Even though the MYC oncogene is a “most-wanted” target in cancer therapy, no MYC inhibitor has yet reached clinical approval. The applicant has developed Omomyc, the first MYC-inhibiting mini-protein to have successfully completed a Phase Ia clinical trial. The goal of this proposal is to maximise the use of this compound, as both a therapeutic and study tool, opening new lines of research in different aspects of MYC biology. To start with, since Omomyc cannot efficiently cross the blood brain barrier, excluding it from use in brain malignancies or brain metastases, in Aim 1, we propose to validate its efficacy when delivered intracranially by different means, including osmotic pumps and hydrogels, as well as to test its delivery by intracarotid injection, in glioblastoma and brain metastases. Then, in Aim 2 and 3, we will explore its combination with personalized medicine, namely PARPi and KRASi, respectively. These 2 aims are derived from two pillars of MYC biology: its role in DNA damage response and the paradigm of oncogene cooperation. Aim 2 will allow us to shed light on the role of MYC in homologous recombination and resistance to PARPi, while Aim 3 will deliver on the molecular mechanisms underlying the cooperation of RAS and MYC in multiple tumour types, where their combined inhibition could represent an unprecedented therapeutic opportunity. Finally, Aim 4 will focus on the characterisation of cancers such as Small Cell Lung Cancer and Gastrointestinal Stromal Tumours that have the peculiarity of being defective for MAX – MYC’s natural partner – but that recapitulate a MYC-dependent tumour phenotype, likely driven by other members of the MYC network, whose function could also be hindered by Omomyc treatment. Notably, each of the aims explores new aspects of MYC biology, tracing new lines of research around the most deregulated oncogene in human tumours as well as having immediate translational applicability in upcoming clinical trials of Omomyc.

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.

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.

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.