Prostate cancer is the 2nd most common cancer in the western world. The advanced stage, metastatic castration-resistant prostate cancer (mCRPC), is a lethal disease. Understanding inter-patient genomic heterogeneity renders the opportunity to advance towards personalised patient care. Prostate cancer is a disease primarily driven by the androgen receptor (AR) pathway; however, the applicant prior work contributed to identifying 1) that up to 25% of mCRPC harbour defects in DNA damage repair (DDR) genes, and 2) that some of these mCPRC patients with DDR defects are sensitive to targeted treatment with PARP inhibitors. In the proposed research plan, we aim to exploit the cross-regulation between AR and DDR pathways to optimize precise therapeutic options for mCRPC patients. To achieve the objectives, the applicant will use models generated at the host through CRISRP/Cas9 to pursue functional studies and characterise how defects in ATM impact DDR function and sensitivity to inhibitors of PARP, ATR and DNA-PK. We hypothesize such sensitivity would be modulated by co-targeting of the AR pathway and by second events such as TP53 loss-of-function. ChIP-Seq assays will be pursued to identify genes co-regulated by the androgen receptor and PARP-1, to identify potential synthetic vulnerabilities. Then, mCRPC patient’s biopsies acquired in clinical practice from patients receiving AR-targeting therapies will be used to study how AR inhibition modulate transcriptional regulation of DDR pathways, to inform the optimal design of combination therapies. These data would be correlated with genomics and immunofluorescence tests of homologous recombination function, in order to refine patient stratification in the clinic. The proposed research will be conducted in parallel to a personalised training and career development plans, designed for the applicant to achieve a position of academic independence as physician-scientist before the end of the fellowship at the host institute.

Metastatic prostate cancer (mPC) is a lethal disease. Androgen deprivation therapy is the mainstay of patient care. In addition, DNA repair defects is a novel therapeutic target in mPC. However, resistances invariably arise, triggered most of the times by tumor genomic evolution. Liquid biopsy has emerged as a tool to non-invasively profile tumor genomics over time. Beyond circulating tumor DNA (ctDNA) and circulating tumor cells (CTC), small extracellular vesicles, known as exosomes, have been identified to contain tumor genomic material. Over the last years, I have developed a method to pursue analysis of tumor genomic material from exosomes at a very low cost. The analysis of exoDNA/RNA is a promising tool that represents a new non-invasive, sensitive and very informative new method for PC monitoring. In this project, I aim to integrate the genomic analysis of exoDNA/RNA together with ctDNA and CTCs in advanced PC to:1) Identify prognostic signatures for clinically-relevant patient stratification; 2) Define circulating predictive signatures of drug response/resistance; and 3) Validate biomarkers of therapy response for selection of subsequent lines of treatment. Therefore, this fellowship would allow me to take a significant step towards the implementation of this new technology in the study of mPC genomics and mechanisms of response/resistance to novel targeted drugs. Furthermore, I will be able to integrate my research into clinical trials and, ultimately, impact personalized patient care.

Current cancer therapies target redundant cellular functions often compensated for by cancer cells, resulting in resistance to treatment. Here we propose an innovative approach to inhibit Myc, a non-redundant and “most-wanted” therapeutic target for human cancer. Targeting Myc has long been considered unfeasible because of the potentially catastrophic side effects in normal tissues. Against this dogma, we showed that Myc inhibition by Omomyc, a Myc mutant designed by Dr. Soucek, has a dramatic therapeutic impact in multiple mouse models of cancer, while causing only limited and reversible side effects. Critically, there is no emergence of resistance. Thanks to the ERC-2013-CoG n° 617473, we discovered the unexpected cell-penetrating properties of the purified Omomyc polypeptide. Moreover, we found that it is anti-tumorigenic after local (intranasal) delivery to mouse models of lung and brain tumors, and could therefore become the first clinically-viable direct Myc inhibitor. With this ERC PoC, we propose to develop a new drug based on an Omomyc variant that enables systemic treatment of several cancer types including lymphoma, breast, and melanoma. In all these cancers Myc contributes to multiple aspects of tumorigenesis including immune suppression. At the end of this project we will have a patent protected therapeutic polypeptide active in vitro and in vivo and ready to enter clinical trials Phase I/II in patients and to continue its commercialization. The forecasted peak revenue for such first-in-class drug in those indications reaches 2.612 M€ annually. With this ERC PoC project we will achieve essential milestones to develop this innovative therapeutic polypeptide by establishing the feasibility, including a commercial data package and cost estimations for the industrial production. Passing these milestones will de-risk the product and increase its value and probability of reaching the market by making it ready to be transferred to a spin-off company.

Colorectal cancer (CRC) is a leading cause of death worldwide. Mutations in components of the canonical Wnt/beta-catenin pathway such as APC, CTNNB1/beta-catenin, AXIN2 and more recently RNF43 or ZNRF3 can contribute to CRC tumorigenesis. The hosting team and Dr. Clevers’ group have recently described that inhibitors of the porcupine enzyme, that is essential for the maturation of Wnt-ligands, have therapeutic efficacy in tumors with RNF43 and ZNRF3 mutations. Hypermutant tumors are characterized by mutations in key components of the DNA mismatch repair (MMR) genes, resulting in the amplification in non-codifiying repetitive sequences in the genome known as microsatellites. Recent studies from the hosting team and Dr. Garraway’s group highlighted that mutations in RNF43 and ZNRF3 preferentially occur in a codifying microsatellite (hotspot) in MMR-deficient tumors. Lynch Syndrome is a hereditary cancer-prone disease where patients also develop MMR-deficient tumors as a consequence of germinal mutations in MMR genes accounting for 3-6% of CRC patients with very few therapeutic opportunities. In this proposal we aim to: 1) characterize Wnt-related genetic alterations in Lynch Syndrome patients and determine enrichment of RNF43 and ZNRF3 mutations compared to CRC sporadic tumors; 2) link MMR-deficiency and acquisition of the druggable Wnt-related mutations in RNF43 and ZNRF3; 3) evaluate the efficacy of PORCN/Wnt inhibitor WNT974 on tumors mutated in RNF43 and ZNRF3. We believe that not only Lynch Syndrome but any cancer patient with tumors presenting RNF43 and ZNRF3 mutations could benefit from the treatment with such new generation of Wnt/beta-catenin inhibitors. Our collaboration with the Oncology Service and pharmaceutical companies will accelerate the translation of our findings into the clinical practice and hopefully provide a new therapeutic opportunity for CRC patients. This would therefore have a general impact on cancer treatment in Europe.

Global cancer market is growing at a CAGR of 6.9% with an estimated value of $81bn in 2016. Although the huge R&D investment observed in the past years in the development of new treatments, there is still lack on an effective treatment in many tumour types. In particular, the median survival for glioblastoma multiforme (GBM), a high-grade brain tumour affecting 23,000 patients a year in US and EU, is 14 months and its 5-yr survival less than 5%. It is therefore urgent to develop more effective treatments against this fatal disease. There are two main reasons that explain the lack of success for the current treatments: In one hand, Cancer Stem cells (CSCs) are responsible from tumour initiation, maintenance, relapse and metastasis. On the other hand, the tumour has mechanisms to repress the patient’s immune system that attacks tumour cells. Our team has discovered a molecular pathway critical in the regulation of CSCs and the immune checkpoint. The project presented here entails the proof of concept and pre-clinical development of a humanized antibody blocking this pathway. At the end of the ERC POC project we will have a patent protected and fully humanized antibody active in vivo and in vitro and ready to enter Phase I clinical trials in humans to continue its commercialization process. The forecasted annual peak revenue for this therapeutic antibody in GBM is $590M with additional sales coming from line extensions in other cancer indications. With the ERC POC project we are dramatically increasing the commercial value of the therapeutic antibody, transforming an R&D finding (a pathway is critical for cancer) into a potential new solution to patients (a therapeutic antibody). Hence, we are de-risking the product, advancing it through the commercialization path and creating a product and a commercial data package with a good expectative in the cancer market that is ready to be transferred to a spin-off company.