NEW TARGETS FOR NEUROENDOCRINE PROSTATE CANCER

Bench-to-bedside approach identified a new molecular target for neuroendocrine prostate cancer

23.11.11

Category: Scientific News

The study was only possible because a number of investigators from the USA and Europe sent samples of this rare tumor

A recent report in the journal Cancer Discovery suggests that a new treatment may be on the horizon for neuroendocrine prostate cancers, the most lethal subtype of this disease. An international team of researchers has discovered a genetic vulnerability that can be attacked by a targeted drug that is already in clinical trials to treat other types of cancers.

According to Dr Mark Rubin, professor of pathology and laboratory medicine at Weill Cornell Medical College, less than 2% of prostate tumors in men are initially classified as neuroendocrine, but many common prostate adenocarcinomas change their biology during hormone therapy and morph into this aggressive subtype.

Largest analysis of neuroendocrine prostate cancer

This form of prostate cancer is rare and it's hard to get samples. The current study is the largest in-depth analysis of neuroendocrine prostate cancer yet undertaken. Dr Rubin and colleagues used next-generation RNA sequencing to profile samples of seven neuroendocrine prostate cancers, 30 prostate adenocarcinomas and five benign samples of prostate tissue.

They found that the genes AURKA and MYCN were overexpressed and amplified in 40% of neuroendocrine prostate cancers and in 5% of prostate adenocarcinomas.

The AURKA gene produces aurora A kinase that plays an important role in cell growth, and some studies have suggested it is an oncogene. Overproduction of AURKA protein has been identified in colon, pancreatic, breast, liver, head and neck cancers, as well as other tumor types. MYCN encodes a transcription factor that is involved in nervous system development and works to turn on other genes. Alterations in the MYCN gene have not previously been seen in prostate cancer.

In neuroendocrine prostate cancer, the AURKA and MYCN mutations need to work together to promote cancer development. The kind of lethal interaction has also been found in neuroblastoma.

Aurora kinase inhibitors against human neuroendocrine prostate cells

Aurora kinase (AURKA) inhibitors have been developed and are being tested in a variety of cancers. Aurora kinase inhibitor, PHA-739358, has been studied in prostate cancers before without success, but this may be due to the fact that previously studied prostate cancers were not neuroendocrine cancers.

The latest study demonstrated that the investigational PHA-739358 worked against human neuroendocrine prostate cells in the laboratory, and that it had a dramatic response in animal models of neuroendocrine prostate cancer. It shrank large tumors to very small sizes in a short period of time, compared to untreated mice. There was also significantly enhanced sensitivity of neuroendocrine prostate cancer compared to prostate adenocarcinoma. A clinical trial to test an AURKA inhibitor in prostate cancer patients whose tumors contain neuroendocrine cancer cells or similar molecular alterations involving AURKA and MYCN is planned.

Not only are researchers eager to test the investigational drug in patients diagnosed with neuroendocrine prostate cancer, they hope to develop biomarkers that can help in screening patients for these cells before the cancer advances.

Androgen suppression therapy increases the risk of future development of neuroendocrine prostate tumors

Prostate cancer is not a homogenous disease. It is needed to continue to sort out the aggressive disease from the indolent form and treat accordingly.

The study finding is especially important because many patients with prostate adenocarcinoma are now being treated with new, highly potent androgen suppression therapy, which the study researchers believe will significantly increase the risk of future development of neuroendocrine tumors. Androgen suppression therapy does not affect neuroendocrine cells that may have been part of the tumor mix, and those untreatable cells have room to grow and spread. It is currently impossible to know how many patients with prostate adenocarcinoma develop neuroendocrine tumors because they are not usually biopsied at that stage in their disease. Studies to define changing biology in prostate cancer are only now starting.

Working with the Weill Cornell researchers on the study were researchers from the Yale University, the University of British Columbia, the University of Pittsburgh School of Medicine, the University of Michigan, Howard Hughes Medical Institute, and INSERM, a French biomedical research institution.

The research was sponsored by the Ann and William Bresnan Foundation, the Prostate Cancer Foundation, the USA National Cancer Institute Early Detection Research Network, and the USA Department of Defense.