A New Use for One of the Oldest “New” Drugs

With the profusion of new targeted agents entering the clinical arena, a report from the American Society of Hematology bears consideration.

The trial known as the SORAML trial enrolled 276 patients with newly diagnosed acute myelogenous leukemia. The patients were between the ages of 18 and 60. All patients received a standard chemotherapy regimen. The patients were then randomized to receive Sorafenib or placebo. Patients on the Sorafenib arm then remained on a maintenance therapy for twelve months.

While the achievement of complete remission was almost identical between the two arms at 59% and 60%, the event free survival demonstrably favored the Sorafenib group at 20.5 months versus 9.2 months. At three years of follow-up 40% of the Sorafenib group were well with only 22% of the placebo group still in remission. This corresponds to a three-year relapse free survival of 38% for placebo and 56% for Sorafenib (P=0.017).

The results are of interest on several levels.
1.    Sorafenib a multitargeted tyrosine kinase inhibitor was approved in December 2005 for the treatment of renal cell carcinoma. This makes Sorafenib one of the first targeted agents to achieve FDA approval.

2.     Sorafenib has many modes of action and it is not entirely clear which of its functions were responsible for the superior survival in this AML study.

3.    Sorafenib’s approval reflects a rather convoluted and interesting history. When first developed the drug was designed to target the oncogene B-Raf. As a result the drug was introduced into early clinical trials for the treatment of advanced melanoma, a disease known to be associated with B-Raf mutation. As the drug proved ineffective, it appeared unlikely to gain FDA approval. That is, until it showed cross reactivity with VEGF pathway associated with tumor cell vascularity. A successful trial published in the New England Journal of Medicine then led to the approval.

Now, nine years later this old new drug has gained new life. This time in acute myelogenous leukemia.

The term “dirty drug” refers to agents that target many kinases at the same time. Sorafenib is an example of a “dirty drug.” However it is Sorafenib’s “dirty drug” quality that led first to its approval and most likely now leads to its application in AML. This reflects the fact that Sorafenib may be inhibiting B-Raf signaling associated with the common mutation in Ras upstream of B-Raf or it may reflect Flt3 a secondary activity associated with Sorafenib.

Indeed B-Raf and Flt3 may not be upregulated in every patient, but could serve a function of permissive activity granting an additional survival signal to the AML cells as they go through induction therapy. These subtleties of drug effect may escape genomic analysis as the true “target” may not be mutated, upregulated or amplified. No doubt the investigators in this study will conduct gene sequencing to determine whether there is a driver mutation associated with the advantage reported in this clinical study. What will be intriguing is to determine whether that advantage is an abnormal gene functioning within these cancerous cells or possibly a normal gene functioning abnormally in these cancer cells. More to come.

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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