ABSTRACT
Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.
ABSTRACT
Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
ABSTRACT
Objective To investigate clinical and pathological features of pseudoepitheliomatous keratotic and micaceous balanitis (PKMB).Methods The clinical and pathological features as well as treatment of PKMB were retrospectively analyzed in 5 male patients collected from Janumy 2008 to December 2013.Results The age at onset of PKMB varied from 56 to 67 years in these 5 patients,and none of the patients had received prepucectomy.Indurated keratotic plaques were observed in the glans of penis and inner lamina of the prepuce with no tenderness on palpation,whose surfaces were covered with grayish yellow,adherent and hard micaceous crusts.Histopathological study revealed obvious hyperkeratosis complicated by parakeratosis,epidermal pseudoepitheliomatous hyperplasia,thickened spinous layer,and normal cell polarity in the epidermis,as well as telangiectasis and mild to moderate lymphocytic infiltration in the upper dermis.Immunohistochemical examination showed positive nuclear staining of epidermal cells for human papillomavirus (HPV) in 2 cases.Two patients took small doses of prednisone,but achieved no obvious improvement.Oral isotretinoin had resulted in a favorable outcome in another two cases,but relapse occurred after dose reduction,and thick crusts still appeared after topical application of glucocorticoid cream and tacrolimus cream,or carbon dioxide laser treatment and photodynamic therapy.Conclusions PKMB is a chronic and obstinate disease,and should be diagnosed based on pathological findings.Its treatment is difficult,and tretinoin has some effects,but relapse often occurs after drug withdrawal and maintenance treatment is needed.
ABSTRACT
ObjectiveTo explore the expression of novel protein kinase C ε (PKCε) in normal prostate (NP) tissue, benign prostate hyperplasia(BPH), peficancerous (PC) tissue and prostate cancer (Pca), and study its correlation with the grade and stage of Pca.MethodsTen NP slides, ten BPH slides, ten PC slides and 43 Pca slides were collected from our hospital. These slides were routinely proceased and analyzed according to the requirement of immunohistochemical staining. Tumors were classified according to the 2002 TNM staging system. The grading system used in the study was based on the Gleason grade.ResultsWe was found that the expression of PKCεs in Pca (27/43) were significantly higher than those in NP(1/10), BPH (0/10) and PC (2/10) tissue, and the difference was statistically significant ( P ＜0.05 ). With regard to grade of prostate cancer, the expression of PKCε in Pca with Gleason score ≥8 group (12/13) was higher than the Gleason score 2 -4 group (4/10) and the Gleason score 5 -7 group (11/20). The difference was statistically significant (P ＜ 0.05 ). Moreover, the T3 and T4 stages had a more positive rate (10/12 & 9/10) than the T1 and T2 stages( 1/6 &7/15). There is statistically significant difference between early and advanced stage of prostate cancer ( P ＜ 0. 05 ). Furthermore, the positive expression of PKCε in prostatic carcinoma samples increased significantly in the metastasis group (9/10)compared to the non-metastasis group ( 18/33 ) ( P ＜ 0. 05 ), but the difference was not statistically significant between the concentration of prostate-specific antigen in blood serum ( P ＞ 0. 05 ).Conclusions PKCε is expressed in prostate cancer, and it correlates with the grade and stage of prostate cancer. PKCε may be related to the origin and the development of Pca, and it may be used as a prognostic factor for Pca.