The Tumor Micro Environment

As I was reading the October 1 issue of the Journal of Clinical Oncology, past the pages of advertisement by gene profiling companies, I came upon an article of very real interest.

While most scientists continue to focus on cancer-gene analyses, a report in this issue from a collaboration between American and European investigators provided compelling evidence for the role of tumor associated inflammatory cells in metastatic human cancer. (Asgharzadeh, S J Clin Oncol 30 (28)3525–3532 Oct 1, 2012) Through the analysis of children with metastatic neuroblastoma, they found that the degree of infiltration into the tumor environment by macrophages had a profound effect upon clinical outcome. This study confirmed earlier reports that macrophage infiltration is an integral part and potential driver of the malignant process.

Using immunohistochemistry and light microscopy the investigators scored patients for the number of CD163(+) macrophages, representing the alternatively activated (M2) subset within the tumor tissue. They then examined inflammation related gene expressions to develop a “high” risk, “low” risk algorithm and applied it to the progression free survival in these children.

Highly significant differences were observed between the two groups. This report adds to a growing body of literature that describes the interplay between cancer cells and their microenvironment. Similar studies in breast cancer, melanoma and multiple myeloma have shown that tumor cells “co-opt” their non-malignant counterparts as they drive transformation from benign to malignant, from in-situ to invasive and from localized disease to metastatic. These same forces have the potential to strongly influence cellular responses to stressors like chemotherapy and growth factor withdrawal. While we may now be on the verge of identifying these tumor attributes and characterizing their impact upon survival, these analyses represent little more than increasingly sophisticated prognostics.

The task at hand remains the elucidation of those attributes and features that characterize each patient’s tumor response to injury toward ultimate therapeutic response. To address this level of complexity, we need the guidance of more global measures of human tumor biology, measures that incorporate the dynamic interplay between tumors cells, their stroma, vasculature and the inflammatory environment.  These are the “real-time” insights that can only be achieved using human tissue in its native state. Ex vivo analyses offer these insights. Their information moves us from the realm of prognostics to one of predictives, and it is after all predictive measures that our patients are most desperately in need of today.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

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