Last week a very interesting article appeared in Cancer Discovery that reported a new target in neuroendocrine tumours (NET) of the prostate, a particularly aggressive subtype. Now, these tumours are “rare” and “uncommon” based on a spot check with a couple of oncology specialists I asked this morning. In fact, according to this latest research, fewer than 2% of men with prostate cancer actually present with neuroendocrine disease and adenocarcinoma of prostate can also (rarely) evolve into neuroendocrine disease, but overall, the prognosis for NET of the prostate is generally poor.
What did they find?
Rubin and et al., (2011) used next-generation RNA sequencing to profile samples of neuroendocrine prostate cancers or NEPC (n=7), prostate adenocarcinomas or PCA (n=30) and benign (BEN) samples of prostate tissue (n=5) to try and characterise the molecular imprint. Previously, it has been shown by Tomlins et al., (2005) that TMPRSS2-ERG occurs in 50% of prostate NET, which is approximately the same rate as adenocarcinoma of the prostate. The big question is whether other molecular subtypes can be identified?
In this research, it was discovered that the genes AURKA and MYCN were overexpressed and amplified in neuroendocrine prostate cancers (40%) and in prostate adenocarcinomas (5%). The findings were then validated in tumours from a larger cohort of patients (n=37 with NEPC, n=169 with PCA, and n=22 with BEN) using immunohistochemistry and FISH:
“We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA tumors, respectively, and evidence that they cooperate to induce a neuroendocrine phenotype in prostate cells.”
For those of you interested in the Aurora kinase, here’s what AurA looks like from a broad perspective as part of the cell cycle pathway:
In order to determine if AURKA was a valid (driver rather than passenger) target, treatment with an aurora kinase (AURKA) inhibitor (PHA-739358, Nerviano Medical Sciences) was evaluated in cell lines and xenografts to determine if the agent inhibited the growth of the neuroendocrine tumours:
“There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment.”
What do these results mean?
This study has identified new potential targets in neuroendocrine tumours of the prostate in AURKA and N-myc that are well worth evaluating in clinical trials with patients who have this condition:
“We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC and that future clinical trials will help determine the efficacy of Aurora kinase inhibitor therapy.”
Interestingly, PHA-739358 (danusertib) has been studied in prostate cancer before without success, but this may be due to the fact that the trial was in patients with adenocarcinomas and not neuroendocrine tumours.
What we learn from this is that the oft heralded argument about targeted therapy – ie first find a valid driver target still holds true – some subsets may respond to therapy while others will not, so identifying the right subset for therapeutic intervention is critical if we wish to increase the chances of success in clinical testing. While a number of aurora kinase inhibitors have gone by the wayside due to lack of efficacy or excessive toxicities, the good news is that there are still several other aurora kinase A inhibitors in active R&D in addition to PHA-739358, including:
- MLN8237 (Millennium)
- AT9283 (Astex)
- AZD1152 (AstraZeneca)
- AMG 900, a pan aurora kinase inhibitor (Amgen)
There are probably a few others, but these are the ones I can remember off the top of my head.
Overall, I think these results are very promising indeed, albeit for a small subset of patients with prostate cancer. That said, it does suggest that another ‘slice of the pie’ has potentially been identified and I look forward to seeing a more precise and well defined clinical trial emerge in the near future in NET prostate cancer to validate the new research findings.
Beltran, H., Rickman, D., Park, K., Chae, S., Sboner, A., MacDonald, T., Wang, Y., Sheikh, K., Terry, S., Tagawa, S., Dhir, R., Nelson, J., de la Taille, A., Allory, Y., Gerstein, M., Perner, S., Pienta, K., Chinnaiyan, A., Wang, Y., Collins, C., Gleave, M., Demichelis, F., Nanus, D., & Rubin, M. (2011). Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets Cancer Discovery, 1 (6), 487-495 DOI: 10.1158/2159-8290.CD-11-0130
Tomlins, S. (2005). Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer Science, 310 (5748), 644-648 DOI: 10.1126/science.1117679