Preclinical Development of Therapeutics in Murine Models of Lung Cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

In the course of extensive collaboration efforts with Dr. Anish Thomas' laboratory, CAPR preclinical researchers successfully established and evaluated multiple PDX models for small cell lung cancer. Several of these models have been fully characterized by applying extensive toolkits of tissue histopathology, biomarker, molecular omics and single-cell transcriptome evaluations. Several well-powered preclinical drug assessment studies have been conducted using these PDX models, for example to examine responses in a non-neuroendocrine type of SCLC PDXs to recently approved RNA Polymerase II inhibitors, either alone or in combination with ATR inhibition. Furthermore, work on evaluating cell plasticity has been completed by CAPR lung cancer modeling program to categorize and compare several distinct classes of SCLC represented in a set of developed PDX models. Such cancer cell-specific plasticity mechanisms are being currently explored as contributing factors in guiding tumor responses to therapeutic treatments, e.g. based on neuro-vs. non-neuroendocrine status of a given SCLC tumor. This collaboration yielded recently two publications in EMBO Mol. Med. (Jul 2023) and Nat. Commun. (Apr 2022). Another significant collaboration, with Dr. Azam Gafoor's program, pursued development of animal cohorts for GEM models known as RP and RPM GEMs. These animals carry conditional alleles for pRb and Trp53 genes alone or in combination with activated Myc allele, correspondingly, and require somatic in vivo activation of corresponding oncogenic events via respiratory application of recombinant adenoviruses expressing Cre under control of neuroendocrine cell specific CGRP promoter. CAPR researchers completed the full characterization of both models, also employing advanced molecular technologies such as RNA-seq and ATAC-seq analyses. RPM model has been characterized in addition by establishing MRI imaging endpoints, as well as by validation of several histopathology and immune system-specific markers. Preclinical evaluation of the high profile HDAC inhibitor entinostat, also in combination with PD1 immune checkpoint blockage has been completed and is in preparation for a joint publication.