Predictive biomarkers of response to DNA repair targeting agents in sporadic prostate cancer

Prostate cancer is the commonest cancer in men, but despite recent advances with new drugs approved over the last few years, there is a lack of tests to select individually the best treatment for each patient. We observe in the daily clinical practice how some patients with prostate cancer have a very indolent course of disease whereas others may have a very aggressive type of cancer and may not respond to standard therapies. Our research aims to provide a tool to identify early who are the patients who may have a disease with worst prognosis and may need a different treatment, by assessing how the tumour cells repairs its integrity after damages.

A group of proteins (each of them codified by one gene) is involved in the response of the cell to some types of damage, in a process called "DNA repair". We now know that a proportion of patients with advanced prostate cancer would have one or more genetic switches in the different genes involved in this DNA repair system. PARP inhibitors are a class of drugs in current development to treat cancer in patients; the biggest success so far has occurred in treating patients with particular inherited switches in the DNA repair genes BRCA1/2. People with this BRCA mutations are more likely to develop beast, ovarian or prostate tumours, among other cancers and it has been shown that these people develop a very aggressive subtype of prostate cancer, with quicker progression and worst outcome.

Some studies in the laboratory have shown that when a cell has one or more defects in other genes involved in the DNA repair system, it could also become equally responsive to PARP inhibition. Indeed, there is clinical evidence of some benefit of PARP inhibition in ovarian cancer in patients without BRCA1/2 inherited mutations.

At the Institute of Cancer Research, together with The Royal Marsden NHS Trust, we are currently running clinical trials of PARP inhibitors for patients with advanced prostate cancer without an inherited BRCA mutation.

The research project we present aims to:

a) Determine the frequency of defects in the genes involved in DNA repair in sporadic (non-hereditary) prostate cancers and to determine how relevant are these defects in terms of determining the prognosis of the patient or the likelihood of responding to standard treatments.
b) Analyse the differences in the genomic profile from the patients with sporadic prostate cancer who have benefited from PARP inhibitors to those who have not responded to these drugs.
b) Evaluate in laboratory cell models how these genetic switches impact in the capacity of the cells to repair DNA damage and how these determine the sensitivity to different treatments.
d) Set up a laboratory test that can be performed in any patient with prostate cancer to predict if their particular disease is likely to be sensitive to PARP inhibitors. These test will be used to optimise the recruitment of advanced prostate cancer patients for large clinical trials with PARP inhibitors.

Prostate cancer (PC) is the commonest cancer in men and is highly heterogeneous; despite this, molecular stratification to guide treatment is not standard of care. Defects in DNA repair genes in sporadic PC present a therapeutic opportunity. Preclinical studies indicate that cell lines defective in genes involved in homologous recombination, including BRCA1/2, ATM, ATR, CHEK2 and RAD51, are sensitive to PARP inhibitors (PARPi). We have now shown that PARPi have antitumour activity in sporadic PC in clinical trials of niraparib (Sandhu et al, 2013) and olaparib (unpublished).

AIMS
I. To determine the frequency of DNA repair defects in sporadic PC and the impact of these on prognosis and response to endocrine treatment.
II. To determine the prevalence of DNA repair defects in patients responding or resistant to PARPi.
III. To evaluate the functional relevance, in preclinical models, of genomic aberrations identified in these tumor biopsies studied in Aims I and II.
IV. To clinically qualify a biomarker suite that will serve as a predictive biomarker of sensitivity to PARPi in sporadic CRPC.

METHODOLOGY
1. Next generation sequencing (NGS) of CRPC samples using a customized panel to identify DNA repair defects. These data will be correlated with clinical data.
2. Use of whole genome sequencing data of sporadic CRPC responding or resistant to PARPi to identify defects in DNA repair that associate with response.
3. Knockout and knock-in functional studies of identified genes, in in vitro studies, to determine their impact on PARPi sensitivity and DNA repair.
4. Customized, high throughput, targeted and high coverage NGS (>1000 fold coverage) using the MiSeq Illumina platform of all the identified genes to prospectively select patients for planned large randomized studies.

IMPLICATIONS: It is envisioned that these studies will generate the first biomarker suite to guide systemic treatment selection for prostate cancer.

Who will benefit from this project and how will they?

1.- Patients with prostate cancer in the UK (short term): validation of the screening sequencing panel would permit a more rational selection of patients to be included in the TO-PARP and other clinical trials that are currently planned to evaluate drugs targeting DNA repair in prostate cancer in several British academic institutions. That includes PARP inhibitors, platinum salts, DNA-PKc inhibitors and others.

2.- Patients with prostate cancer (mid-long term): publication of these results aims to contribute to one of the more urgent challenges in prostate cancer medical care, the lack of molecular tests to subclassify the disease and predict its aggressiveness. We would be able eventually to recommend patients whether they need a more or less agressive course of treatment, avoid unnecessary treatment for patients with indolent disease and select alternative therapeutic options for patients who are likely not to respond to endocrine therapies.

The results of this research can have implications towards improving the knowledge and the treatment of other cancers dependants on DNA repair.

3.- Public and private health system providers: stratification of patients with prostate cancer would be a long-term benefit for health care providers as, whereas the cost of sequencing screening tests is progressively decreasing, the cost of new drugs entering the market continues to raise. Therefore, this research would impact in health resource planning by:
a) identify patients whom disease may have different degrees of aggressiveness and so may need different levels of health care attention
b) decrease the rates of patients who are prescribed on a drug that is not likely to benefit them
c) prescribe novel treatment only to those subgroups of patients who are more likely to benefit

4.- Academic investigators in prostate cancer: a better understanding of the role of DNA repair in prostate cancer and a sequencing tool that can be easily implemented in major academic institutions in the Western world would help in the development of other therapeutic strategies in prostate cancer

5.- Pharmaceutical industries with interest in PARP inhibitors: five pharmaceutical companies have compounds targeting PARP at different stages of clinical development. If our hypothesis is demonstrated, the population in which PARP inhibitors can be developed for would increase dramatically. Even if the biomarker suite developed turns out to identify a groups of patients that represents a small percentage of prostate cancer patients, considering it is the commonest cancer in men, the total number of potential patients could be enormous.