Introduction Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to CNS and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively. Materials and Methods Patients with metastatic ALK+ NSCLC treated with crizotinib (n=38) and EGFR-MT NSCLC treated with erlotinib (n=27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression free survival (PFS1) and site of first progression were recorded. A subset of patients with either non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded. Results PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 patients progressed again, with median PFS2 of 6.2 months Discussion Oncogene addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with >6 months of additional disease control.

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

Most current knowledge about DNA polymerase zeta (pol ζ) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol ζ can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7(MAD2B) in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

The limitations of cancer cell lines have led to the development of direct patient derived xenograft (PDX) models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg−/− (NSG) mouse on which a patient’s tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal, and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice – an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice, and provide a more accurate tumor model to guide patient treatment.

Purpose A preliminary analysis demonstrated that local ablative therapy (LAT) can provide short-term control of extra-CNS (eCNS) lesion progression in tyrosine-kinase addicted non-small cell lung cancer (NSCLC) patients. However, little is known about the long-term efficacy and safety of single and multiple courses of radiotherapy when used to treat these sites of progressive disease. This study analyzes the durability and toxicity of radiotherapeutic LAT applied to eCNS disease progression in ALK+ NSCLC patients. Materials and Methods ALK+ NSCLC patients receiving crizotinib manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results 33 of 38 patients progressed on crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1–3 courses of LAT with radiotherapy. The 6 and 12 month actuarial local lesion control rates (LC) with radiotherapy was 100 and 86%, respectively. The 12 month LC with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% vs. 60% (p = 0.01). No acute or late grade >2 radiotherapy-related toxicities were observed. Median overall time on crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs ≤12 months had a 2 year OS of 72% vs 12%, respectively (p < 0.0001). Conclusions LAT safely and durably eradicated sites of individual lesion progression in ALK+ NSCLC patients receiving crizotinib. A dose-response relationship for LC was observed. The suppression of OPD on crizotinib by LAT allowed an extended duration of exposure to crizotinib, which was associated with longer OS.