Fellow' research: Are we treating prostate cancer right?
24 Jan 2020
Prostate cancer occurs when the cells of the prostate gland—a male reproductive organ—start growing abnormally due to the elevated level of androgens. Androgens are hormones required for development and maintenance of the male reproductive system. Androgen Deprivation Therapy (ADT) is the most commonly used treatment against prostate cancer, wherein the androgen production is reduced or the receptors, which are required for androgen to function, are blocked with the help of drugs like enzalutamide and apalutamide. A drawback of this therapy, however, is that cancer eventually relapses in the majority of these men in a few years. In such cases, the disease aggressively progresses and develops resistance to anti-androgen drugs. This advanced form of prostate cancer is called castration resistant prostate cancer, which eventually progresses to neuroendocrine prostate cancer, another aggressive and difficult to manage subtype.
Scientists have identified many factors that are responsible for prostate cancer, including an increased expression of a gene called SPINK1. In a new study, researchers from the Indian Institute of Technology Kanpur (IIT Kanpur), in collaboration with CSIR-Central Drug Research Institute, Lucknow, and other groups working on prostate cancer from Canada, USA and Finland, have highlighted how Androgen Deprivation Therapy aggravates prostate cancer instead of curing it. They have also suggested an alternative approach to cure it, based on repressing the expression of SPINK1 gene. The study was published in the journal Nature Communications and was funded by the Wellcome Trust/DBT India Alliance.
Previous studies have shown that SPINK1 is highly expressed in about 10-25% prostate cancer tissues. In the current study, the researchers focused on understanding the reason behind this by conducting a series of experiments. They analysed the cancer tissue biopsies obtained from patients affected by prostate cancer, implanted cancerous tissues into healthy mice with reduced immunity, and used data from publicly-available gene expression datasets to show that SPINK1 gene is repressed via action of androgen receptor and its partner REST.
The researchers, for the first time, showed that a series of messages, conveyed by androgens, regulates the SPINK1 gene expression. Patients with elevated levels of androgen receptors expressed lower levels of SPINK1 and vice versa. They further found that by blocking the action of androgen receptors with anti-androgen drugs, SPINK1 expression goes up, indicating the role of androgen signalling in influencing the gene expression.
The researchers have shown that SPINK1 is also associated with the development of the aggressive neuroendocrine prostate cancer and exhibits other cancerous properties. “It is associated with cell plasticity, wherein cancer cells undergo multiple changes at the molecular and phenotypic levels to support cancer progression,'' says Prof Bushra Ateeq from IIT Kanpur, who led the study.
When the prostate tumours expression were implanted into mice, and were treated with anti-androgenic drugs, the tumors in mice showed a robust increase in the SPINK1 as well as markers for neuroendocrine cancer, implicating its role in aggressive prostate cancers.
The study also found that in addition to androgen receptors, other proteins involved in the androgen signalling pathway also influence SPINK1 regulation. The REST protein partners with androgen receptor, and represses the SPINK1 expression. The researchers also reported that SOX2 is involved in prostate tumour progression by raising the SPINK1 expression. Most importantly, the authors have shown that Casein Kinase 1 inhibitor restores the levels of REST, which causes reduced expression of SPINK1, leading to reduced stemness and cellular plasticity.
As an alternative to Androgen Deprivation Therapy, the researchers propose to look at other therapeutic targets that target Casein Kinase 1. For example, since REST is regulated by Casein Kinase 1, using an inhibitor against this enzyme can stabilize the abundance of this protein. Although targeting this protein might seem like an indirect approach for controlling prostate cancer, it might be suitable given the grave consequence of using Androgen Deprivation Therapy. Clinical trials are going on using Umbralisib, a Casein Kinase 1ε inhibitor for Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia.
“For now, our findings are alarming, considering the widespread use of androgen deprivation therapy for prostate cancer patients. A well-informed decision should be taken before administration of anti-androgen therapy to prostate cancer patients,” suggests Prof Ateeq.
As an immediate next step, the researchers plan to proceed with clinical trials using Casein Kinase-1 inhibitors to treat advanced stage prostate cancer patients.
Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer. Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Mushtaq A. Nengroo, Dipak Datta, Shannon Carskadon, Nilesh Gupta, Michael Sigouros, Francesca Khani, Matti Poutanen, Amina Zoubeidi, Himisha Beltran, Nallasivam Palanisamy & Bushra Ateeq. Nature Communications volume 11, Article number: 384 (2020)
Banner image: Prostate cancer cells, Annie Cavanagh, CC BY-NC (wellcomecollection.org)