From genes to therapies -- Systems Medicine of Neuro Endocrine Prostate Cancer - Beyond the Abstract

Prostate cancer is the most commonly diagnosed cancer in men. More than 200,000 new cases are added each year in the US, translating to a lifetime risk of 1 in 7 men. A recent estimate suggests around 26,000 deaths due to prostate cancer in the United States this year. The clinical behavior of prostate cancer ranges from a slow growing tumor that may never be clinically significant to an aggressive, high-grade cancer that will ultimately spread in the body and cause death.

Although the incidence rises with age, prostate cancer can also develop in younger men. Biologically, both the normal prostate glands and the malignant prostate cells depend on male hormones (androgens) to grow and thrive. Hence, the most common treatments for prostate cancer revolve around strategies to deprive them of androgens, the male hormones. One way to rectify the hormonal imbalance is by removing the primary source of androgens, i.e., removing the testis, blocking the hormone production or using anti-androgens. Whereas many of the prostate cancers can have positive outcomes with such strategies, some will break through and become, what is called resistant to hormonal manipulations or castrate resistant in the medical parlance. Why some prostate cancers become resistant, has been a mystery and a medical challenge. The Mount Sinai Hospital and the team under the leadership of Drs. Ash Tewari and Joel Dudley are hard at work to unlock those mysteries using various genomic sciences and other research tools. This unique combination of a leading surgeon from the Department of Urology and translational bioinformatics researchers from Department of Genetics and Genomic Sciences are attempting to identify and develop new therapeutic strategies for prostate cancer.

An example of this effort is a recent perspective article "Systems Medicine approaches to improving understanding, treatment, and clinical management of Neuroendocrine Prostate Cancer", authored by K. K. Yadav, K. Shameer, B. Readhead, S. S.Yadav, L. Li, A. Kasarksis, Ash K Tewari and J.T Dudley. The invited article has been accepted in a special issue of the journal, Current Pharmaceutical Design. The paper deals with ways to understand a particularly aggressive type of prostate cancer called neuroendocrine prostate cancer (NEPC). This kind of cancer is very often androgen resistant and has a reduced 5-year overall survival rate of 12.6%. The researchers dug into the publically available genomic databases to identify different possibilities for developing "systems medicine based therapeutic and curative models to understand and target prostate cancer and specifically the neuroendocrine variety." They have suggested the use of a neuroendocrine cell line (NCI-H660) that exhibits most of the genomic and biological characteristics of the neuroendocrine prostate cancer. They are also leveraging the repertoire of genetic variants associated with prostate cancer, Figure 1.

One of the lead authors, Dr. Yadav states that "designing experimental and computational strategies for the systematic targeting of pathways, genes or genetic variations involved in prostate cancer or neuroendocrine prostate cancer could help to find better therapies for such diseases”. The progress in genomics has made it easier and faster to detect genetic mutations and the genes that make the cancers grow (driver genes). "We now have a vast amount of public oncology datasets and high-performance computing and machine learning tools. Applying these innovations in data science and artificial intelligence to tackle cancer - the emperor of all maladies is the way to move forward”, another lead author Dr. Shameer adds.

The newer technologies have also made it possible to identify the various signaling pathways that make the tumors tick. Attacking the various points in the key driver pathways can interrupt the growth of the cancers, or their ability to metastasize to other parts of the body. Another novel way is to repurpose drugs that have already been developed and approved by the FDA. “Now that we can track the cancer cell's metabolic pathways and can have its full genomic profile, we can try using drugs that work in similar scenarios in other types of cancer”, says Dr. Yadav. In other words, the groups are looking at the feasibility of using a medication that is; let us say approved for lung cancer (or any other disease) and repurpose it in the treatment of prostate cancer if the set of genetic mutation or alterations in the pathways is similar even though the two tumors have developed in different organs. With the unique collaboration of cross-functional team including surgeons, urology physicians, genomics scientists, biomedical and healthcare data scientists, this audacious goal is not just a pipe dream; it is very close to reality. Once fully developed, this strategy will allow us to leapfrog, as we will not have to spend decades in the new drug development. The department of Urology at Mt. Sinai Hospital is much closer to the “Moon Shot” goal that President Obama spoke about at the State of the Union address and the initiative that Vice President of the United States, Joe Biden is promoting.

Written By:

Khalid Rehman, MD
Department of Urology
Icahn School of Medicine at Mount Sinai,
Mount Sinai Health System, New York, NY, USA