Research

We study how SCLC tumors diversify across clinical, genetic, transcriptional, epigenetic and microenvironmental dimensions and how this heterogeneity shapes metastatic potential, treatment response and relapse. Our work has shown that SCLC remains difficult to control even when detected by CT screening (Chest, 2018) and that distinct etiologic subsets, including SCLC in never-smokers, have unique clinical and genomic features (Chest, 2020). We identified a germline-mutated SCLC subset that responded favorably to DNA repair-targeted therapies (Science Translational Medicine, 2021), defined transcriptionally distinct neuroendocrine and non-neuroendocrine states in metastatic tumors and patient-derived models (Nature Communications, 2022), and showed that low neuroendocrine differentiation and Notch activation are associated with greater sensitivity to immune checkpoint blockade (Nature Communications, 2021)

Building on these studies, we have mapped genetic and ecological drivers of SCLC plasticity, including extrachromosomal DNA as a mechanism of MYC-driven heterogeneity and poor outcome (Cancer Discovery, 2023), and tumor-microenvironment interactions that reshape neuroendocrine cell states and expose therapeutic vulnerabilities (Cell Reports Medicine, 2024). We are also developing non-invasive approaches to capture SCLC heterogeneity in patients, including plasma cell-free nucleosome profiling to infer tumor transcriptional states (bioRxiv, 2025) and circulating free DNA profiling to connect genomic alterations with matched metastatic tumor phenotypes (Genome Medicine, 2025). Together, these studies provide the foundation for a state-informed therapeutic framework for SCLC, as outlined in our recent review of emerging therapeutic strategies (Nature Cancer, 2025), and for ongoing work defining context-dependent resistance mechanisms such as TGF-β–associated hyperprogression (Cancer Discovery, 2026).

We study metastasis as a multiorgan disease in which distinct tissue environments impose site-specific selective pressures on disseminated tumor cells. This organ-informed framework argues that metastatic disease should not be treated as a uniform systemic process but as a collection of organ-shaped tumor states with distinct biology, vulnerabilities and therapeutic responses (Cancer Discovery, 2026).

Using the National Cancer Institute's rapid autopsy program, patient-derived xenograft models and multi-omic profiling, our group is developing experimental systems to define how SCLC adapts to the liver, brain and other metastatic niches. These studies include the development of patient-derived models of SCLC organotropism, including the first brain metastasis models of SCLC, which reveal pathways critical for organ-specific metastatic colonization and therapeutic vulnerability (bioRxiv, 2024/2025).

A major focus of the lab is liver metastasis, where we investigate how hepatic microenvironmental cues drive tumor-cell plasticity, progenitor-like reprogramming, metabolic-epigenetic remodeling and hepatocyte-like adaptation. This work supports the concept that metastatic niches can reshape tumor identity and create organ-specific dependencies that may be therapeutically exploited. In parallel, we are developing strategies to target liver-metastatic disease more effectively, including engineered nanocarriers designed to improve intracellular delivery and overcome barriers imposed by the hepatic metastatic niche.

SCLC is marked by profound genomic instability and high replication stress, creating vulnerabilities that can be therapeutically exploited. Our work helped establish the conceptual framework for revisiting DNA-damaging chemotherapy in SCLC and combining it with replication stress-response inhibitors, including ATR, CHK1, WEE1 and PARP inhibitors (Science Translational Medicine, 2016).

Building on this rationale, we led the first published clinical trial targeting ATR, the master regulator of replication stress, in combination with topotecan (Journal of Clinical Oncology, 2018). Subsequent work demonstrated that ATR inhibition can produce durable regressions in SCLC and extrapulmonary small-cell cancers with high replication stress, defining molecular subgroups most likely to benefit from replication-stress-targeted therapy (Cancer Cell, 2021). We further developed and validated a pan-cancer transcriptional replication-stress signature that predicts responses to replication-stress-targeted drugs and patient outcomes (Cancer Research Communications, 2022).

Our studies also test rational combinations that intensify DNA damage or impair damage tolerance. These include PARP inhibition with immune checkpoint blockade (Journal of Thoracic Oncology, 2019), ATR inhibition with lurbinectedin (EMBO Molecular Medicine, 2023) and berzosertib plus topotecan in the first randomized study of ATR inhibition in relapsed SCLC (JAMA Oncology, 2023). Together, these studies support a biomarker-guided strategy for matching DNA-damaging therapies and DNA damage response inhibitors to tumors with high replication stress.

More recently, we defined Lamin A/C loss as a mechanism of genome instability in SCLC. LMNA loss disrupts nuclear architecture and RNA export, promotes R-loop accumulation, increases replication stress and is associated with poor survival and altered sensitivity to replication-stress-targeted therapies (PNAS, 2025). We are now applying these insights to develop therapies that intensify replication stress or exploit impaired DNA damage tolerance, including TOP1 inhibitor payloads, antibody-drug conjugates, and related DNA-damaging strategies in SCLC and other neuroendocrine cancers.

We develop tumor-targeted drug delivery strategies to improve the therapeutic index of DNA-damaging therapy. This work builds on the rationale that TOP1 inhibitors remain highly relevant anticancer agents, but their clinical impact can be limited by systemic toxicity, narrow scheduling windows and challenges combining them with DNA damage response inhibitors. Our review of TOP1 targeting outlined precision strategies to improve their use through novel chemical scaffolds, biomarker-guided combinations, and tumor-targeted delivery platforms, including liposomes, PEGylation, nanoparticles, and antibody–drug conjugates (Clinical Cancer Research, 2019).

Our clinical and translational studies test whether engineered delivery can preserve DNA-damaging activity while reducing dose-limiting toxicity. Strategies include long-acting PEGylated TOP1 inhibitor delivery with PLX038 (Molecular Cancer Therapeutics, 2022), liposomal irinotecan combined with PARP inhibition (The Oncologist, 2023), antibody–drug conjugate delivery of SN-38 with sacituzumab govitecan plus ATR inhibition (Clinical Cancer Research, 2023), and nanoparticle TOP1 inhibitor delivery with optimized gapped PARP inhibitor scheduling (Nature Communications, 2025). We have also explored miniature drug-conjugate approaches, including PEN-866, an HSP90-targeted SN-38 conjugate, designed to promote tumor accumulation and sustained intratumoral payload release (Journal of Clinical Oncology, 2020).