Project description
From diabetes research to cancer therapy
The Tudor domain protein SMNDC1 plays a crucial role in gene expression by regulating RNA splicing events. It has been implicated in both the repression of insulin in pancreatic alpha cells and the splicing of key signalling molecules in cancer, making it a significant focus of research for therapeutic development. Given that SMNDC1 exhibits broad expression, it is not an ideal target for diabetes treatment. Researchers of the ERC-funded ONCO-SPLICE project propose to test SMNDC1 inhibitors in cancer models for treatment. The study will investigate the protein’s effects and develop a strategy for the clinical translation of SMNDC1 inhibitors as cancer therapeutics.
Objective
In our effort to characterize metabolic activities in the cells nucleus, we discovered that the understudied Tudor domain protein SMNDC1 controls the repression of insulin in pancreatic alpha cells through its role as a splicing modulator. Based on this finding, we developed the first selective SMNDC1 Tudor domain inhibitors, for which we observe interesting preliminary data on insulin induction in primary human pancreatic islets. However, as a pan-essential gene expressed in most tissues, SMNDC1 is not an ideal therapeutic target in diabetes, where exceptionally high safety margins are required.
Interestingly, independent findings published in a preprint established a role for SMNDC1 in cancer. These data show that SMNDC1 controls splicing of the ERK1 exon that bears the phosphorylation signal mediating RAS/RAF/MEK/ERK signaling. A significant fraction of ovarian and pancreatic carcinomas harbor SMNDC1 amplifications, and cells derived from these tumors depend on SMNDC1 both in vitro and in xenograft models.
We here propose to evaluate the potential of our SMNDC1 inhibitors for cancer therapy. Experimentally, we will test these compounds in the ERK1 splicing dependent models in collaboration with the groups that described these findings, and we will profile their antiproliferative effects against a panel of >900 cancer cell lines. In parallel, we will conduct detailed analysis on the chemical scaffolds we discovered and develop a medicinal chemistry proposal to expand the scope of the filed patent application. Additionally, we will commission analyses for an optimal translation pathway of these compounds to the clinic, aiming an ideal positioning for certain cancer subtypes based on market size, competitive situation, clinical needs and trial design opportunities.
Finally, we will develop a plan for the further translation of our discoveries, ideally by foundation of a new spin-off company following successful completion of the ONCO-SPLICE project.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine endocrinology diabetes
- medical and health sciences clinical medicine oncology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2024-POC
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1090 Wien
Austria
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