Title: Targeting Src as a Driver of CNS Grp 4 Medulloblastoma and Glioma
Funder: The Brain Tumour Charity

Abstract: Aims and background. Advanced genetic (genomic) technologies have increased the precision of clinical diagnosis but have failed to identify new treatments for brain-tumours, so that increases in survival have stagnated. Many of the complex events which underlie the development of brain tumours, and which may represent new targets for drug discovery, are invisible at a genetic level. We recently utilised “proteomics”, a technology that directly quantitates cancer proteins (the targets of cancer drugs), to detect changes in thousands of cancer proteins within brain-tumour tissues. We discovered that genomic data is imprecise in its ability to detect changes in cancer proteins, that alterations in the SRC cancer-protein were present across all pooroutcome (Group4) medulloblastomas, that SRC could stimulate formation of Group4 medulloblastomas in mice engineered to and finally that a clinic-ready SRC drug we developed penetrates brain tissue and is effective in early animal studies. We now aim to: 1) establish whether our SRC drug effectively blocks the growth of Group4 medulloblastomas in mice, 2) find additional proteins that interact with SRC and therefore could be additional drug targets, and 3) determine if proteomics with an expanded dataset can identify additional drug targets. Why this research is needed. Brain tumours are the most unsurvivable of childhood malignancies, for which few new treatments have been developed even with application of large-scale genomic technologies. Existing research suffers from a lack of accurate experimental mouse models of native brain-tumours and from weakness in power of existing technologies to identify potentially druggable events. We contend that detailed crosscomparison of genomic and proteomic data is required to discover new targets, that validation of targets requires use of native, gene-driven mouse models, and that drug efficacy can only be properly established within a mouse-hospital suitably able to conduct advanced preclinical drug trials incorporating surgery, imaging and other that resemble clinical therapy. Methodology. We are one of few teams worldwide with sufficient resource and multidisciplinary expertise that can apply these approaches effectively. We will interrogate our unique transcriptomic and proteomic datasets, which are highly annotated with clinical information, to discover new SRC-related (and completely new and unrelated) cancer proteins that could be targeted with drugs. We will validate our findings in novel experimental mouse models and establish efficacy of drugs within our mouse hospital, using advanced clinical imaging and treatments that resemble hospital-based therapy. We will focus on the role of SRC protein but in the course of probing our proteomic data and modelling SRC-driven tumours in our animal models, we will focus on identification of new SRC-related and unrelated proteins that themselves could be drug targets. In so doing we will move forward development of 1-3 new targets to clinical trials. Patient and Public Involvement. Clinicians within our group will analyse the data in detail to guide clinical implementation in their roles as clinical trials leaders. We work closely with parents and patients to develop our research, some of whom are RIN members. We disseminate all findings in public databases, at international conferences, and in publications.

Lay abstract: Aims and background. Advanced genetic (genomic) technologies have increased the precision of clinical diagnosis but have failed to identify new treatments for brain-tumours, so that increases in survival have stagnated. Many of the complex events which underlie the development of brain tumours, and which may represent new targets for drug discovery, are invisible at a genetic level. We recently utilised “proteomics”, a technology that directly quantitates cancer proteins (the targets of cancer drugs), to detect changes in thousands of cancer proteins within brain-tumour tissues. We discovered that genomic data is imprecise in its ability to detect changes in cancer proteins, that alterations in the SRC cancer-protein were present across all pooroutcome (Group4) medulloblastomas, that SRC could stimulate formation of Group4 medulloblastomas in mice engineered to and finally that a clinic-ready SRC drug we developed penetrates brain tissue and is effective in early animal studies. We now aim to: 1) establish whether our SRC drug effectively blocks the growth of Group4 medulloblastomas in mice, 2) find additional proteins that interact with SRC and therefore could be additional drug targets, and 3) determine if proteomics with an expanded dataset can identify additional drug targets. Why this research is needed. Brain tumours are the most unsurvivable of childhood malignancies, for which few new treatments have been developed even with application of large-scale genomic technologies. Existing research suffers from a lack of accurate experimental mouse models of native brain-tumours and from weakness in power of existing technologies to identify potentially druggable events. We contend that detailed crosscomparison of genomic and proteomic data is required to discover new targets, that validation of targets requires use of native, gene-driven mouse models, and that drug efficacy can only be properly established within a mouse-hospital suitably able to conduct advanced preclinical drug trials incorporating surgery, imaging and other that resemble clinical therapy. Methodology. We are one of few teams worldwide with sufficient resource and multidisciplinary expertise that can apply these approaches effectively. We will interrogate our unique transcriptomic and proteomic datasets, which are highly annotated with clinical information, to discover new SRC-related (and completely new and unrelated) cancer proteins that could be targeted with drugs. We will validate our findings in novel experimental mouse models and establish efficacy of drugs within our mouse hospital, using advanced clinical imaging and treatments that resemble hospital-based therapy. We will focus on the role of SRC protein but in the course of probing our proteomic data and modelling SRC-driven tumours in our animal models, we will focus on identification of new SRC-related and unrelated proteins that themselves could be drug targets. In so doing we will move forward development of 1-3 new targets to clinical trials. Patient and Public Involvement. Clinicians within our group will analyse the data in detail to guide clinical implementation in their roles as clinical trials leaders. We work closely with parents and patients to develop our research, some of whom are RIN members. We disseminate all findings in public databases, at international conferences, and in publications.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS