The overarching goal of our research program is to develop a better understanding of the initiation, maintenance, progression, and treatment response of carcinomas. Our work focuses on two main areas:
1. Normal and cancer stem cell biology and its implications for cancer therapy.
2. Development of genomics-based biomarkers for identifying the presence of malignant cells, prognostication, and predicting response to therapy.
Specific areas of focus include cancers of the lung, breast, and gastrointestinal system. We employ tools of genomics, stem cell biology, mouse genetics, and computational biology. Clinically, Dr. Diehn specializes in the treatment of lung cancer and leads an active clinical research program. Our ultimate goal is to develop improved treatments for patients with lung, breast, and gastrointestinal cancers.
Associate Professor of Radiation Oncology (Radiation Therapy)
- Integrating genomic features for non-invasive early lung cancer detection NATURE 2020 Hide More
Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
View details for DOI 10.1016/j.cell.2020.09.001
View details for PubMedID 33007267
Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer
View details for DOI 10.1038/s43018-019-0011-0
KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition.
Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.
View details for DOI 10.1158/2159-8290.CD-20-0282
View details for PubMedID 33071215
- Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA CANCER DISCOVERY 2019; 9 (4): 500–509 Hide More