NIH/NIA- JUVENILE MICRORNAS PROMOTING HEALTHIER ADULT AGING:
We showed first that microRNAs control aging and that they act upstream of insulin and insulin-like receptor (IIS) and other known longevity pathways. In this proposal, we propose to use discovery-based and hypothesis-based methods that we previously developed to identify juvenile microRNAs with roles in aging and to test whether their heterochronic expression in older animals will affect lifespan. Since microRNAs are emerging as therapeutics, this brings up the possibility of using microRNAs to intervene in diseases of aging.
NIH/NCI- TARGETING MICRORNAS IN THE TUMOR MICROENVIRONMENT WITH PHLIP CONJUGATED NEXT GENERATION CHEMICALLY MODIFIED PNAS:
Diffuse large B-cell lymphoma patients are resistant to current standard of care therapies, including RCHOP, and their tumors over-express an oncogenic microRNA, miR-155. In this proposal, we will develop next generation chemically modified and highly active antisense peptide nucleic acids (PNAs) for potent inhibition of miR-155 in mouse models of lymphoma, both genetically engineered and patient-derived. The proposal is built on the collaborative work of a team of experienced investigators with complementary expertise in pH-dependent peptide delivery to tumors, PNA design and synthesis, and mouse models of microRNA-driven malignancies, with the goal of developing this novel class of highly targeted anti-neoplastic agents for further clinical development.
NIH/NCI- PRECISION MICRORNA MEDICINE IN CANCER:
I pioneered many aspects of the microRNA (miRNA) field, e.g. discovering key roles for microRNAs in development, aging and cancer and translating these discoveries towards the clinic. Here I outline my vision of unifying miRNA profiling in individual tumors with functional testing for actionable miRNAs and targeted delivery, with an eye towards personalized miRNA-based therapeutics targeted to the patient’s tumor, and ultimately testing the possibility of integrating miRNAs into standard of care for cancer patients. These studies will be a significant step towards developing precision miRNA therapeutic approaches that could be efficacious in lethal cancers affecting hundreds of thousands of Americans.
NIH/NCI- MICRORNA THERAPEUTICS IN NON-SMALL CELL LUNG CANCER:
Patients with metastatic non-small cell lung cancer (NSCLC) remain incurable with few options despite recent advances in tumor biology. Thus, new therapies based on a better understanding of the biology of lung cancer are a major public health goal. Here we propose to reverse the lung tumor phenotype with a novel microRNA- based therapeutics strategy using a microRNA mimic, MRX34, first in proof of principle experiments in mouse models and then in human clinical trials with imaging and biomarker endpoints.