Philip Hahnfeldt, PhD


Senior Investigator
Center of Cancer Systems Biology

Email: hahnfeldt [at] cancer-systems-biology.org
 

Philip Hahnfeldt is Senior Investigator in the Center of Cancer Systems Biology and was an Associate Professor of Medicine, Tufts University School of Medicine. He joined the CCSB at its founding from the Department 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, Dr. Hahnfeldt 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 (Benzekry & Hahnfeldt, 2013). 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 (under DOE funding) and cancer treatment response (through the NCI's Integrative Cancer Biology Program [ICBP]). Dr. Hahnfeldt is currently employing mathematical methods to understand the unifying mechanisms more precisely, specifically in the areas of stem cell kinetics, metastasis, and immune response. In stem cell kinetics, his group has observed how cell killing can paradoxically cause promotion of a tumor (Hillen, Enderling, & Hahnfeldt, 2013). Similarly unexpected population dynamics have emerged in studies of tumor response to the immune system (Wilkie & Hahnfeldt, 2013). In addition, the Hahnfeldt group has proposed how two hallmarks of cancer previously thought to be distinct—metabolic reprogramming and immune action—are, in fact, quite interrelated (Kareva & Hahnfeldt, 2013).
 

Synergistic Activities:

Dr. Hahnfeldt is on the Editorial Board of Biology Direct and has served on Program and PI grant review committees for the National Institutes of Health (NIH), NASA, and the U.S. Department of Energy (DOE). He has also served as Executive Summary reviewer for the National Academies and as 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.
 

Publications:
(click on title to go to manuscript abstract)