p53, Aging, and Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

1) In collaboration with Dr. Carl June (University of Pennsylvania), we have completed the study showing that d133p53a-armored CAR-T cells exert superior anti-tumor activity in CAR-T/tumor co-culture and mouse xenograft injection models, with potential clinical implications in non-responsive and refractory cases of chronic lymphocytic leukemia (CLL) (Roselle et al., PNAS 121: e2317735121, 2024). We are modifying and improving the d133p53a-armored CAR-T cells toward applications in hard-to-treat solid tumors such as GBM and lung cancer. 2) The d133p53a-transgenic mice, which we generated in previous years, are being used to investigate whether d133p53a has beneficial or therapeutic effects in vivo for natural or pathological aging. A progeria model mouse strain (LmnaG609G), which recapitulates Hutchinson-Gilford progeria syndrome, was crossbred with our d133p53a-transgenic mice. The expression of d133p53a in this progeria model resulted in inhibition of cellular senescence, reduced production of inflammatory cytokines (e.g., IL-6), restored tissue integrity of aorta (a major tissue affected in progeria mice and patients), transcriptomic profiles in skeletal muscle supporting enhanced regeneration and reduced frailty, no increase in tumorigenesis, and extended lifespan. The effects of d133p53a on natural aging phenotypes are currently under investigation. Our d133p53a-transgenic mice are also applied to mouse studies on other aging/senescence-associated diseases such as various neurodegenerative diseases (e.g., Alzheimer's disease) and idiopathic pulmonary fibrosis. 3) We have performed a high-throughput screening of small-molecule libraries and identified two prototype drugs that increase the endogenous expression of d133p53a. Consistent with our previous findings from the vector-driven expression of d133p53a, these drugs inhibit cellular senescence and proinflammatory secretory phenotypes in normal human astrocytes, with therapeutic implications in neurodegenerative diseases. Their effects on cellular senescence, inflammatory cytokine production and accumulated DNA damage in cells derived from progeria patients are currently under investigation, exploring potential future therapeutic applications for this disease. 4) We have identified siRNA knockdown of a splicing factor SRSF3 as a novel therapeutic strategy for hard-to-treat cancer types such as lung cancer and GBM. In case of lung cancer, it induces cellular senescence in a wide range of lung cancer cell lines with or without a targetable tyrosine kinase mutation (e.g., EGFR or ALK), suggesting its potential benefit for currently non-targetable cases. In p53-mutant GBM cells, SRSF3 knockdown-induced p53beta (which has the corresponding p53 mutation such as R273H) plays an essential role in inducing cancer cell senescence and apoptosis in both cell culture and mouse intracranial xenograft models, potentially representing a novel therapeutic strategy. Aiming at an efficient and cancer-specific delivery of SRSF3 siRNA, we in collaboration with Dr. Drew Weissman (University of Pennsylvania) have generated the lipid nanoparticles (LNPs) encapsulating SRSF3 siRNA and coated with an scFv antibody to cancer-specific cell surface proteins.