SCLC has metabolically different, targetable subtypes
BY NEIL OSTERWEIL
MDedge News
A diagnosis of small-cell lung cancer (SCLC) carries with it a grim prognosis. Standard therapy for extensive-stage disease, which consists of combination chemotherapy and radiation, is associated with 5-year overall survival rates of just 5%-10%.
Recent evidence, however, suggests that SCLC, similar to non–small cell lung cancer (NSCLC), may actually be a family of malignancies with variant molecular features that may be targetable with more specific therapies.
At the 2019 annual meeting of the American Association for Cancer Research (AACR), Trudy G. Oliver, PhD, associate professor of oncological sciences at the University of Utah Huntsman Cancer Institute in Salt Lake City, moderated a session titled “Small-Cell Lung Cancer: A Glimmer of Light at the End of the Tunnel.”
In this session, Dr. Oliver and colleagues described research into newly identified SCLC subtypes and outlined potential therapeutic approaches.
Trudy G. Oliver, PhD
“Small cell is a highly metastatic tumor type. Typically, when these patients are diagnosed, tumors have already metastasized. In about two-thirds of cases, patients respond quite well to chemotherapy; the problem is that this is a transient response. Patients return to the clinic months later with recalcitrant, chemo-resistant disease, and there’s not much that can be done for these patients,”
Target: CREBBP
In his lab, Dr. MacPherson and colleagues use a host of techniques to study SCLC at the molecular level, including genetically engineered mouse models, genomics and genetic screens of human SCLC cell lines, circulating tumor cell analyses, and patient-derived xenografts (PDX).
SCLC is a tumor type marked by high mutational burden that typically arises in patients who have been smoking for decades.
“It’s also characterized by frequent mutations in tumor suppressor genes, especially poorly characterized tumor suppressor genes, and we’ve been interested in the fact that many of these genes are chromatin regulators, and their function in tumor suppression is poorly understood,” he said.
They have identified CREBBP, a gene encoding for an acetyltransferase, as a tumor suppressor gene. When inactivated or deleted, CREBBP loss results in reduced expression of cell adhesion genes, including Cdh1. This leads to reduced histone acetylation and reduced transcription of cellular adhesion genes.
“If that is the case, then perhaps we could fight back at the level of histone acetylation and try to reverse some of those effects,” Dr. MacPherson said.
They found that treatment with the investigational histone deacetylation (HDAC) inhibitor pracinostat “showed the potential for exceptional responses in CREBBP-deleted small cell,” he said.
“From a differentiation perspective, and also the aggressive nature of the tumor, these tumors appear to be fundamentally distinct, and our lab has since gone on to ask what other ways are these tumors distinct from each other,” Dr. Oliver said.
Target: MYC
Dr. Oliver and colleagues use a mouse model developed in her lab to investigate MYC-driven SCLC in both cell lines and xenograft models.
“These tumors develop a different subtype or morphology of small cell,” she said.
Her group has shown that, in this SCLC variant, the combination of MYC expression with Rb1 and Trp53 loss promotes the growth of aggressive tumors with a strong metastatic proclivity that are at first sensitive to chemotherapy but soon relapse, similar to SCLC in humans.
In these tumors, unlike the majority of SCLC in models, the transcriptional factor ASCL1 (Achaete-Scute Family BHLH Transcription Factor 1) is missing and the tumors instead express transcription factors such as NEUROD1 (Neuronal Differentiation 1).
“From a differentiation perspective, and also the aggressive nature of the tumor, these tumors appear to be fundamentally distinct, and our lab has since gone on to ask what other ways are these tumors distinct from each other,” Dr. Oliver said.
They found that MYC-driven tumors are metabolically distinct, showing alterations in nucleotide biosynthesis and pathways related to the amino acid arginine. Specifically, they demonstrated in multiple human SCLC cell lines, genetically engineered mouse models, human xenograft models, and PDX models that MYC-driven cells are highly dependent on arginine and that enzymatic depletion of arginine may be an effective therapeutic strategy for MYC-driven SCLC.
Target: POU2F3
“Our central focus over several years has been the essentiality of the transcriptional apparatus. Why is it that specific transcriptional regulators are absolutely essential in certain cancers, but dispensable in others? We are of course particularly interested in the regulators that are critical to sustain a tumor cell but might be dispensable to sustain most normal cell types,” said Christopher R. Vakoc, MD, PhD, from the Cold Spring Harbor (N.Y.) Laboratory.
Dr. Vakoc and colleagues are using CRISPR (clustered regularly interspersed short palindromic repeats)-guided RNAs to target the functional protein domains of genes to screen a subset of SCLCs that do not express neuroendocrine markers but have genetics similar to those of neuroendocrine-high tumors and have similarly poor clinical outcomes.
They have discovered that POU2F3 (POU class 2 homeobox 3), a gene encoding for a transcription factor, is expressed in neuroendocrine-low SCLC tumors.
“What we realized is that a subset of these small-cell lung cancer cell lines expresses POU2F3 at very high levels; the vast majority of small-cell lines, including the neuroendocrine subtypes, have undetectable expression of POU2F3. In every small-cell line in which it’s expressed, it is essential, and it’s as essential as a ribosome,” he said.
Christopher R. Vakoc, MD, PhD
POU2F3 has been identified as a master regulator of the tuft cell lineage. Tuft cells are also called solitary chemosensory, microvillous, or brush cells, and there are a handful of articles in the scientific literature regarding brush cells in the lung, Dr. Vakoc noted.
“Tufts cells are rare, almost like neuroendocrine cells, peppered throughout the gastrointestinal tract and respiratory tract,” he said.
His group has found that POU2F3-expressing SCLC cells express specific markers for tuft cells that are largely absent from neuroendocrine cells, suggesting distinct tuft-cell lineage and neuroendocrine-lineage tumor types that may respond differently to targeted therapy.
“Every clinical trial that I’m aware of that has ever been performed in small-cell lung cancer has always grouped these two lineages into one disease, and it’s not uncommon to get rare responses in a phase 2 trial in this disease,” he said. “Is it possible that targeted therapies could exploit some of the differences between these two tumors?”
Dr. Vakoc’s work is internally supported. He reported serving as an adviser to KSQ Therapeutics.
Dr. MacPherson, Dr. Oliver, and Dr. Vakoc are coauthors of a recent paper in Nature Reviews Cancer proposing a system for classifying SCLC based on the expression of different transcription factors.
Dr. MacPherson’s work is supported by the National Cancer Institute, Roche, JSeattle Translational Tumor Research, Addario Foundation, and the International Association for the Study of Lung Cancer (IASLC). He reported research funding from Janssen.
Dr. Oliver’s work is supported by the National Institutes of Health, the V Foundation for Cancer Research, the American Lung Association, the Lung Cancer Research Foundation, the American Cancer Society, and the Damon Runyon Cancer Research Foundation. She reported no conflicts of interest.
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