Transposable elements as novel therapeutic targets for PARPi-induced lethality in osteosarcoma

Primary supervisor: Mohammad Mahdi Karimi, King’s College London

Secondary supervisor: Sibylle Mittnacht, UCL

Project

Osteosarcoma (OS) is the most common primary human bone malignancy. More than half of cases arise in children and young adults, with disproportionate contribution to cancer death in these age groups [1]. Aggressive multimodal treatment involving combination chemotherapy substantially increases survival. However, less than 30% of patients diagnosed with metastatic disease show long-term response; and relapse and treatment associated toxicity in patients diagnosed with localised disease remain chief concerns [1,2]. Emerging OS genomics data reveal the prominent presence of deleterious mutations in the known tumour suppressors TP53, RB1, ATRX and CDKN2A [3,4]. In a recent publication by Professor Mittnacht’s group, it was shown that there is a selective hypersensitivity to clinically approved inhibitors of Poly-ADP-Polymerase [1,2] inhibitors (PARPi) in RB1-defective OS derived cell models, including an extended panel of OS-derived lines [5]. The cause of the exquisite PARPi sensitivity in RB1 defective OS is now known. Interestingly, PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that predict PARPi sensitivity in cancers with BRCA1,2 loss.

Transposable elements (TEs), comprising around 50% of the human genome, have recently been shown to regulate various key cellular processes, including gene expression, DNA damage responses (DDR) and immune responses. In a collaborative project between Dr Karimi and Professor Eric So in King’s College London, which is under review in Nature Genetics, they showed that co-inactivation of Asxl1 and Ezh2 in haematopoietic stem and progenitor cells resulted in highly penetrant haematological malignancies of myeloid or lymphoid lineages with marked reactivation of TEs and DDR. Using both mouse models and primary patient samples, they showed that Asxl1/Ezh2 mutated leukaemia cells are highly sensitive to PARPi treatment, which led to excessive DNA damage and cell death. PARPi significantly extended disease latency in vivo, which intriguingly can be overridden by reverse transcriptase inhibitors that specifically interrupt the life cycle of TEs.

Combining these two significant findings of the effectiveness of PARPi in OS treatment and the functional role that TEs play in PARPi-induced lethality, we hypothesize that reactivation of TEs may also be a determinant of PARPi vulnerability in OS. The project will bring together translational sarcoma biology techniques and OS focussed resources such as extended OS-focussed cell lines with complete genetic characterization and near-patient models, including patient-derived early passage Xenograft in Professor Mittnacht’s lab with the biology and bioinformatics knowledge of TEs from Dr Karimi’s group to investigate the potential roles of TEs in OS biology including PARPi response. Throughout this project, we will produce transcriptomics and proteomics data for pre and post-in vitro (cell lines) and in vivo (xenograft) PARPi-treated OS samples to investigate the link between RTE expression, oncogenicity, and PARPi sensitivity in OS.

Candidate background

This project would suit candidates with a background in molecular biology. In addition to regular experimental work, the PhD candidate is expected to learn R and Python scripting, acquire analytical skills in statistical genomics/transcriptomics, and integrate multi-omics data.

Potential Research Placements

1. Agi Grigoriadis, Centre for Craniofacial & Regenerative Biology, King’s College London
2. Ali Awan, Genomics Innovation Unit, Guy’s and St. Thomas’ NHS Foundation Trust, King’s College London
3. Graeme Hewitt, Comprehensive Cancer Centre, King’s College London

References

1. Casali PG, Bielack S, Abecassis N, et al. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv79-iv95. doi:10.1093/annonc/mdy310
2. Smeland S, Bielack SS, Whelan J, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer. 2019;109:36-50. doi:10.1016/j.ejca.2018.11.027
3. Kovac M, Blattmann C, Ribi S, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940. Published 2015 Dec 3. doi:10.1038/ncomms9940
4. Behjati S, Tarpey PS, Haase K, et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat Commun. 2017;8:15936. Published 2017 Jun 23. doi:10.1038/ncomms15936
5. Zoumpoulidou G, Alvarez-Mendoza C, Mancusi C, et al. Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma. Nat Commun. 2021;12(1):7064. Published 2021 Dec 3. doi:10.1038/s41467-021-27291-8