Technological Landscapes: The Pharmaceutical War on Lung Cancer

The United States Centers for Disease Control and Prevention (CDC) has reported that the number of annual deaths in the United States in 2008 from lung cancer was approximately one-hundred and sixty-thousand. The American Lung Association estimates that in 2012 lung cancer deaths will exceed the death rate for prostate, pancreas, breast and colon cancer combined.

The disease presents itself in the form of a lung carcinoma (hereafter "tumor”). After diagnosis, based on the disease’s spread throughout the body, the five-year survival rate ranges from about fifty percent down to four percent. Smoking causes about eighty-seven percent of all lung cancer deaths per year. Approximately three-thousand people die each year from second-hand smoke.

Treatment for lung cancer depends on the type of cancer. The classification is either small-cell or non-small-cell. For example, the Cedars-Sinai Medical Center reports that it prefers chemotherapy and radiation therapy for small-cell cancer. Surgery followed by additional therapies is the preference for non-small-cell cancer.

Imagine what a miraculous event it would be if lung cancer could be destroyed without the need for surgery and its associated therapies. Just imagine how wonderful it would be if a pharmaceutical bullet could be found that specifically seeks out lung tumors and destroys them.

That is exactly what Lexington-based Synta Pharmaceuticals Corporation has achieved with its inhibitor lung-cancer drug named “ganetespib” (hereafter “Synta inhibitor”).

The design of an effective lung-cancer inhibitor requires knowledge of the source that provides energy to the tumor. In the case of non-small-cell lung cancer it is a protein named “Hsp90”, the most widely studied of the HSP class of proteins. The initials stand for “heat-shock protein” because the cell’s reproduction rate is significantly increased by either heating or by other types of environmental stress. The number “90” indicates its molecular weight. A weight of 90 is considered to be relatively high. HSP proteins are an integral part of essentially all living organisms.

Wikipedia reports that in the mid-1980s it was discovered that HSP protein cells increased dramatically when exposed to cancer-related infection and inflammation. In particular, the Hsp90 protein acted as a molecular chaperone that signaled other client-proteins to enhance tumor growth. Client proteins are those with which the Hsp90 cell has an affinity to bind. Since then, numerous anticancer research papers indicated that the Synta inhibitor acted directly on the Hsp90 molecule to vigorously degrade this binding ability in such a way that it resulted in cancer-cell death. A dramatic reduction in tumor mass was repeatedly achieved following three doses of the Synta inhibitor over a typical three week clinical trial. Ultimately, the Synta inhibitor proved to be of greater potency than other targeted agents and chemo-therapeutic methods utilized in non-small-cell lung-cancer therapy.

Synta’s development of its inhibitor began in 2007 and full clinical development was initiated in 2011. The power of the Synta inhibitor rests in its ability to simultaneously degrade multiple protein contributors to tumor growth by just targeting and shutting down one molecule. This process has proven to be so effective in degrading lung cancer in over five-hundred patients during extended clinical studies that there are currently dozens of cancer centers in the United States and Europe collaborating on the use of the Synta inhibitor.

To wage a successful pharmaceutical war on lung cancer requires a multi-year, arduous task not only because of the number of different forms of lung cancer but because complex proteins such as Hsp90 tend to mutate and form escape routes in order to bypass inhibitor bullets. This process is commonly referred to as “drug resistance”. For example, the sophistication required to develop effective inhibitors sometimes involves the use of the Synta inhibitor in combination with other inhibitors. Such combinations generally enhance the potency of Synta’s overall inhibitor performance.

Another crucial issue is in the form of side-effects and considerable effort is under way at Synta to ensure that the human retina is not damaged as it can be during the use of other inhibitors. Most importantly, Synta’s inhibitor has not exhibited either ocular or severe liver toxicity during advanced clinical trials and has shown promise as an inhibitor of breast cancer.

The vitality of Synta’s war on lung cancer was exemplified in 2012 through a series of co-authored seminal presentations at prestigious forums, i.e., the American Society of Clinical Oncology (ASCO), the American Association for Cancer Research (AACR) and the AACR-IASLC Joint Conference on Molecular origins of Lung Cancer. The papers were co-authored by medical specialists from global lung-cancer centers that include Canada, Germany, Spain and the United Kingdom. The papers clearly define Synta’s next assault on this pervasive malignancy.