Project 1 investigators have recently exploited the provocative and unexpected finding from this initial landscape study (Cell. 2015 May 21;161(5):1215-28) where 8% of men with CRPC were found to have a germ-line mutation in a DNA repair gene. Out of all enrolled patients (49/50) who had evaluable data, 16 had a response to olaparib, including 6 patients having a radiological response and 4 patients having responses lasting more than a year. In addition, NGS sequencing study in these patient samples detected mutations in genes associated with DNA repair in 16 of 49 patients. Of those, 13 of 16 patients responded to olaparib. The most common aberrations were BRCA2 biallelic loss (either somatic or germline) but we also identified ATM, PALB2, HDAC2 and BRCA1 genomic aberrations associated with responses, among others (N Engl J Med. 2015 Oct 29;373(18):1697-708).
We extended this observation to 692 men that included additional men in the SU2C ‘CRPC 500’. We determined that the frequency of germline DNA repair gene mutations was 11.6% which was quite consistent across 7 different case series. The mutation frequency was substantially higher than the population frequency of ~2.7% in the ExAC database and ~5% in primary prostate cancers in the TCGA study where a majority of tumors were classified as NCCN high-risk. In view of clinical responses to PARPi and platinum chemotherapy, the identification of a germline DNA repair gene mutation has treatment implications. Further, the identification of an individual with a germline DNA repair gene mutation has important implication for family members regarding cancer predisposition. These results have been accepted for publication in the New England Journal of Medicine.
Project 2 researchers first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)) to assess the role of AR signaling on MET inhibition. This identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, they showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone (Neoplasia. 2016 Jan;18(1):1-9).
Project 3 investigators made additional optimization on CF53 to further improve its binding affinities to BET proteins, its cellular activity and its physiochemical properties. We have made over 50 new analogues and have identified ZBC11 as a superior compound to CF53. Their data provided evidence that both ZBC11 and CF-53 target cellular BRD4 proteins and potently and effectively inhibit AR and AR-ERG signaling pathway in AR+ prostate cancer cells. However, ZBC11 is 5-10 times more potent than CF53. They also showed that both CF-53 and ZBC11 are capable of inhibiting tumor growth in a dose-dependent manner with oral administration. Daily dosing of ZBC11 and CF53 effectively inhibit tumor growth but ZBC11 is more effective than CF53 at the same dose-schedule.
Project 4 researchersresearchers examined expression of the RNA molecule SChLAP1 in a large group of prostate cancer patients with long-term follow-up and found that patients with high SChLAP1 expression had a significantly higher chance of developing lethal disease. Of the 937 patients evaluated, 89 (9.5%) had high SChLAP1 expression (ISH score ≥100), which in patients treated with radical prostatectomy was strongly associated with development of lethal PCa independent of age, Gleason score, pathologic stage, and PTEN status (Eur Urol. 2015 Dec 23. pii: S0302-2838(15)01211-7. doi: 10.1016/j.eururo.2015.12.003).