Optimalisering: Development of small molecule cancer immunotherapy

A major problem for cancer treatment is that cancer cells escape detection of the immune system. Several treatments have been developed that re-activate the immune system to kill the cancer cells. These treatments have revolutionized cancer treatment. However, only a minority of patients appears to benefit from these treatments, which is at least in part due to the fact that thus far only very few immune treatments have been clinically approved. We previously identified a compound that may modulate the immune response. This project was aimed at further developing this compound. In brief, the findings of this project are that this compound kills a wide variety of tumor cells. We investigated its mechanism of action, and found that it induces rapid loss of c-Myc from the cell, while simultaneously activating p53. c-Myc is a protein that is important for survival and proliferation of most tumor types and is also well known to modulate the sensitivity of cancer cells to the immune system; p53 is a protein that protects the organism against cancer by inducing apoptosis of malignant cells. Indeed, treatment of tumor cells with the compound halted cell proliferation, induced cell differentiation and triggered cell death. In-depth mechanistic studies revealed that the compound may insert itself into the DNA of cells (intercalation), thereby preventing synthesis of c-Myc and activating p53. At the physiological level, we have determined how well the compound is taken up by cells, how stable it is, and what the maximum tolerated dose in animals is. The exact immune-modulating properties of this compound are presently less clear, although they appear to be dependent upon the tumor type. This will need to be studied in further detail in future studies. Finally, we explored IPR for this compound, and found that commercial potential of the compound is limited by the fact that it intercalates DNA, which is regarded as lower priority by many pharmaceutical companies. In conclusion, we discovered a novel compound that inhibits c-Myc and selectively kills tumor cells. As such, this compound is a promising starting point for development of more selective compounds with anti-tumor activity. At present, we believe its main commercial potential will likely come from its usefulness as a research tool in academic studies.

The main impact of our findings for the research field comes from the fact that we have identified a range of molecules that induce depletion of c-Myc from cells. c-Myc is essential for growth and survival of cancer cells, but very few small-molecule tools exist to modulate the activity of c-Myc. Our compounds will be an important addition to the toolset for these studies. In addition, we expect that our compounds will serve as a useful starting point for development of more specific anti-cancer drugs, which we are currently pursuing in follow-up research projects. The project resulted in establishment of valuable new competence at our department. Given that our department is mainly focused on basic research, there is limited experience with the processes and requirements for obtaining IPR and for commercialization of research findings. We have now built a knowledge structure that will facilitate innovation, IPR and commercialization at our development.

Immune checkpoint proteins regulate the duration and amplitude of physiological immune responses in normal tissues, which is crucial for self-tolerance and which prevents collateral damage from the immune system. Cancer cells co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. We have recently identified and characterized a small molecule hit compound from a 20K library screen that inhibits the expression of immune checkpoint proteins on the surface of cancer cells. Our preliminary data indicate that DJ34 is active against leukemic cells, including AML and ALL cells; other cancer have not yet been tested. This project is aimed at optimizing this compound and to explore its commercial potential as novel anti-immune checkpoint cancer therapy. We will further characterize the physicochemical properties of this compound, determine its cancer cell sensitivity and demonstrate its efficacy in a relevant animal model of disease. We further aim to optimize the chemical template of the hit compound, to develop novel chemical entities with superior properties, with respect to ADME/PK, safety and efficacy. During the project, we will also seek to secure IPR protection for the hit compound and analogs/derivatives, perform market analysis to determine the competitive landscape and therapeutic fields of greatest unmet medical need, and engage both clinical key opinion leaders and relevant pharmaceutical industry. By the end of the project we aim to have demonstrated in vivo proof-of-concept, identified a preliminary lead suitable for further preclinical development, selected a preliminary primary target indication, and developed a strategy/plan for further commercial development of the novel therapeutic strategy.