Of Cells, Proteins and Cancer Drug Development

Our recent presentation at the American Association for Cancer Research meeting reported our work with a novel class of compounds known as the HSP90 inhibitors. AACR 2015-HSP90 Abstract

The field began decades earlier when it was found that certain proteins in cells were required to protect the function of other newly formed proteins hormone receptors and signaling molecules. Estrogen and androgen receptors, among others, require careful attention following their manufacture or they will find themselves in the cellular waste bin.

230px-Geldanamycin.svgAs each new protein is formed it risks digestion at the hands of a garbage disposal-like device known as a proteasome (named for its protein digesting capabilities). To the rescue comes HSP90 that chaperones these newly created proteins through the cell and protects them until they can assume their important roles in cell function and survival.

Recognizing that these proteins were critical for cell viability, investigators at Sloan-Kettering and others developed a number of molecules to block HSP90. The original compounds known as ansamycins underwent clinical trials with evidence of activity in some breast cancers. The next generation of compounds was tested in other diseases. Though the clinical results have been mixed, the concept remains attractive.

We compared two drugs of this type and showed that they shared similar function but had different chemical properties and that the concentrations required to kill cells differed. What is interesting is the activity of these drugs seems to be patient-specific. That is, each patient, whether they had breast or lung cancer, showed a unique profile that was not directly connected to the type of cancer they had. This has important implications.

Today, pharmaceutical companies develop drugs by disease type. Compounds enter Phase II trials with 30 to 50 lung cancer patients treated, then 30 to 50 breast cancer patients treated and so on. This continues until (it is hoped) one of the diseases provides a favorable profile and the data is submitted to the FDA for a disease-specific approval. As home runs are rare, most drugs never see the light of day failing to provide sufficient response in any disease to warrant the enormous expense of bringing them to market.

What we found with the HSP90 inhibitors is that some breast cancers are extremely sensitive while others are not. Similarly some lung cancers are extremely sensitive while others are resistant. This forces us once again to confront the fact that cancer patients are unique.

Pharmaceutical companies exploring the role of targeted agents like the HSP90 inhibitors must learn to incorporate patient individuality into the drug development process. Failing to do so not only risks the loss of billions of dollars but more importantly denies patients access to active novel agents.

The future of drug development can be bright if the pharmaceutical industry embraces the concept that each patient’s profile of response is unique and that these responses reflect patient-specific, not diagnosis-based drivers. Clinical trials must incorporate individual patient profiles. Drugs could be made more available once Phase I studies were complete by using biomarkers for response, such as the EVA-PCD assay, which has the capacity to enhance access and streamline drug development.

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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