The LDER program, which was modeled after the U.S. Department of Energy’s Laboratory Directed Research and Development program, provides FNL scientists the opportunity to compete for funding to conduct the research that they believe is important to the FNL’s mission but is outside their day-to-day research activities. In doing so, LDER promotes creative and novel research, including potentially high-risk, high-payoff activities that advance research against cancer and HIV/AIDS or other health challenges. Including the five new projects set to start this summer, the LDER program has funded 34 projects since its launch in 2015.
In addition, two ongoing LDER projects, led by George Zaki, Ph.D., and Yichuan Wang, Ph.D., were awarded funding to continue for a second year, bringing the total number of projects for the next year to seven.
LDER projects are selected on a competitive basis through a rigorous review process. The awarded projects represent a diverse portfolio of exploratory research. Summaries of the five new projects are below:
Artificial intelligence-based drug discovery and design of anticancer drugs that target centromere-associated protein E
Pinyi Lu, Ph.D., of the Cancer Data Science Initiatives in the Cancer Research Technology Program, is leading a project in collaboration with Akihiro Ohashi, Ph.D., of the National Cancer Center Japan. The project aims to accelerate the discovery of chemical inhibitors of centromere-associated protein-E (CENP-E) with improved therapeutic efficacy. CENP-E inhibitors are a potentially promising oncology therapeutic, due to their potential use when joined with checkpoint inhibitors.
To achieve this aim, the researchers plan to leverage recent advances in artificial intelligence for prediction of chemical properties and deep learning-based generative design, including the Accelerating Therapeutics Opportunities in Medicine (ATOM) Modeling PipeLine (AMPL) and Generative Molecular Design.
Assessing the dynamics of recrudescent virus in semen following treatment interruption in SIV infected macaques
Claire Deleage’s, Ph.D., project is her second LDER project, and it builds upon the results of her 2021 project, which were recently presented at the Conference on Retroviruses and Opportunistic Infections. The first pilot study, focusing on the acute phase of the infection, showed a week-long delay for the virus to be detected in the semen compared to the blood. The viral RNA and viral DNA levels in the semen were remarkably high two weeks post infection, further building a case for the importance of the acute phase in new transmission. When trying to identify the cells harboring the virus, Deleage surprisingly found that myeloid cells were the main infected cells present in the semen and in male genital tract organs, questioning their role and importance in sexual transmission.
As a next step, Deleage, who is part of the AIDS and Cancer Virus Program, will use a nonhuman primate model to continue exploring key questions regarding the sexual transmission of HIV by tracking the presence of virus in semen and its genetic composition prior to antiretroviral therapy (ART), during ART, and after treatment interruption.
“Sexual intercourse is the main and most efficient way that HIV spreads,” Deleage said. “However, there is still controversial data regarding the shedding of virus in semen while individuals are under effective treatment.”
Therefore, this study strives to increase understanding of the potential for HIV transmission during ART and the impact of treatment interruption on seminal HIV load and transmission.
Consequences of body mass index (BMI) and diabetes on lung cancer survival in diverse populations
Xi (Hill) Liu, Ph.D., of the Molecular Pharmacology Program will lead a project that seeks to investigate a paradox in lung cancer. While obesity is linked to metabolic and cardiovascular diseases, increased body mass index (BMI) has been correlated with improved overall survival in non-small cell lung cancer patients after surgery.
“Successful conclusion of the project may elucidate the precise relationship between BMI, diabetes, and lung cancer survival in majority and minority populations,” Liu said.
Developing bifunctional inhibitors of APOBEC3A/3B for cancer therapeutics
Wazo Myint, Ph.D., of the Basic Science Program, aims to develop an inhibitor of A3A/A3B activity as a potential anti-cancer therapeutic.
“Despite their role in immunity, the mutagenic activities of A3A/A3B are a double-edged sword and likely contribute to cancer mutagenesis,” Myint said. “Stopping A3A/A3B protein activity has the potential to impede cancer progression.”
Genetic determinants of HLA-E-regulated immune responses
Arman Bashirova, Ph.D., of the Basic Science Program, proposed a study to provide new insights into the impact of genetic polymorphism on regulation of immune responses by HLA-E.
The HLA-E is one of several HLA genes that encodes cell-surface proteins responsible for regulation of the immune system. To perform its function, HLA-E must bind epitopes derived from signal peptides of other HLA molecules, HLA-A, HLA-B and HLA-C. These signal peptides are polymorphic, meaning that different people have different signal peptide variants encoded by their genome. The polymorphism in HLA signal peptides has not been systematically studied before but may affect immune function, and this diversity of immune responses may impact various disease outcomes. The results of this project may help guide clinicians in selecting immunotherapy regimens that will most benefit their patients using HLA genotyping.
“HLA-E is expressed at substantially lower levels than other HLA molecules,” Bashirova said. “But it appears to have considerable power to regulate immune responses. HLA-E can be targeted in immunotherapy and vaccine design. In this regard, it will be important to determine how genetic variation influences HLA-E function.”