Novel compound to target breast cancer stem cells
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Relevance
 
 Aided by our advocate, Dr. Helen Eckmann, this research project aims at evaluating the potential of novel chemical compound SMIP004 (and its close relatives) as agents to selectively and safely target breast cancer stem cells, the cells from which drug-resistant breast cancer develops. If successful, these studies will lead the way toward further development of SMIP004 toward clinical application. 
 
 
 
 
 
 
 
 Genomic studies over the past years have revealed that, based on gene signature, human breast cancer can be classified into at least four different subtypes. However, from the perspective of the breast cancer patient, there are only two relevant subtypes: drug sensitive and drug resistant cancers. Whereas most tumors are initially drug sensitive and therefore respond to therapy, relapse is common and thus a main barrier to long-term disease control and cure. Breast cancer relapses are attributed to breast cancer stem cells. Breast cancer stem cells make up only a tiny fraction of the total initial tumor mass but they have deadly properties. Although they remain dormant for prolonged periods, they have a different metabolic state and are resistant to killing by standard drug therapies. New drugs that can specifically attack breast cancer stem cells are therefore urgently needed to combat or even prevent relapsing breast cancer. The main innovation of the current project lies with the concept of selective metabolic targeting of breast cancer stem cells with the metabolic inhibitor SMIP004 as a novel agent. 
 
 
 
 
 
 
 
 Central hypotheses of the research
 
 During recent years, our laboratory has discovered chemical compound SMIP004 as an agent that selectively kills human cancer cells. We have subsequently determined that SMIP004 works through blocking energy metabolism in mitochondria, the cells’ “power plants”. In addition, we found that SMIP004 inhibits an aggressive form of breast cancer – triple negative breast cancer – in a mouse model. Meanwhile, other laboratories have made the unexpected observation that breast cancer stem cells are strictly dependent - or addicted - to the exact same metabolic function that is inhibited by SMIP004. Taken together, this has raised the intriguing prospect that SMIP004 might be the long sought “magic bullet” against breast cancer stem cells. In the proposed project, we want to experimentally test this possibility, addressing two specific research goals: 
 
 
 
 
 
 -Test the activity and mechanism of the metabolic inhibitor SMIP004 in killing breast cancer stem cells in tissue culture.-
 
 Test the activity of SMIP004 in eradicating tumors arising from mouse and human breast cancer stem cells in rodent models.
 
 
 
 
 
 
 
 General methodology
 
 We are in a unique position to perform these studies, because at Sanford Burnham Prebys Cancer Center and through our collaborator, Dr. Jochen Maurer from the University of Freiburg, Germany, we have access to a collection of well characterized breast cancer stem cells which are very hard to come by because they represent such a minor portion of a bulk tumor. In addition, we have established all necessary procedures and collaborations for testing and can readily vet SMIP004 within the 18-month time frame of this project. 
 
 
 
 
 
 
 
 Innovative elements of the project and potential impact
 
 Strategies for the selective and safe elimination of cancer stem cells are akin to the “holy grail” of translational cancer research. If we can directly demonstrate robust and safe activity of SMIP004 against breast cancer stem cells, the compound could be developed into a novel therapy for relapsing, drug-resistant breast cancer, especially “triple negative breast cancer”.