Research

Our laboratory research is directed at using high-throughput profiling techniques to identify candidate predictive biomarkers and potential new therapeutic targets in lung cancers. Our research focuses on the identification of new targets and predictive biomarkers using a variety of molecular tools. Projects in my laboratory encompass areas such as developing biomarkers of therapeutic response and acquired resistance as well as discriminating the molecular changes that drive the acquisition of resistance. Most projects in my group are translational in nature — focusing on projects that can be rapidly moved from the lab to the clinic.

Current projects include:

Small cell lung cancer (SCLC) subtyping

Recently, we developed the first comprehensive framework for classifying SCLC into distinct molecular subtypes. Using an unbiased approach, we identified distinct mRNA expression patterns among SCLC cancers, leading to the identification of four mutually exclusive molecular subtypes of SCLC (Gay et al, Cancer Cell 2021). Three subtypes are characterized by high levels of specific transcription factors: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P). We also uncovered a previously unrecognized, novel fourth subtype — “SCLC-Inflamed” (or SCLC-I). SCLC-I does not express the major transcription factors, but instead is characterized by high expression of interferon signature genes, immune checkpoints, and HLA genes. We further determined using clinical outcome data that patients benefiting from immunotherapy were likely those with this SCLC-Inflamed subtype. While patients with subtypes SCLC-A, -N, and -P, received almost no benefit from immunotherapy, we have identified unique therapeutic vulnerabilities for each of the four subtypes. We have more recently developed a cfDNA based approach that uses DNA methylation to assign subtypes (Heeke et al, Cancer Cell 2024). Ongoing projects include developing subtype specific therapies, and using liquid biopsies to track SCLC evolution.

Immuno-oncology in SCLC

Recently, frontline treat treatment for SCLC has changed from chemotherapy to chemotherapy with the addition of an immune checkpoint inhibitor. Building on this, and our expertise in targeting the DNA damage response (DDR) pathways with PARP and CHK1 inhibitors, we have shown striking responses in animal models treated with combinations of DDR inhibitors and an immune checkpoint inhibitor through activation of an innate immune response (Sen et al, Cancer Discovery 2019). Ongoing projects in the lab include testing additional drug combinations and alternative strategies for engaging the immune system for the treatment of SCLC patients.

Establishing new pre-clinical models of SCLC

Historically, SCLC research has been hampered by limited pre-clinical models and tissue specimens. To address this limitation, we have established a pipeline led by Dr. Stewart that uses circulating tumor cells (CTC) to establish CTC-derived xenograft models (CDX) (Stewart et al, Nature Cancer 2020). Over the last several years we have established a panel of over 50 such models that have been comprehensively profiled and represent the four major subtypes of SCLC. We are continuing to develop additional CDX and PDX models from patients receiving both standard-of-care and those enrolled in our clinical trials.

SCLC intra-tumoral heterogeneity

Using single cell transcriptional profiling, we have identified changes in intra-tumoral heterogeneity that are associated with relapse to treatment (Stewart et al, Nature Cancer 2020). Ongoing projects in lab, in conjunction with the labs of John Heymach and Jay Zhang as part of a joint NCI U01 award, are exploring novel mechanisms of resistance to treatments and approaches to specifically target drug-resistant tumor cell populations.

Targeting the cell surface of SCLC

Recently there has been enhanced interest in using approaches such as antibody-drug conjugates (ADC) and engineered immune cells (e.g. CAR T-cells) to target cancer cells using proteins expressed on the cell surface. In SCLC examples include AMG119 (a DLL3 targeting CAR T-cell) which was the first cellular therapeutic tested in a clinical trial for SCLC patients (PI: Byers). Ongoing projects in the lab are exploring ways to more effectively targets cells expressing DLL3 or other novel proteins.

PARP inhibition in SCLC

One of the early successes of the lab was pre-clinical work showing the effectiveness of single agent PARP inhibition in SCLC (Byers et al, Cancer Discovery 2012 & Cardnell et al, CCR 2013) which has directly resulted in the clinical testing of these in SCLC patients. Additional pre-clinical projects have identified SLFN11 as a mechanism of innate and acquired resistance to PARP inhibition in SCLC (Stewart et al, Oncotarget 2017). SLFN11 was then validated as a candidate biomarker by the team in two retrospective analyses of patients enrolled onto two phase II randomized studies testing the addition of veliparib (a PARP inhibitor) to chemotherapy in ES-SCLC (Pietanza et al, JCO 2018). The SLFN11 IHC assay has subsequently been validated and deployed in the institutional CLIA laboratory, allowing MDACC to serve as the central testing site for the first biomarker-driven trial of PARP inhibitor therapy for SCLC (SWOG1929). As part of SWOG1929 which used SLFN11 IHC to select patients for treatment, we screened over 300 patients with an average turnaround time of less than seven days demonstrating the feasibility of biomarker driven trials for patients with SCLC.

Computational biology

Working with the thoracic biomarker working group (lead by myself and Jing Wang, Ph.D.), we are utilizing computational approaches to identify new therapeutic targets and markers of response. Projects have included:

• Development of transcriptional EMT scores (Byers et al, Clinical Cancer Research, Mak et al, Clinical Cancer Research 2016)
• “DISARM” (Differential Sensitivity Analysis of Resistant Malignancies) which addresses the simple, yet vexing question of “If a cancer is resistant to drug X, to what drug(s) is it sensitive?” (Gay et al, CCR 2019)
• Molecular subtyping of SCLC (Gay et al, Cancer Cell 2021)
• Single cell transcriptional profiling (Stewart et al, Nature Cancer 2020)

I have also served in leadership roles for several of the TCGA projects including lung adenocarcinoma, lung squamous carcinoma, and the pan-cancer atlas.