The advancement of immune-therapeutics in cancer treatment has proven to be promising in various malignant diseases. However, in castration resistant prostate cancer (mCRPC) major Phase III trials have been unexpectedly disappointing. To contribute to a broader understanding of the role and use of immune-therapeutics in mCRPC, we conducted a systematic review. We searched the websites ClinicalTrials.gov, PubMed and ASCO Meeting Library for clinical trials employing immune checkpoint inhibitors in mCRPC. This article not only describes the rationale of individual trials, but it also summarizes the current status of the field and sheds light on strategies for future success.

Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions.

In recent years, the concept of synthetic lethality, describing a cellular state where loss of two genes leads to a non-viable phenotype while loss of one gene can be compensated, has emerged as a novel strategy for cancer therapy. Various compounds targeting synthetic lethal pathways are either under clinical investigation or are already routinely used in multiple cancer entities such as breast cancer. Most of them target the well-described synthetic lethal interplay between PARP1 and BRCA1/2. In our study, we investigated, using an in silico methodological approach, clinically utilized drug combinations for breast cancer treatment, by correlating their known molecular targets with known homologous interaction partners that cause synthetic lethality in yeast. Further, by creating a machine-learning algorithm, we were able to suggest novel synthetic lethal drug combinations of low-toxicity drugs in breast cancer and showed their negative effects on cancer cell viability in vitro. Our findings foster the understanding of evolutionarily conserved synthetic lethality in breast cancer cells and might lead to new drug combinations with favorable toxicity profile in this entity.

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Neuroendocrine differentiation of prostate cancer (PCa) occurs frequently during the development of castration resistance and rarely in primary tumors. Using the transgenic mouse model of prostate cancer (TRAMP) in a B6/C57 background, we were able to detect, isolate and further characterize basal, luminal and neuroendocrine subsets of cancer cells. We performed allograft experiments in NSG mice to ensure cellular stem and progenitor properties as well as metastatic potential, and thus created a murine model of neuroendocrine prostate cancer. Whilst all three previously described cell populations were present in approximately three quarters of primary TRAMP tumors, some tumors lacked basal stem cells and showed a more aggressive phenotype. These tumors, mainly consisting of small cancer cells, expressed markers of neuroendocrine differentiation such as synaptophysin and chromogranin A as shown by immunohistochemistry and are further referred to as neuroendocrine carcinomas (NECs), as ruled by an experienced uropathologist of our institution. Adenocarcinoma-like tumors (ACs), in contrast, showed high expression of cytokeratins and retained glandular histology. Using fluorescence-activated cell sorting (FACS) against newly discovered NEC markers within the TRAMP model, we found a relative increase of neuroendocrine progenitors in prostate NECs compared to ACs (approximately 75 vs. 33%, respectively). In ACs, on the other hand, luminal progenitors were found to be the predominant drivers of cancer progression. To further evaluate this, we transplanted single-cell-suspensions into NSG mice without androgen supplementation and observed successful engraftment of both non-basal cell populations. Additionally, we were able to passage the resulted tumors for at least two generations and observed maintenance of histology and biological features for tumors of both luminal and neuroendocrine origin. Based on a RNA sequencing, we were able to define gene signatures for neuroendocrine and luminal progenitors, uncovering a number of novel potential therapeutic targets. Ultimately, we were able to evaluate the prognostic value of the signatures obtained from mice in the human disease by in-silico analyses of publically available gene expression profile databases. In conclusion, we created and characterized a murine model of neuroendocrine prostate cancer using flow cytometry and murine allografts. Further, we established gene expression signatures of luminal and neuroendocrine progenitors and translated them to the human disease. Our findings foster the understanding of neuroendocrine differentiation in prostate cancer and may help in developing new targeted approaches in this entity. Citation Format: Maximilian Marhold, Erwin Tomasich, Simon Udovica, Gerwin Heller, Corinna Altenberger, Andreas Spittler, Reinhard Horvat, Peter Horak, Michael Krainer. Neuroendocrine and luminal progenitors drive cancer progression in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2407.