Four Geisel School of Medicine students presented their research at April's Medical Student Grand Rounds at DHMC. Their work spanned three projects: RNA-based biomarkers to guide tarlatamab therapy in small cell lung cancer; treatment exposures and disease severity among rural New England patients with a chronic inflammatory skin disorder; and a data analysis of how rural health systems have underutilized of the Northern New England 24-Hour Ambulatory Blood Pressure Monitoring Registry.
Here are summaries of their presentations:
Zofia Cieslak MED’28
Genomic and Transcriptomic Correlates of Response to Tarlatamab in Small Cell Lung Cancer
“Tarlatamab is a DLL3 bispecific T-cell engager which has demonstrated clinically meaningful activity in small cell lung cancer (SCLC). Determinants of response or resistance to tarlatamab are not fully understood. We aimed to describe genomic and transcriptional correlates of tarlatamab sensitivity by using the clinical sequencing pipeline, DHCancerSeq, at a single comprehensive cancer center.
“We performed a retrospective analysis of 12 patients with biopsy-proven SCLC treated with tarlatamab, using whole-exome sequencing and whole-transcriptome sequencing on 12 pre-treatment biopsies and 2 post-treatment biopsies. Integrative analysis examined correlation between molecular features and clinical outcomes. The overall response rate was 50. Differences between SCLC driver alterations and tumor mutational burden were not significant between responders and non-responders, but homologous recombination deficiency scores were higher in responsive tumors. DLL3 expression was significantly greater in responders and demonstrated predictive discrimination for clinical response (AUC 0.83). Tumors responsive to tarlatamab were predominantly ASCL1-driven (SCLC-A) and demonstrated increased immune activation, such as enrichment of cytotoxic T-cell, NK-cell, and T cell transcriptional programs. Transcriptional subtype and a composite metric consisting of DLL3 expression and immune activity (DLI score) further discriminated between responders and non-responders (sensitivity 0.83, specificity 1). Paired post-treatment sample analysis identified loss of ASCL1 lineage and emergence of YAP1 expression and downregulation of DLL3, consistent with lineage plasticity as a mechanism of acquired resistance.
“We concluded that sensitivity to tarlatamab is correlated with a combination of increased DLL3 expression, ASCL1-driven lineage, and an increased immune activation. Lineage state reprogramming and decrease in DLL3 expression accompany acquired resistance to tarlatamab. These findings highlight the utility of RNA based biomarkers which integrate target expression, lineage state, and immune context to guide tarlatamab therapy in SCLC. Prospective validation of the whole-transcriptome DLI score and transcriptional subtype will inform tarlatamab response prediction.”
Effat Rahman MED’29
Patterns of Medical and Surgical Therapy for Hidradenitis Suppurativa in Rural New England
“Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, tunnels, and scarring, affecting areas such as the axillae, groin, and inframammary folds. The average worldwide prevalence of HS is estimated at 1% but varies geographically. In the United States, the prevalence has been reported to range from 0.1-1.0%. This condition has been shown to be 2-3x more prevalent in women than men, and 3x more prevalent in Black patients compared to White patients based in the United States. While HS pathophysiology is not fully understood, it is associated with an excessive and dysregulated inflammatory response around hair follicles, causing deep abscesses and tunneling under the skin. Treatment includes topical therapies, lifestyle modifications, systemic medications, pain management, and procedural interventions.
“Under the guidance of Dr. Natalie Fragoso at the Dartmouth Health Department of Dermatology, we conducted a retrospective chart review of 598 patients and collected data on patient demographics and treatment types. Our aim with this study is to characterize treatment exposures and disease severity among patients at a rural academic medical center in New England, to help inform future efforts regarding care design in specialized HS settings.”
Jason Weiss MED’27 and Dain Shirmer MED’27
The Northern New England 24-Hour Ambulatory Blood Pressure Monitoring Registry
“Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is the gold standard for characterizing blood pressure burden, circadian patterns, and short-term variability, yet remains underutilized in rural health systems. We describe the Northern New England ABPM Cohort, a cohort of roughly 650 adults undergoing 24-hour ABPM through a tertiary hypertension program serving a predominantly rural population. The registry integrates ambulatory blood pressure metrics with demographic, clinical, renal, and geographic data to provide a foundation for physiologic and epidemiologic analyses. The goal of this registry is to provide a prospective cohort of ambulatory blood pressure measurements to follow over time and evaluate how factors like rurality, sex, and demographic factors impact blood pressures over the course of a 24-hour day.
“We are also analyzing the data cross-sectionally to identify factors contributing to hypertensive morbidity in DHMC patients at present. Previous studies using this technology have focused on urban populations at large research centers—this study is unique in its sample size and focus on rurality as a modifier of blood pressure patterns. Collaborating with a team including the principal investigator Charles Hopley, MD, Todd Mackenzie, PhD, as well as two MPH students at Geisel: Cameron Diehl and Prerana Dubey, we hope to begin publishing our data this summer. Any feedback on how best to use this data from the greater Geisel community is greatly appreciated!”