S. John Jacob
Honorary Senior Clinical Research Fellow
- Consultant Neurologist
Cancer is a collection of many diseases, each with its own unique repertoire of genetic mutations that present many challenges for scientists and clinicians attempting to treat patients. The genetic complexity of cancer means that treatments ultimately need to be tailored to individuals to get the best outcomes. The brain cancer, medulloblastoma is the commonest malignant brain cancer in children and can also affect adults. In under a decade remarkable progress has been made in distinguishing different types of medulloblastoma, yet the treatment approaches have not changed for many years, and have debilitating side-effects.
A major subtype of medulloblastoma is initiated by activating mutations in the sonic hedgehog (SHH) signalling pathway, which is important for growth, stem cell maintenance, and is implicated in multiple other tumour types. Other biochemical pathways in the cell influence SHH signalling, and we and others showed that cholesterol is required for SHH signalling. There are already many drugs that regulate cholesterol synthesis, in particular statins. In collaboration with colleagues in the Department of Oncology (https://www.oncology.ox.ac.uk), and in the Francis-Crick Institute, London we are investigating whether drugs that inhibit cholesterol synthesis can reverse aberrant SHH signalling in SHH-medulloblastoma in the hope that these agents can be repurposed as useful adjuncts in the treatment of SHH medulloblastoma.
In pursuing this goal, a fundamental limitation is the lack of suitable human cellular SHH-MB models that could be used to test novel drugs. Studies in humans show that SHH-MB is genetically heterogeneous which explains why current therapies have variable outcomes. Therefore, there is an urgent need for new cellular models of SHH medulloblastoma which recapitulate the genetic diversity of the human disease. A major bottleneck in achieving this goal is the development of robust protocols to generate the cells of origin of SHH medulloblastoma. In collaboration with colleagues in the Department of Anatomy, Physiology and Genetics we are beginning to produce the neural progenitor cells from which SHH medulloblastoma arise, with a view to engineering relevant genetic mutations using state-of-the-art genome editing technology.
Lipid metabolism fattens up hedgehog signaling
Blassberg R. and Jacob J., (2017), Bmc biology, 15
Focal precentral gyrus involvement in osmotic demyelination.
Turner MR. et al, (2017), Pract neurol, 17, 410 - 411
Reduced cholesterol levels impair Smoothened activation in Smith-Lemli-Opitz syndrome.
Blassberg R. et al, (2016), Hum mol genet, 25, 693 - 705
Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.
Jacob J., (2016), Epilepsia, 57, 182 - 193
THE LINK BETWEEN CHOLESTEROL AND HEDGEHOG SIGNALLING IN EPILEPSY AND AUTISM SPECTRUM DISORDER: A CELLULAR MODEL OF SMITH-LEMLI-OPITZ SYNDROME
Jacob J. and Blassberg R., (2015), Epilepsia, 56, 120 - 120