the Dept. of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School. He graduated from MIT in Applied Mathematics and went on to attend graduate school under a National Science Foundation Fellowship. He was awarded his doctorate at MIT in 1991 while receiving biomedical training at the Yale University School of Medicine. His dissertation, "The Suitability and Formulation of a Continuous-Time, Markov Chain Approach to Cellular DNA Radiation Damage and Repair", investigated chromosome-level kinetic responses to ionizing radiation bearing on cell killing and oncogenic transformation. Dr. Hahnfeldt continued and expanded on these investigations as a Research Associate, then as Instructor at the Joint Center for Radiation Therapy, Harvard Medical School. He was appointed Assistant Professor in Radiation Oncology at Harvard Medical School and worked with the Chief Resident in Radiation Oncology to organize and teach the training program for residents, serving as course instructor from 1999-2001.

Research interests:

Dr. Hahnfeldt's interests span four major subdisciplines in cancer biology: 1) modeling of DNA damage and repair, relating these to chromosome geometry; 2) theoretically describing the kinetics of tumor growth suppression under anti-angiogenic therapy, 3) examining how intra-tumor heterogeneity is expressed and may be defeated; and 4) exploring the role of inter-tissue interactions in carcinogenesis.

Research summary:

The chromosome damage/repair studies have interrelated results on cytogenetics and interphase chromosome localization and geometry. By developing a revised theory for double-strand break repair/misrepair following ionizing radiation, Dr. Hahnfeldt found it possible to improve upon the commonly-accepted repair models, in the process obtaining information on how chromosomes are packaged within the nucleus. Incomplete exchange models developed from these studies were also able to explain the relation between acentric and dicentric counts and the excess dispersion (variance/mean) for the number of acentric fragments relative to dicentrics seen in human lymphocytes exposed to various radiation types and doses.

As a second research focus, extending from collaboration with the late Dr. Judah Folkman of Children's Hospital, Boston, he is exploring the unique tumor/vascular regression kinetics of anti-angiogenic therapy. The indirect means by which tumor suppression is here accomplished, coupled with the recent finding that tumors both stimulate and inhibit their own vascularization, points to a need to formulate tumor-vascular models that properly capture the dynamics. Dr. Hahnfeldt has undertaken to do this, using sets of differential equations that simultaneously consider vascular response to anti-angiogenic agents and subsequent suppression of tumor growth. The result is a formalism that is proving to be both explanatory and clinically predictive. This work is an example of quantitative translational research, a "workstation-to-bench-to-bedside" research strategy embraced by the CCSB. An important dynamic to surface from these studies is the self-imposed Gompertz restriction on growth imposed by a tumor on itself. Implications for the general organogenic control of tissue mass are suggested. Another study of dose rate effects addresses an as yet un-quantified effect -- the utility of so-called "metronomic" (small, evenly-spaced) dosing on the treatment response of a tumor population. It was shown considering the response of a heterogeneous target to various dosing protocols that: 1) metronomic dosing does indeed offer the best tumor suppression, and 2) the shift to metronomic dosing from more traditional "up-front" dosing regimens favors the endothelial cell compartment. The theory offers one explanation for numerous reports of an antiangiogenic response using the metronomic scheme.

A unifying theme in both the DNA repair and angiogenesis studies is the role tumor heterogeneity and inter-tissue interactions play in carcinogenesis risk and cancer treatment response. Under our NASA NSCOR Program Project dedicated to examining how inter-cellular interactions modulate carcinogenesis (Lynn Hlatky -- PI, Philip Hahnfeldt -- Project leader), Dr. Hahnfeldt is currently employing quantitative methods to understand the unifying mechanisms more precisely. A deterministic carcinogenesis risk model that incorporates cell-cell interactions was developed which compares favorably to the current stochastic model standard in explaining epidemiologic data on atom bomb survivors. Additional unpublished studies are now showing that inter-cellular interactions may even decide the course of cancer after the fact of tumor cell creation, proving these interactions to be a vital augment to current cell-centric focuses on cancer origin and treatment response.

Synergistic Activities:

Dr. Hahnfeldt is on the Editorial Board of Biology Direct and has served on Program and PI grant review committees for NIH, NASA, and DOE. He has also served as Executive Summary reviewer for the National Academies and is an advisor to the National Council on Radiological Protection and Measurements on methods of integrating low-dose radiation effects data into reliable predictive models of human health effects of exposure to low-dose radiation.

Selected Publications:

• Feinendegen L, Hahnfeldt P, Schadt EE, Stumpf M, Voit EO. Systems biology and its potential role in radiobiology. Radiat Environ Biophys. 2008;47(1):5-23.
   
• Sachs RK, Shuryak I, Brenner D, Fakir H, Hlatky L, Hahnfeldt P. Second cancers after fractionated radiotherapy: stochastic population dynamics effects. J Theor Biol. 2007;249(3):518-31.
   
• Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, Hauser K, Hahnfeldt P, Hlatky L, Debus J, Peters JM, Friess H, Folkman J, Huber PE. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci USA 2007;104(31):12890-5.
   
• Shuryak I, Sachs RK, Hlatky L, Little MP, Hahnfeldt P, Brenner DJ. Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks. J Natl Cancer Inst 2006;98(24):1794-806.
   
• Ponomarev AL, Belli M, Hahnfeldt PJ, Hlatky L, Sachs RK, Cucinotta FA. A robust procedure for removing background damage in assays of radiation-induced DNA fragment distributions. Radiat Res 2006;166(6):908-16.
   
• Sachs RK, Chan M, Hlatky L, Hahnfeldt P. Modeling intercellular interactions during carcinogenesis. Radiat Res 2005;164:324-31.
   
• Abdollahi A, Hahnfeldt P, Maercker C, Rastert R, Ansorge W, Folkman J, Hlatky L, Huber P. Endostatin's anti-angiogenic signaling network. Molec Cell 2004;13(5):649-63.
   
• Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 2003;220:545-54.
   
• Browder T, Folkman J, Hahnfeldt P, Heymach J, Hlatky L, Kieran M, Rogers MS. Antiangiogenic therapy and p53. Science 2002;297:471.
   
• Sachs R, Arsuaga J, Vazquez M, Hlatky L, Hahnfeldt P. Using graph theory to describe and model chromosome aberrations. Radiat Res 2002;158:556-67.
   
• Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst 2002;94:883-93.
   
• Sachs RK, Hlatky LR, Hahnfeldt P. Simple ODE models of tumor growth and anti-angiogenic or radiation treatment. Mathematical and Computer Modeling 2001;33:1297-305.
   
• Folkman J, Hahnfeldt P, Hlatky L. Cancer: looking outside the genome. Nature Revs: Molec Cell Biol 2000;1:76-9.
   
• Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L. Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 1999;59:4770-5.
   
• Hahnfeldt P, Hlatky L. Cell resensitization during protracted dosing of heterogeneous cell populations. Radiat Res 1998;150:681-7.
   
• Hahnfeldt P, Hlatky L. Resensitization due to redistribution of cells in the phases of the cell cycle during arbitrary radiation protocols. Radiat Res 1996;145:134-43.
   
• Hahnfeldt P, Hlatky LR, Brenner DJ, Sachs RK. Chromosome aberrations produced by radiation: the relationship between excess acentric fragments and dicentrics. Radiat Res 1995;141:136-52.
   
• Hahnfeldt P, Hlatky LR. A Monte-Carlo/Markov-chain model for the association of data for chromosome aberrations and formation of micronuclei. Radiat Res 1994;138:239-45.
   
• Hahnfeldt P, Hearst JE, Brenner DJ, Sachs RK, Hlatky LR. Polymer models for interphase chromosomes. Proc Natl Acad Sci 1993;90:7854-8.
   
• Hlatky LR, Sachs RK, Hahnfeldt P. The ratio of dicentrics to centric rings produced in human lymphocytes by acute low LET irradiation. Radiat Res 1992;129:304-8.
   
• Hahnfeldt P, Sachs RK, Hlatky L. Evolution of DNA damage in irradiated cells. J Math Biol 1992;30:493-511.
   
• Hlatky L, Sachs R, Hahnfeldt P. Reaction kinetics for the development of radiation-induced chromosome aberrations. Int J Radiat Biol 1991;59:1147-72.