Our laboratory is focused on understanding small cell lung carcinoma (SCLC), a highly aggressive and recalcitrant neuroendocrine cancer type. Typically, SCLC has metastasized by the time of diagnosis, and survival rates are dismal. Striking initial responses to chemotherapy in SCLC are transient. Research projects are focused on a number of overlapping questions:
1) What gene alterations promote SCLC and how?
2) Are there subtypes of SCLC with unique vulnerabilities that should be differentially treated?
3) What are the mechanisms through which SCLC acquires resistance to chemotherapy after initially showing exquisite chemosensitivity?
4) Why is the tumor microenvironment in SCLC immunorepressive, and are there ways to bolster responses to immunotherapy?
Projects employ mouse models, patient derived xenograft studies, genome-scale functional screens and genomic/epigenomic analyses. Many projects include a therapeutic component, as we try to leverage the model systems developed and the biological insights gained to improve SCLC treatment. Our research team includes those interested in basic biology and those with more translational interests, including clinician scientists in training.
Drivers of SCLC
We identified major driver genes mutated in human SCLC using next-generation sequencing approaches. We have become particularly interested in understanding cancer-mutated genes that alter chromatin, as in general, there is a poor understanding of how such mutations drive cancer. To explore key activities of SCLC-mutated genes we have generated and study a panel of new mouse models of SCLC. We aim to recapitulate major genetic subtypes of human SCLC using mouse models. We recently showed that the CREBBP acetyltransferase is a tumor suppressor in SCLC and discovered a novel means through which CREBBP exerts tumor suppressor activity (Jia et al, Cancer Discovery, 2018). Genomic analyses (DNAseq, RNAseq, ChIPseq, CUT&RUN etc.) and functional genomics (genome-scale CRISPR inactivation and cDNA overexpression screens) are used in our efforts to understand driver gene function. Our mouse models are also used for translational studies to link driver mutations to therapeutic sensitivities.
Translational studies in SCLC
Working with our clinical colleagues at the Seattle Cancer Care Alliance, we generate patient derived xenograft (PDX) models of SCLC. PDX and genetically engineered mouse models are used to link mutations in key SCLC driver genes to exceptional responses to novel therapies. As an example, in our recent study of a novel drug target in SCLC, the lysine demethylase LSD1, we delineated a mechanism through which LSD1 inhibition in an exceptionally responding PDX model of SCLC led to complete and durable tumor regression (Augert, Eastwood et al, 2019 Science Signaling). We are now investigating whether certain genetic alterations might contribute to strong responses to LSD1 inhibition, as such knowledge could help us direct this treatment to SCLC patients most likely to respond.
To identify novel drug targets for SCLC or defined subsets of SCLC, we take unbiased genetic approaches. Using genome-scale CRISPR-inactivation libraries, we identify genes that SCLC cells rely upon to survive and proliferate. Some such genes are targets of existing drugs. We have recently been awarded a U01 grant from the NIH to identify therapeutic targets for SCLC using CRISPR screens and to test identified drugs using our in vivo models.
Mechanisms underlying chemoresistance
Dramatic tumor regressions following chemotherapy occur in many SCLC patients but these are rarely sustained. We believe that if the acquisition of chemoresistance in SCLC could be better understood, then increased durable responses might be achieved by combining chemotherapy upfront with an agent targeted towards the identified mechanism of resistance. Importantly, the patient response to chemotherapy is recapitulated in PDX models that we derive from chemosensitive patients and is lost in those models that we generate from chemoresistant patients. An exciting new area of research in the lab involves the conversion of chemosensitive PDX models of SCLC to chemoresistant models using genetic perturbation. Functional screens are being extended to these in vivo models with a goal to identify and understand drivers of chemoresistance.