Author: Kurfürstová, Daniela ; Bouchal, Jan ; Morong, Martin ; Souček, Karel ; Kharaishvili, Gvantsa ; Levková, Monika ; Študent, Vladimír ; Überall, Ivo ; Mičková, Alena ; Drápela, Stanislav

BACKGROUNDCurrent in vitro model systems do not fully reflect the bio-logical and clinical diversity of prostate cancer (PCa). Organoids are 3D in vitro cell cultures that may better recapitulate disease heterogeneity and retain parental tumor characteristics. Short-term ex vivo culture of PCa tissues may also facilitate drug testing in personalized medicine.MATERIALS AND METHODSFor organoid culture, we have processed both cancer and normal tissues from 50 patients who underwent radical prostatectomy or transurethral resection of the prostate. In addition, we exploited the ex vivo tissue culture technique and performed short-term chemotherapy assay using gemcitabine and Chk1 inhibitor MU380 in 10 patient samples.RESULTSIn total, we were able to cultivate organoids from 58% of tumors (29/50) and 69% of normal tissue (20/29). Immunohistochemical staining of two representative cases revealed cell positivity for pan-cytokeratin confirming the presence of epithelial cells. However, the overexpression of AMACR and ERG proteins in tumors was not recapitulated in organoids. Another limitation was the propagation of organoids only up to 3 weeks till the first passage. Next, a short-term drug test was performed for ten patients using ex vivo tissue culture. Samples from prostatectomies mostly presented a low proliferation rate as assessed by Ki-67 staining. Another drawback of this ap-proach was inconsistent tissue morphology among particular tissue fragments. Only one case showed a high proliferation rate for drug testing and tumor tissue was present in all tested samples. In our work, we also provide an overview of recent studies and a detailed comparison of culture conditions.CONCLUSIONWe have established cultures of both organoids and tissue fragments from PCa patient samples. However, the expression of tumor markers was not recapitulated in organoids. Inconsistent morphology among tissue fragments and low proliferation hampered the interpretation of the drug testing in most cases. Still, these approaches may be promising using tissues from metastatic castration-resistant prostate cancer.

01 Oct 2020·Molecular OncologyQ2 · MEDICINE

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel‐resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe

Q2 · MEDICINE

ArticleOA

Author: Souček, Karel ; van Weerden, Wytske M. ; Drápela, Stanislav ; Khirsariya, Prashant ; Fedr, Radek ; Červený, Jan ; Krejčí, Lumír ; Culig, Zoran ; Watson, William R. ; Paruch, Kamil ; Suchánková, Tereza ; Búzová, Diana ; Hampl, Aleš ; Puhr, Martin

As treatment options for patients with incurable metastatic castration‐resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK‐8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339‐DOC and PC346C‐DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

01 Dec 2019·HaematologicaQ1 · MEDICINE

Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells

Q1 · MEDICINE

Article

Author: Mraz, Marek ; Verner, Jan ; Jaros, Josef ; Seda, Vaclav ; Boudny, Miroslav ; Zemanova, Jana ; Brychtova, Yvona ; Spunarova, Michaela ; Paruch, Kamil ; Borsky, Marek ; Cerna, Jana ; Soucek, Karel ; Oltova, Alexandra ; Jaskova, Zuzana ; Mayer, Jiri ; Kasparkova, Marie ; Trbusek, Martin ; Drapela, Stanislav ; Khirsariya, Prashant

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G₂/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγ^null ) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Lymphocytic Leukemia	Preclinical	CZ	Masaryk University	-

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