Metabolic regulation of radiation response
Tumor exhibits altered metabolism, some of which is associated with radiation resistance. Recent work from our laboratory and others has demonstrated that radiation effectively modifies the microenvironmental metabolism, subsequently influencing DNA damage repair responses. Currently, there is a lack of strategies for targeting metabolism to sensitize tumors to radiation or protect normal tissue from its damage. This challenge partly arises from the complexity of cellular metabolism and the fact that existing work conducted in culture dishes may not accurately reflect the intricate microenvironment.
Through CRISPR screens utilizing a comprehensive metabolic library in vitro and in vivo, we have identified pathways crucial for radiation sensitivity and resistance in non-small cell lung cancer. Our ongoing efforts are focused on validating these targets, understanding the underlying mechanisms, and developing metabolic tumor sensitizers and normal tissue protectors for clinical testing. We anticipate that this work will have a positive impact on the lives of cancer patients undergoing radiation treatment, as well as help safeguard national defense and the public from occupational and environmental exposure to radiation.
Techniques: in vivo and in vitro CRISPR screening, metabolomics, isotope-labeled nutrient tracing, biochemistry (western, IP, protein purification), molecular cloning, and radiobiological assays pertaining DNA damage and cell cycle.
Harnessing radiation insight to prevent heterotopic ossification
Heterotopic Ossification (HO) is the abnormal growth of bone in soft tissues such as joints and muscles, a condition seen in over 60% of severe burn cases, major combat injuries, and around 10% of patients undergoing invasive surgical procedures. HO results in chronic pain, limited joint motion, and debilitating deformities. Unfortunately, effective treatment options are lacking, highlighting the importance of preventive measures. Although clinical studies demonstrate that radiation therapy (RT) can reduce HO, the optimal regimen and mechanisms remain unclear due to limited research and lack of relevant animal models. Collaborating with the Levi laboratory, we've shown that RT is effective in a mouse model that simulates burn and trauma patient, and we've also identified changes in the trauma environment that influence HO development. Our ongoing research aims to unravel the mechanisms of RT, refine treatment strategies for clinical application, and explore ways to extend its benefits to burn and trauma patients who are at high risk of severe HO and its associated complications.
We anticipate this work to enhance functional recovery and improve the quality of life for trauma patients, while advancing our understanding of HO pathogenesis and normal tissue response to radiation.
Techniques: modeling trauma/burn relevant HO in syngeneic and transgenic mice, single cell RNA-sequencing, immunofluorescent IHC, DNA damage and cell cycle analyses, immune profiling with flow cytometry and CYTOF, patient biospecimen analyses and outcome assessment.
Targeting immuno-metabolism to halt lung cancer progression
Lymph node spread is the defining feature of stage III, locally advanced non-small cell lung cancer (NSCLC), often indicating a poorer prognosis. Following concurrent chemoradiation, consolidation durvalumab has improved the survival of this patient cohort (the Pacific trial) and is now a standard of care. To assess the optimal integration of immunotherapy, we launched a phase 2 clinical trial testing concurrent immunotherapy instead of chemotherapy alongside radiation (STUx PI: Zhang). Despite expecting better efficacy with fewer side effects, we observed a high rate of adverse events and early disease progression. We are delving into these findings to better the treatment for patients with lymph node metastases through several ongoing projects:
- A biomarker trial to investigate the chemokines and cytokines associated with toxicities in cancer patients undergoing immunotherapy and radiotherapy.
- Examination of tumor microenvironment in a humanized mouse model of NSCLC treated with immunotherapy and radiation.
- Establishment of an ultrasensitive, optical imaging-guided, orthotopic model for locally advanced lung cancer, in collaboration with the BIRT laboratory and the Kim laboratory.
- Validation of the results of in vivo CRISPR screen for NSCLC lymph node metastasis
We anticipate providing mechanistic understanding of clinical trial observations through the examination of patient biospecimens and in vivo modeling in mice. We expect to establish an ultrasensitive, optical imaging-guided animal model for locally advanced lung cancer enabling preclinical therapeutic testing to inform future clinical trial designs. Through the validation of in vivo CRISPR screens designed to unveil metabolic regulators of lymph node metastasis, we aim to develop therapies to prevent lymph node metastasis.
Techniques: in vivo CRISPR screens, modeling lymph node metastasis in orthotopic and syngeneic mouse models, optical/functional/metabolic imaging techniques, biochemical engineering, multiplex cytokine analysis, CYTOF, multi-omics analysis and metastatic assays, patient biospecimen analyses and outcome assessment.
Interested in these projects? Contact us! We are often looking for researchers and students to join our group.