CANBIO - PhD Training Program

Individual projects - Induced Escape Mechanisms

The aim of the second work package is to propose and test novel strategies based on the identification of key resistance mechanisms of selected cancer types evolved in response to targeted therapies, DNA damaging agents or changing environments (e.g. hypoxia). These aspects will be studied using complementary molecular and cellular approaches and relevant pre-clinical animal models.

Understanding the underlying mechanisms that govern therapy-induced escape mechanisms of tumour cells is crucial to prevent tumour relapse and promote the rational design of combinatorial as well as personalised treatment approach.

Project 1: Targeting DNA repair mechanisms in primary glioblastoma and their recurrences: from basic mechanisms to pre-clinical aspects and personalized therapy

Previous work has identified a list of DNA repair genes whose depletion in glioblastoma (GBM) cells leads to sensitivity to the DNA damaging agent temozolomide, and revealed gene-expression alterations that shape the “DNA repair makeup” of GBMs in clinical samples. This project will integrate in vitro approaches and the characterization of animal models of GBM to validate a selection of the most promising DNA repair factors in our list and test novel chemotherapeutic strategies against GBM.

Project 2: Targeting the Jak/STAT pathway in cancer: inhibitors and resistance mechanisms

The Jak/STAT pathway is often found constitutively active in cancer cells, either due to driver mutations in the signalling players (e.g. Jak2V617F in myeloproliferative neoplasms and leukemias), or due to upregulation of activators of the pathway. It can also contribute to resistance against drugs targeting other pathways. This project aims at the identification and characterization of drugs affecting Jak/STAT signaling. Moreover, tumour escape mechanisms involving the Jak/STAT pathway in the context of therapy resistance will be addressed

Project 3: Identifying and targeting the metabolic escape mechanisms in IDH mutant gliomas

The vast majority of low grade gliomas carries a mutation in the enzyme isocitrate dehydrogenase (IDH) which leads to the generation of the oncometabolite 2-hydroxyglutarate. We have used in situ metabolic profiling to determine the key metabolic aberrations in IDH mutant gliomas. Here we will determine the metabolic response and the escape mechanisms devoloped in gliomas after treatment with novel mutant IDH-inhibiting compounds.

For this project a PhD candidate has been recruited.

Project 4: Novel therapeutic strategies to target metabolic escape mechanisms in Glioblastoma

Anti-angiogenic treatment increases hypoxia, autophagy invasion and induces a metabolic switch in Glioblastoma towards increased glycolysis. We have shown previously that inhibiting glycolytic enzymes strongly affects Glioblastoma growth in pre-clinical in vivo.

Project 5: Effect of environmental stress factors on colon cancer and its microenvironment

Environmental stress conditions such as hypoxia influence tumour initiating cells and tumour-associated stromal cells. The project focusses on the role of hypoxia in tumor progression and the cross-talk between stromal cells and tumor-initiating cells. The study will take advantage of an in¬house collection of patient-derived tumor sphere cultures and stromal cells and ultimately aims at the identification of factors that drive metastasis and chemoresistance.

For this project a PhD candidate has been recruited.

Project 6: Signalling cross-talk between cytokines and environmental stress factors

The inflammatory cytokine Interleukin 6 (IL6) plays an important role in the development of hepatocellular carcinoma (HCC). It acts on the expansion of liver cancer stem cells, thereby also affecting metastasis formation and tumor recurrence after therapy. This project aims at identifying and targeting long non-coding RNAs involved in IL6/Jak/STAT3 signal transduction. The cross-talk between IL6 and hypoxic signaling pathways will also be addressed. Our study may help to develop therapeutic strategies targeting inflammatory networks in HCC.