Targeting SCLC Plasticity with Constellation Pharmacology

Trudy Oliver, PhD and Baldomero Olivera, PhD

Small cell lung cancer (SCLC) is an aggressive cancer that has seen only limited progress in treatment options over the last 40 years. One reason for this is that SCLC lacks druggable kinase alterations and is instead characterized by loss of tumor suppressors RB1 and TP53 and alterations in epigenetic regulators and transcription factors, which are notoriously difficult to drug. Although pioneering studies have demonstrated that SCLC comprises multiple molecular subtypes with unique therapeutic vulnerabilities for each subtype state, intratumoral heterogeneity and remarkable plasticity has undermined SCLC treatment efficacy to date and  new approaches are needed.

Now, Trudy Oliver and Baldomero Olivera will team up to tackle this problem in a multidisciplinary manner. Olivera’s lab has developed a technique called Constellation Pharmacology (CP)—a phenotypic screening platform that is amenable to large-scale pharmacological screening by calcium imaging. CP was previously applied to characterize the diversity of neuronal cell types in distinct brain regions and to track the progression of chronic pain at a cell-specific molecular level. CP monitors the functional expression of receptors and ion channels in individual cells (within a pool of heterogenous cell types) and provides a quantitative cell-specific “functional fingerprint”. This functional imaging platform is coupled with single cell RNA-sequencing to deconvolute drug responses in individual cell types that can be tracked with disease progression over time.

In this ASPIRE Award, they will extend this platform to study the diversity of cancer cell types in SCLC. The team has shown that MYC-driven induction of Notch signaling can drive SCLC subtype plasticity, but pharmacological plasticity blockade has not been previously/sufficiently explored. They will use CP to explore drug response heterogeneity and plasticity in state-of-the-art human and mouse SCLC models developed by the Oliver Lab. These innovative technologies and concepts will advance our understanding and treatment of SCLC plasticity, with likely extension into other cancers. This project will ultimately determine the feasibility to use constellation pharmacology to identify plasticity-directed therapies, and for rapid in-house screening of human biopsies to discover patient-specific combination therapies.