Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

List of genes differentially expressed in SUM159 cells expressing shNLGN4X.

Supplementary Figure S1. Transcription factors enriched in TNBC. Supplementary Figure S2. EN1 is a dependency in TNBC cell lines. Supplementary Figure S3. Transcriptional and genomic targets of EN1 in TNBC cells. Supplementary Figure S4. The effect of CTNNB1 expression in TNBC cells. Supplementary Figure S5. Cellular and molecular changes following EN1 expression in MCF7 cells. Supplementary Figure S6. Expression of EN1 in human breast tumors.

List of TLE3 and beta-catenin peaks in SUM149 and SUM159 cells.

EN1 targets in breast cancer cell lines.

FOXA1 peaks in MCF7 cells expressing lacZ or EN1-V5.

The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies. Cancer therapy has changed substantially since the beginning of the century, with advances including kinase inhibitors and immunotherapies resulting in substantial improvements in treatment outcomes. This Review summarizes trends in the approval of oncology therapeutic products by the FDA since 2000 and discusses the implications for the future of anticancer drug development.

The National Cancer Institute's Small Business Innovation Research Development Center (NCI SBIR) provides federal research and development funding and commercialization resources to more than 400 small businesses each year developing novel technologies to prevent, diagnose, and treat cancer. Although federal funding is vital for life science startups at the early stage of development, it is often insufficient to translate the technology from discovery to commercial product. Early-stage startups must connect to follow-on capital and resources to bring NCI-funded technologies to patients. Most startups face challenges in securing additional funding due to lack of access to investors and strategic partners and the ability to effectively pitch their technology. In 2015, the NCI SBIR started the Investor Initiatives program to connect funded small businesses with targeted investors and strategic partners to address the aforementioned obstacles. This program leverages an extensive network of investors and partners to conduct business-focused reviews and provide pitch coaching. The program incentivizes earlier collaborations between NCI-funded companies and private investors through various channels. The program has supported 117 companies from years 2016-2019 to attend 27 investor showcase events. Follow-up surveys show that the program and the assistance offered by NCI SBIR have contributed to a total of 32 completed deals as of April 29, 2020. This paper will discuss the Investor Initiatives program and its outcomes from 2016 to 2019 and demonstrate the effectiveness of a federal program that leverages public-private partnerships to assist portfolio companies with raising follow-on funding to accelerate the translation of research into clinical practice.

e14067 Background: Traditional chemotherapy agents are cytotoxic and typically act on all rapidly dividing cells. In contrast, targeted cancer therapies take advantage of unique genetic or proteomic susceptibility in cancer cells, their microenvironment, or the immune system to selectively target tumor tissue or stimulate immune activity. We catalogued oncology drug approvals in the U.S. in the 21st century to study the evolution of molecular targets over the last twenty years. Methods: We used internal FDA databases and data repositories to generate a dataset of all oncology approvals granted 1/1/2000-12/31/2019. This dataset was curated through a comprehensive survey of drug labels, drug reviews, and published literature to include target gene(s), mechanism of action, drug class, and approved indications for each drug. Approvals were grouped into five-year periods for trend analyses. Results: There has been an increase in the number of oncology approvals over the last twenty years, the vast majority of which are targeted therapies. There have been considerable recent advances in some disease sites. Three disease sites (ovary, bladder, and liver) had many approvals in the last five years after few to none 2000-2014; lung cancer and melanoma have seen substantial advances in the last ten years. Additionally, the first site-agnostic approvals occurred in the last five years. Kinase inhibitors are the most common drug class by both number of drugs and indications. Immune checkpoint inhibitors (ICI) are the second most common class by number of indications, despite having only entered the market in 2011 and being the sixth most common class by number of drugs. The target gene PD-1 has the highest number of approved indications, followed by EGFR and the BCR-ABL fusion gene. The number of novel genes targeted by drugs approved in 2010-2019 is nearly double that of 2000-2009, with the most novel gene targets in 2019 (n = 7). Conclusions: This analysis captures the landscape of targeted drug approvals in the 21st century, including the continued dominance of kinase inhibitors despite the dramatic impact of ICIs on cancer care since their introduction in 2011. The promise of targeted therapy in oncology is especially evident from the introduction of site-agnostic indications, new approvals in cancer types with limited therapy options, and ICIs with many indications due to targeting tumors indirectly via the immune system. The continual introduction of novel gene targets provides a snapshot of ongoing novel drug development, and it will be interesting to see whether this trend continues over the next twenty years.

Abstract To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. Significance: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.

Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.

ABSTRACT Bacterial leaf streak, caused by Xanthomonas oryzae pv. oryzicola, is an important disease of rice. Transposon-mediated mutational analysis of the pathogen with a quantitative assay revealed candidate virulence factors including genes involved in the pathogenesis of other phytopathogenic bacteria, virulence factors of animal pathogens, and genes not previously associated with virulence.