Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes. Advances with new targeted therapies have been achieved and available options for treating CRC patients have prolonged patient's survival. Drugs specific for driven mutations are already available in clinical settings; nonetheless CRC has the ability to develop resistance. Additionally, some patients do not have to date any specific targeted therapy necessitating further research and treatment development.
Hedgehog-GLI (HH-GLI) pathway is a potent morphogen and master regulator of stem/progenitor cells, specifically dysregulated in different types of tumors (e.g. colon, brain and lung).
We hypothesize that the subpopulation of colorectal cancer cells with stemness, the colorectal cancer stem cells (CR-CSCs), together with the aberrant HH-GLI signaling are involved in CRC resistance to therapy. This project is based on preliminary studies suggesting that HH-GLI activation has a function in CR-CSCs maintenance and the aim of this proposal is to investigate whether HH-GLI is involved in the mechanisms underlying treatment resistance.
The project specifically addresses three strategic issues:
1. Providing data on patterns of HH-GLI pathway components expression among CR-CSCs carrying different mutations.
2. Investigation the function of GLI1, transcription activator of HH-GLI, in controlling CR-CSCs behavior and resistance to therapy.
3. Study of the effects of GLI1 inhibition in vitro.
The project aims to identify promising molecular target candidates that could be ultimately used to design personalized safe and effective treatments on the basis of each patient's features to improve the efficacy of therapy.
Innovation of proposed project.
Until now, the use of current treatments in CRC patients has proven to be insufficient, a problem that the scientific community has not yet been able to resolve. The proposed project is a study with the overall purpose of uncovering molecular mechanisms that determine or support drug resistance in CRC patients. We can envisage an important impact due to the possibility of identification of new therapeutic targets thus avoiding expensive ineffective treatments and toxicity. Since patient mortality and high-risk disease are characterized by the presence of metastatic lesions, there is significant interest in unraveling the role of HH-GLI signaling pathway in this context.
Advancement of knowledge expected from the proposed project.
This project can contribute to the advancement of knowledge for the following reasons: Prof. Vacca has many years of experience and specific expertise in the fields involved in this project. She has concentrated her interest on tumorigenic key events investigating their molecular aspects and focusing on how this information can be used in different types of tumors, including colorectal cancers. The research unit coordinated by Prof. Vacca is located in the Department of Experimental Medicine of Sapienza University and provides laboratories of biochemistry, molecular biology and cell culture/cell biology.