Current Research Focus
Application of chemical engineering principles
to the study of tumor formation and treatment is fertile new ground for
research and is necessary for the advancement of cancer therapy. Over
the last century, researchers have discovered many of the genetic causes
of cancer and yet nearly 46,000 people will die this year from cancer
in the United States alone. Standard cancer therapies often fail because
of spatial heterogeneity of nutrients, wastes, and therapeutics. Transport
barriers prevent therapeutic agents from reaching effective concentrations
throughout tumors. Models based on mass balance, transport phenomena and
reaction kinetics are powerful tools able clarify the connection between
the genetic aberrations and the compositional heterogeneity of tumors.
Therapeutic strategies designed using engineering principles will be able
to overcome transport barriers and create more effective therapies.
Single treatments of radiation or chemotherapy
often do not kill all cancer cells within a tumor. Between treatments,
surviving cells proliferate and regrow as tumors and metastases, eventually
leading to death. Chaotic and irregular tumor vasculature and high interstitial
pressure prevent blood-borne chemotherapeutics from diffusing equally
throughout all tumor regions. Additionally, non-proliferating cells, distant
from vasculature, survive chemotherapeutic therapies specifically targeted
to proliferating cells. Radiation therapy is also less effective in the
low oxygen regions distant from vasculature because it depends on the
formation of oxygen radicals. Furthermore, low oxygen environments have
been shown to select for more aggressive and metastatic cells.
In my laboratory we characterize and utilize tumor
heterogeneity to develop novel cancer therapies that overcome the limitations
of current cancer therapies. Unique three-dimensional tumor models are
designed to mimic the metabolic variations observed in tumors in vivo.
The metabolic profiles of the tumor models, both in vitro and in vivo,
are characterized using fluorescence microscopy, nuclear magnetic resonance
spectroscopy and metabolic flux analysis.
Current Research Topics
Targeted Bacteriolytic Therapy:
To specifically target tumors we are investigating motile, facultative anaerobic bacteria that specifically target and accumulate within the therapeutically inaccessible regions of tumors. Over the past 50 years numerous strains of bacteria have been shown to localize and cause lysis in transplanted mouse tumors, but their application has had minimal success in the clinic. By specifically targeting bacteria to specific sub-regions of tumors we hope to dramatically increase their affectivity.Bacteria selected by these strategies have numerous uses. Administered alone, selected bacteria will compete with the tumor for nutrients, killing cells in inaccessible tumor regions. A combination of bacteriolytic therapy and standard anti-proliferative chemotherapy, which selectively kills proliferating cells growing close to vasculature, will attack tumors from both the inside and out. Additionally, selected bacteria could deliver therapeutic agents or amplification agents (e.g. toxins, prodrug cleaving enzymes or anti-angiogenic factors), or could express markers detectable by MRI, PET, or another imaging device.
Localized Quantification of Tumor Metabolism:
In addition to diffusion, cells with different metabolic profiles cause component gradients and distinct regions of proliferation in tumors. Most people over 50 have pre-malignant lesions throughout their breasts and prostates. These lesions are kept small (<1mm) by a balance of cell proliferation and death. Cells at the centers die because of nutrient depletion and waste toxicity. Once the lesions develop vasculature, proliferation exceeds death and the tumor grows. Thus, both metabolism and diffusion play key roles in the early formation of tumors.In my laboratory we quantify the metabolic state of different tumor regions in order to map nutrient gradients and explain mechanistically why cell growth diminishes away from vasculature. Metabolic flux analysis determines the flow of carbon through the pathways of primary and secondary metabolism using nuclear magnetic resonance spectra of extracted cellular cytoplasm. Whole cell models of metabolism are capable of i) quantifying metabolite transport across biological membranes, ii) quantifying changes in enzyme activity due to extracellular signals and iii) detect inactive pathways. In addition to explaining cancer cell proliferation, metabolic flux analysis will identify enzymatic targets for inhibitors of metabolism and proliferation in the different tumor regions.
Bacterial Migration and Segregation in Solid Tumors:
In collaboration with Baystate Medical Center we
are investigating how bacteria segregate in tumors. The ability of bacteria
to migrate within a tumor defines their usefulness for drug delivery.
We use surgical, histological and standard staining techniques to measure
the rate of bacterial spread throughout subcutaneous tumors in mice following
systemic injection. These experiments were designed to determine the mechanism
of specific bacterial localization in tumors.
