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Research Summary
For several decades, researchers have designed small molecules controlling target’s function to inhibit the proliferation of cancer cells. Recently, scientists have improved the treatment methods to combat cancers by selectively targeting cancer-specific pathways or boosting immune responses facilitating surveillance and destruction of cancer cells. However, current treatment regimens are facing significant limitations by lack of clinical efficacy and safety tolerance. In addition, many of the best-known cancer specific targets remain “undruggable” and no treatment option is available
Research Focus
- Cell Cycle & Checkpoints
- DNA Damage Response
- Synthetic Lethality
- Drug R&D in Avelos Therapeutics
Cell Cycle & Checkpoints
Cell growth and division are tightly controlled by cell cycle checkpoints to maintain genome stability and integrity. However, these processes are defective in cancers and these defects result in neoplastic transformation, genomic instability, excessive cell proliferation, and resistance to programmed cell death, which are hallmarks of many cancers. Most of the cell cycle inhibitors used in clinic are traditional cytotoxic chemotherapies. While these cytotoxic drugs have been important part of cancer treatment and given significant impact to clinical efficacies, they tend to associate with serious safety issues since they can kill normal cells in addition to the prolific cancer cells. In addition, development of variety of drug resistant mechanisms by the cancer cells has been a major cause of failure of the chemotherapeutics. To overcome the drug resistance and at the same time to reduce the toxicity, better cancer treatments targeting more selective drugs to cancer-specific defects and overcoming drug resistant has been the main focus of recent efforts of cancer drug development.
DNA Damage Response
DNA Damage Response (DDR) is a cellular surveillance to maintain the integrity of DNA and genome stability. DDR comprises of cell-cycle checkpoint pathways and DNA damage repair mechanisms which are important steps of the cell cycle and cell survival. When DNA damage cannot be repaired, the DDR activates the mechanisms to stop cell division and replication, or to initiate programmed cell death. Dysfunction of the DDR mechanisms a key feature of cancer and inhibition to DDR has been shown to be an effective cancer treatment. One of the best-known DDR inhibitors is PARP inhibitor which can effectively kill cancers with homologous recombination deficient (HRD) such as those carrying BRCA mutations. After the four FDA-approved PARP inhibitors have been successfully treated cancer patients in the market for several years, the patients have become resistance to the PARP inhibitors, poses a significant issue to the continuous use of PARP inhibitors and desperate need of alternative treatment options.
Synthetic Lethality
Synthetic lethality is defined as the setting in which inactivation of either of two genes individually has little effect on cell viability but simultaneous loss of function of both genes leads to cell death. In cancer, inactivation of one gene by deletion or mutation and pharmacological inhibition of the other leads to death of cancer cells whereas normal cells are spared the effect of the drug. The concept of synthetic lethality has provided new opportunities for the development of new therapies without the risk of major side-effects.
Drug R&D in Avelos Therapeutics
Avelos Therapeutics develops next-generation, targeted, biomarker-driven onco-therapeutics to deal with the unmet medical needs, focused in the areas of cell cycle regulation, DNA damage response and undruggable cancer targets, primarily based on the concept of synthetic lethality. We have established innovative drug discovery programs designed to deliver treatments to various cancer patients with distinct modes of action in these focused cancer therapeutic areas. Avelos Therapeutics is currently developing a synthetic lethality platform called “SMILOG (Small Molecules Inducing Lethality in OncoGenic cells)” to find new and more reliable synthetic lethal targets combining genetic analysis of tumor cells and cytotoxicity profiling of target specific inhibitors.