Sub-clonal RNASH2B/RB1 loss, luminal-to-basal transformation, and novel therapeutic vulnerabilities in metastatic prostate cancer
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Clinical Studies
Abstract
Advanced prostate cancer is characterised by the emergence of resistance to hormone therapy, and is invariably fatal. The biological mechanisms underlying the evolution to an aggressive, treatment-resistant state are diverse, and have not yet been fully characterised. Further understanding of these mechanisms will allow the development of targeted treatment strategies.
Our DNA is exposed to damage in various forms each day, and relies on our body's innate mechanisms to repair this, and protect our genetic code. Recent evidence has identified defects in the ability to repair damage to DNA in 20-30% of advanced prostate cancer patients. This results in the accumulation of DNA damage, which makes cancer cells dependent on alternative pathways for survival, which we can exploit therapeutically, with agents targeting DNA repair pathways, such as PARP and ATR inhibitors. However, there is a need for more robust tests to easily identify patients who may benefit from such therapies.
DNA repair defects enable the accumulation of DNA damage, which can be expressed as proteins (neo-antigens) on the cancer cell. These make the cancer more visible to the immune system, and therefore more vulnerable to treatments which act on immune cells to trigger an anti-cancer immune response, such as immune checkpoint inhibitors.
A new DNA repair defect, RNASEH2B loss, commonly present in advanced prostate cancer, has recently been identified, and is associated with heightened sensitivity to PARP/ATR inhibition. It is located on chromosome 13, close to RB1, a gene which is frequently deleted in aggressive forms of PC, at a late stage in the disease evolution, and is associated with poor outcomes. Our preliminary data suggests these genes are often deleted together, and this may contribute to the development of aggressive 'basal/neuroendocrine' PC cells which drive hormone resistance. We hypothesise that patients with RNASEH2B loss represent a novel cohort of patients with distinct biology who may respond to PARP/ATR inhibitors and/or immunotherapy.
Here, I seek to explore the incidence of this co-deletion in prostate cancer, and its impact on tumour evolution and sensitivity to PARP/ATR inhibitors and immunotherapy. I hope to demonstrate that RNASEH2B/RB1 loss is identifiable within peripheral blood samples, and can be easily measured to identify candidates for treatment. If I demonstrate enhanced sensitivity to PARPi, ATRi or immunotherapy in pre-clinical models, I will endeavour to establish a proof of concept phase II trial of PARPi +/- ATRi (arm 1) and immunotherapy (arm 2) in RNASEH2B/RB1 deficient prostate cancer.
I envisage that this research will enable better molecular stratification of advanced prostate cancer, and identify and target aggressive, resistant PC cells to enable us to develop novel therapeutic strategies to transform the treatment and outcomes for patients.
Our DNA is exposed to damage in various forms each day, and relies on our body's innate mechanisms to repair this, and protect our genetic code. Recent evidence has identified defects in the ability to repair damage to DNA in 20-30% of advanced prostate cancer patients. This results in the accumulation of DNA damage, which makes cancer cells dependent on alternative pathways for survival, which we can exploit therapeutically, with agents targeting DNA repair pathways, such as PARP and ATR inhibitors. However, there is a need for more robust tests to easily identify patients who may benefit from such therapies.
DNA repair defects enable the accumulation of DNA damage, which can be expressed as proteins (neo-antigens) on the cancer cell. These make the cancer more visible to the immune system, and therefore more vulnerable to treatments which act on immune cells to trigger an anti-cancer immune response, such as immune checkpoint inhibitors.
A new DNA repair defect, RNASEH2B loss, commonly present in advanced prostate cancer, has recently been identified, and is associated with heightened sensitivity to PARP/ATR inhibition. It is located on chromosome 13, close to RB1, a gene which is frequently deleted in aggressive forms of PC, at a late stage in the disease evolution, and is associated with poor outcomes. Our preliminary data suggests these genes are often deleted together, and this may contribute to the development of aggressive 'basal/neuroendocrine' PC cells which drive hormone resistance. We hypothesise that patients with RNASEH2B loss represent a novel cohort of patients with distinct biology who may respond to PARP/ATR inhibitors and/or immunotherapy.
Here, I seek to explore the incidence of this co-deletion in prostate cancer, and its impact on tumour evolution and sensitivity to PARP/ATR inhibitors and immunotherapy. I hope to demonstrate that RNASEH2B/RB1 loss is identifiable within peripheral blood samples, and can be easily measured to identify candidates for treatment. If I demonstrate enhanced sensitivity to PARPi, ATRi or immunotherapy in pre-clinical models, I will endeavour to establish a proof of concept phase II trial of PARPi +/- ATRi (arm 1) and immunotherapy (arm 2) in RNASEH2B/RB1 deficient prostate cancer.
I envisage that this research will enable better molecular stratification of advanced prostate cancer, and identify and target aggressive, resistant PC cells to enable us to develop novel therapeutic strategies to transform the treatment and outcomes for patients.
Technical Summary
Background: Clinical outcomes remain sub-optimal in mCRPC, which is invariably lethal. There is an urgent need for novel therapeutic strategies and predictive biomarkers. 20-30% PC patients harbour DNA repair defects. PARP inhibition is synthetic lethal with defective DNA repair impacting homologous recombination. Our lab recently reported that RNASEH2B loss (gene locus: 13q14.3, adjacent to RB1 on 13q14.2 and BRCA2), which results in the accumulation of misincorporated ribonucleotides into DNA, is synthetic lethal with PARPi. Hypothesis: Sub-clonal co-deletion of RNASH2B and RB1 is a key mCRPC vulnerability related to luminal to basal transition, sensitizing to PARPi, ATRi, and immunotherapy by generating a high neo-antigen burden. Targeting this emerging vulnerability to eradicate aggressive disease sub-clones could improve outcome from mCRPC, detectable through circulating biomarker assays. Aims: I will A) Define clinical emergence of sub-clonal PC RNASEH2B/RB1 loss with endocrine resistance and following exposure to Olaparib. I will correlate this with markers of basal/neuroendocrine differentiation and replication stress (IHC; RNAish; FISH; CTC/cf DNA sequencing); B) Evaluate the impact of RNASEH2B +/- RB1 knockdown on replication stress and response to PARPi/ATRi (CRISPR; PDX-O; Conditional transgenics); C) Determine if RNASEH2B loss associates with an immunogenic phenotype (high neoantigen burden, tumour infiltrating lymphocytes and PD-L1 expression) and immunotherapy sensitivity (Multi-colour immunofluorescence; IHC; Exome/RNAseq). D) If the above hypotheses are proven, I will establish a biomarker-driven phase II trial of PARPi+/-ATRi and immunotherapy in mCRPC with RNASEH2B/RB1 loss. Implications: I envision that this research will improve molecular stratification, targeted treatment, and clinical outcomes of mCRPC, identifying an emerging therapeutic vulnerability for aggressive, resistant basal, 'neuroendocrine', disease sub-clones.
Planned Impact
Academic Impact:
This study aims to better define the evolution of endocrine resistant sub-clones in prostate cancer. This novel approach will enable early identification and tailored treatment of resistant sub-clones, detectable in peripheral blood, with unique therapeutic vulnerabilities, to improve outcomes in aggressive localized disease, de novo NEPC and mCRPC. Through peer-reviewed publications and international/national presentations, we hope to share our findings with the wider scientific community, provide new insight into the development of targeted treatments for advanced prostate cancer, and help to better distinguish between aggressive and indolent disease. RB1 loss is a well- defined resistance mechanism in other types of cancer. The findings will be therefore transferable across tumour types, and will inform our understanding of the evolution of treatment resistance and identify novel tumour agnostic treatment strategies. Our research methodologies, findings and clinical trial design will be published through various avenues to ensure maximum impact on the research community.
Economic and Societal Impact:
A) Patients
I hope to identify effective new treatment strategies, with the ultimate goal of improving outcomes for patients with prostate cancer, and informing the future direction of drug development and trial design. Validation of circulating biomarkers will enable the targeted treatment of evolutionary sub-clones without the future need for invasive biopsies. Clinical detection of resistant sub-clones will also facilitate rapid treatment switches to clear adapting prostate cancer sub-clones as they evolve, before radiological progression, resulting in a paradigm shift in treatment approach. This will improve quality of life by avoiding unnecessary exposure to ineffective therapies, with their associated toxicities, and delivering targeted therapies with better side effect profiles. This approach is likely to have broad applications to better understand tumour evolution and target treatment resistance in a wider population of cancer patients.
B) Economic and wider societal impact
mCRPC is the commonest male malignancy in the UK and therefore carries a high morbidity, mortality and economic burden. Early and effective treatment for patients with aggressive localized disease, in whom endocrine treatment has poor outcomes, may enable cure in some patients. Early eradication of resistant sub-clones may also prolong endocrine sensitivity, reduce disease related complications and treatment burden for these patients, resulting in reduced morbidity and healthcare costs. Non-invasive monitoring of response and tumour evolution through circulating biomarkers will enable the targeted delivery of novel therapies to relevant patient cohorts. This will enable molecular stratification and tailored treatment of prostate cancer patients and inform healthcare policy in the UK and worldwide. The impact of this research will be maximized by distributing findings amongst the academic and wider community, as detailed in the communication plan.
Through my own development, I will learn laboratory techniques and experimental design, enabling my transition to an independent researcher, with the ultimate goal of leading research group and providing long term contributions to the prostate cancer research community.
This study aims to better define the evolution of endocrine resistant sub-clones in prostate cancer. This novel approach will enable early identification and tailored treatment of resistant sub-clones, detectable in peripheral blood, with unique therapeutic vulnerabilities, to improve outcomes in aggressive localized disease, de novo NEPC and mCRPC. Through peer-reviewed publications and international/national presentations, we hope to share our findings with the wider scientific community, provide new insight into the development of targeted treatments for advanced prostate cancer, and help to better distinguish between aggressive and indolent disease. RB1 loss is a well- defined resistance mechanism in other types of cancer. The findings will be therefore transferable across tumour types, and will inform our understanding of the evolution of treatment resistance and identify novel tumour agnostic treatment strategies. Our research methodologies, findings and clinical trial design will be published through various avenues to ensure maximum impact on the research community.
Economic and Societal Impact:
A) Patients
I hope to identify effective new treatment strategies, with the ultimate goal of improving outcomes for patients with prostate cancer, and informing the future direction of drug development and trial design. Validation of circulating biomarkers will enable the targeted treatment of evolutionary sub-clones without the future need for invasive biopsies. Clinical detection of resistant sub-clones will also facilitate rapid treatment switches to clear adapting prostate cancer sub-clones as they evolve, before radiological progression, resulting in a paradigm shift in treatment approach. This will improve quality of life by avoiding unnecessary exposure to ineffective therapies, with their associated toxicities, and delivering targeted therapies with better side effect profiles. This approach is likely to have broad applications to better understand tumour evolution and target treatment resistance in a wider population of cancer patients.
B) Economic and wider societal impact
mCRPC is the commonest male malignancy in the UK and therefore carries a high morbidity, mortality and economic burden. Early and effective treatment for patients with aggressive localized disease, in whom endocrine treatment has poor outcomes, may enable cure in some patients. Early eradication of resistant sub-clones may also prolong endocrine sensitivity, reduce disease related complications and treatment burden for these patients, resulting in reduced morbidity and healthcare costs. Non-invasive monitoring of response and tumour evolution through circulating biomarkers will enable the targeted delivery of novel therapies to relevant patient cohorts. This will enable molecular stratification and tailored treatment of prostate cancer patients and inform healthcare policy in the UK and worldwide. The impact of this research will be maximized by distributing findings amongst the academic and wider community, as detailed in the communication plan.
Through my own development, I will learn laboratory techniques and experimental design, enabling my transition to an independent researcher, with the ultimate goal of leading research group and providing long term contributions to the prostate cancer research community.
| Description | Participation in ACCELERATE paediatric strategy forum on DNA damage repair inhibitors |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | International collaboration to focus research efforts and prioritise DNA damage repair drugs/trials for development in the paediatric population. Conclusions from the meeting not yet published (under review European journal of cancer). |