Community Research and Development Information Service - CORDIS

Final Report Summary - RESICT-PC (Studying Resistance to Cancer Therapeutics in Prostate Cancer)

In Sweden the mortality due to prostate cancer is second highest in Europe and in the UK ~ 30 men die every day from prostate cancer (Prostate cancer mortality statistics: Cancer Research UK).
Nearly all advanced prostate cancer (PC) patients initially respond to androgen deprivation therapy (ADT), with a variable length of response. When a patient relapses a lethal stage of the disease denoted castration resistant prostate cancer (CRPC) develops. Early studies (1) showed the continued importance of the androgen receptor (AR) in the progression and maintenance of this disease with 30% of patients displaying AR amplification after ADT. Data on additional mechanisms of bypassing androgen deprivation soon followed, with up to 15-20% of patients acquiring AR mutations in the ligand binding domain (2,3). This led to the development of novel potent AR inhibitors like abiraterone acetate and enzalutamide that show significant survival benefits in CRPC patients (4,5). Unfortunately 30% of patients have primary resistance to these agents and even in those patients who initially respond secondary resistance develops (100%). There is an unmet need to better understand mechanisms of progression to CRPC and its development of resistance to treatments.
Repeated biopsies, spatially due to the heterogeneity of tumours (Fig. 1) and sequentially during the course of disease, could provide important information on the genomic changes that occur with the development of the disease, but these samples are very invasive, coupled with risks to patients and in many cases not possible to obtain at all. Recent efforts have shown the potential of liquid biopsies in obtaining genomic data on circulating tumour DNA (ctDNA) that is present in the cell-free plasma fraction of blood. Perkins et al (6) have shown that ctDNA in plasma contains tumour-specific mutations and that total levels are significantly higher in advanced breast and prostate cancer patients than healthy volunteers. In metastatic breast cancer patients, changes in levels of ctDNA have been shown to be the earliest indicator of response to treatment (7).
In this project we studied changes in AR during treatment to find genomic changes that associate with resistance to abiraterone (8) by next-generation sequencing (NGS). Next-generation sequencing allows detailed information on the specific characteristics of the tumour in each individual in base-pair resolution. The large diversity in tumour composition as well as in clinical outcome between patients with prostate cancer suggests that this type of personalized characterization will be a necessity in making qualified treatment decisions.
Conclusively, two important findings where made within this project (8 and Fig. 2):
1) primary resistance strongly associates with an aberrant androgen receptor
2) resistance-driving mutations can be detected several months prior to clinical progression determined by PSA or radiological scans. These findings pave the way for early detection and for monitoring aberrations in time by minimally invasive sampling. Additionally, we validated these data with droplet digital PCR, a highly sensitive method that enables high-throughput in testing for AR aberrations. The sensitivity of detection is as low as 0.001% (9) and a turn-around time is 4h for a 96-well format. These data are implemented in a prospective clinical trial where patients are stratified based on their AR status for different treatments. If the results from this trial truly validate our hypothesis, stratifying patients prior to starting treatment will enable selection of those who will best benefit from AR targeting agents and those that will not, saving the latter group from months of treatment they will not benefit from. I believe this will have a huge impact for patients and lead to better outcomes but it will also lead to large savings for the whole health sector, as the cost of abiraterone is several thousands of pounds per patient and month.
The works was published in Science Translational Medicine (8) and made the front cover. Furthermore, the work gained public interest as many news outlets have reported on the findings of this project (see attached PDF for a subset of findings). The study also made the front cover of “New Scientist”: https://www.newscientist.com/article/2079404-how-a-simple-blood-test-could-spot-cancer-earlier/ and will be featured in the magazine “Genetic Engineering News”.

Figure 2: AR copy number (CN) neutral patients are more likely to have 50 and 90 % PSA decline and have significantly longer overall and progression-free survival

References:

1. Visakorpi, T et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet. 1995:9, 401-6
2. Taplin, E et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl. J. Med 1995:332, 1393-8
3. Taplin E et al. Selection for androgen receptor mutations in prostate cancer treated with androgen antagonist. Cancer Res. 1999:59, 2511-5
4. de Bono et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011:364,1995-2005
5. Scher HI et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012:367,1187-97.
6. Perkins G, Yap TA, Pope L et al. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PLoS One. 2012;7:e47020
7. Dawson SJ, Tsui DW, Murtaza M et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013:368:1199-209.
8. Gasi Tandefelt D*/Romanel A*, Contaduca V, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med 2015:7(312):312re1
9. Garcia-Murillas I et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015:7:302ra133

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INSTITUTE OF CANCER RESEARCH - ROYAL CANCER HOSPITAL
United Kingdom
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