“We identified a total of 78 significantly mutated genes (SMGs),” including 37 not previously reported as SMGs for prostate cancer, Dr Armenia told Cancer Therapy Advisor.

“Importantly, we discovered unexpected and completely novel contribution of pathways such as SWI/SNF and splicing,” he said. “Moreover, we were able to identify a set of markers highly altered in metastatic tumors and that may represent a signature of high risk disease. This signature included genomic alterations in TP53, PTEN, RB1, AR, BRCA2, KMT2C and KMT2D.

Epigenetic reprogramming might well play additional roles in the emergence of AR-indifferent cell states.

“There are epigenetic drivers of these changes,” Dr Aparicio said. “To conquer the AR-indifferent state, I think we’ll have to look at the epigenetic determinants and how we can modulate them with available epigenetic drugs. What does it take to change their methylation status. What does it take to change the histone modification patterns in these tumors?”

“It is quite clear that genetic alterations are selected for that promote tumor evolution, but the impact of epigenetic alterations on this process have been far less-well defined in prostate cancer,” said Dr Knudsen. Genome-wide association studies of DNA methylation in lethal metastatic prostate cancer suggest that epigenetic regulation might select for “driver events” that promote tumor progression.6 “Certainly, understanding the prostate cancer epigenome — and evolution thereof — is fertile ground for scientific investigation and design of novel therapeutic strategies.”

Dr Aparicio’s team is now analyzing data from their phase 2 randomized controlled clinical trial of platinum therapy.

“So now we sort of put together the pieces of why we think there’s an AR-indifferent subset of prostate cancers and the question becomes, so what do we do?” said said. “We apply platinum-based therapy early but what are the other treatments and targets?”

DNA damage repair mechanism pathways and H2 inhibitors are also under investigation, with clinical trials planned and accruing. There is “reason to expect” therapeutic interactions between epigenetic and DNA damage repair drugs.

“It’s exciting,” Dr Aparicio said. “There’s a lot of work being done.”

References

  1. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nature Med. 2016;22(3):298-305. doi: 10.1038/nm.4045
  2. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19(13):3621-30.
  3. Aparicio AM, Shen L, Tapia EL, et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin Cancer Res. 2016;22(6):1520-30.
  4. Schrecengost R, Knudsen KE. Molecular pathogenesis and progression of prostate cancer. Semin Oncol. 2013;40(3):244-58.
  5. Thangavel C, Boopathi E, Liu Y, et al. RB loss promotes prostate cancer metastasis. Cancer Res. 6 Dec 2016 doi: 10.1158/0008-5472.CAN-16-1589 [Epub ahead of print]
  6. Sharad S, Ravindranath L, Haffner MC, et al. Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer. Epigenetics. 2014;9(6):918-27. doi: 10.4161/epi.28710